title: TBHQ Alleviated Endoplasmic Reticulum Stress-Apoptosis and Oxidative Stress by PERK-Nrf2 Crosstalk in Methamphetamine-Induced Chronic Pulmonary Toxicity.
abstract: Methamphetamine (MA) leads to cardiac and pulmonary toxicity expressed as increases in inflammatory responses and oxidative stress. However, some interactions may exist between oxidative stress and endoplasmic reticulum stress (ERS). The current study is designed to investigate if both oxidative stress and ERS are involved in MA-induced chronic pulmonary toxicity and if antioxidant tertiary butylhydroquinone (TBHQ) alleviated ERS-apoptosis and oxidative stress by PERK-Nrf2 crosstalk. In this study, the rats were randomly divided into control group, MA-treated group (MA), and MA plus TBHQ-treated group (MA + TBHQ). Chronic exposure to MA resulted in slower growth of weight and pulmonary toxicity of the rats by increasing the pulmonary arterial pressure, promoting the hypertrophy of right ventricle and the remodeling of pulmonary arteries. MA inhibited the Nrf2-mediated antioxidative stress by downregulation of Nrf2, GCS, and HO-1 and upregulation of SOD2. MA increased GRP78 to induce ERS. Overexpression and phosphorylation of PERK rapidly phosphorylated eIF2α, increased ATF4, CHOP, bax, caspase 3, and caspase 12, and decreased bcl-2. These changes can be reversed by antioxidant TBHQ through upregulating expression of Nrf2. The above results indicated that TBHQ can alleviate MA-induced oxidative stress which can accelerate ERS to initiate PERK-dependent apoptosis and that PERK/Nrf2 is likely to be the key crosstalk between oxidative stress and ERS in MA-induced chronic pulmonary toxicity.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
authors.forename: Yun
authors.identifier: 0000-0001-7146-8290
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Gu
authors.affiliation: Department of Drug Control, China Criminal Police University, Shenyang 110035, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
authors.forename: Li-Ye
authors.initials: LY
authors.lastname: Liang
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China; National Key Subject, Institute of Respiratory Diseases, China Medical University, Shenyang 110001, China.
authors.forename: Huai-Liang
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006873:Hydroquinones / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008694:Methamphetamine; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D008694:Methamphetamine; D051267:NF-E2-Related Factor 2; D019892:eIF-2 Kinase; C018855:2-tert-butylhydroquinone