title: Tumour necrosis factor-α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice.
abstract: Lenalidomide (Revlimid; Selleck Chemicals, Houston, TX, USA), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as tumour necrosis factor (TNF)-α, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. The present study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. To this end, C57BL/6 lean and ob/ob obese mice were administered lenalidomide (50 mg/kg per day, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase 3 activity, and levels of Bax, Bcl-2, Bip, caspase 8, caspase 9 and TNF-α were assessed using western blot analysis. Lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice exhibited a reduced GSH/GSSG ratio in the liver, gastrocnemius skeletal muscle and small intestine, as well as enhanced protein carbonyl formation, DNA damage and caspase 3 activity in the liver, kidney, skeletal muscle and intestine; these effects were alleviated by lenalidomide, with the exception of obesity-associated DNA damage in the liver and kidney. Western blot analysis revealed elevated TNF-α, Bax, Bcl-2, Bip, caspase 8 and caspase 9 in ob/ob mice with various degrees of reversal by lenalidomide treatment. Together, these data indicate that lenalidomide protects against obesity-induced tissue injury and protein damage, possibly in association with antagonism of cytokine production and cytokine-induced apoptosis and oxidative stress.
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhu
authors.forename: Shasha
authors.initials: S
authors.lastname: Jiang
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Fuling
authors.initials: F
authors.lastname: Luo
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Kang
authors.forename: Kyla R
authors.initials: KR
authors.lastname: Jones
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D007155:Immunologic Factors / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D000077269:Lenalidomide; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D000077269:Lenalidomide; D005947:Glucose
keywords: apoptosis; lenalidomide; oxidative injury; protein damage; tumour necrosis factor-α