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Tumour necrosis factor‐ α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice
Author(s) -
Zhu Xiaoling,
Jiang Shasha,
Hu Nan,
Luo Fuling,
Dong Hailong,
Kang YuMing,
Jones Kyla R,
Zou Yunzeng,
Xiong Lize,
Ren Jun
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12240
Subject(s) - lenalidomide , glutathione , oxidative stress , endocrinology , medicine , apoptosis , skeletal muscle , necrosis , pharmacology , chemistry , biochemistry , dexamethasone , enzyme
Summary Lenalidomide ( R evlimid; S elleck C hemicals, H ouston, 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, C57 BL /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 C omet 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.