Journal article
Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response
Acta pharmacologica Sinica, Vol.39(2), pp.311-327
02/2018
DOI: 10.1038/aps.2017.95
PMCID: PMC5800476
PMID: 28905938
Abstract
Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury
in vitro
and
in vivo
. TP (5–50000 nmol/L) dose-dependently decreased the viability of TM4 Sertoli cells with an IC
50
value of 669.5–269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO-1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg·kg
−1
·d
−1
, for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK-mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation.
Details
- Title: Subtitle
- Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response
- Creators
- Yu Wang - , Nanjing 210009Su-han Guo - , Nanjing 210009Xue-jun Shang - , Nanjing 210002Li-sha Yu - , Nanjing 210009Jian-wei Zhu - , Nanjing 210009Ang Zhao - Nanjing Tech UniversityYan-fen Zhou - , Nanjing 210009Guo-hua An - , Iowa City, IowaQi Zhang - , Nanjing 210009Bo Ma - , Nanjing 210009
- Resource Type
- Journal article
- Publication Details
- Acta pharmacologica Sinica, Vol.39(2), pp.311-327
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/aps.2017.95
- PMID
- 28905938
- PMCID
- PMC5800476
- ISSN
- 1671-4083
- eISSN
- 1745-7254
- Language
- English
- Date published
- 02/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984065312202771
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