ACTA PHARMACOLOGICA SINICA
·
2019
·Vol. 40
·期 10
·1334-1342
·
IF 4.01
Lu Bin,Chen Xiao-bing,Hong Yu-cai,Zhu Hong,He Qiao-jun,Yang Bo,Ying Mei-dan,Cao Ji
Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.
研究领域:
癌症生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science of Advanced Materials
·
2023
·Vol. 15
·期 2
·256-266
·
IF 0.9
Li Wenqin,Zou Chuanxin
Since there are many problems in the clinical application of traditional chemotherapy drugs for gastric cancer (GC), including poor water solubility and insufficient targeting, the preparation of docetaxel nanoparticles (NPs) with chitosan (CS) as the carrier under nanotechnology can
improve its water solubility and targeting and thus improve the bioavailability and antitumor effect. GX1 was used as a GC target molecule, N-deoxycholic acid (DCA) hydroxyethyl CS was used as a nanodrug carrier, and docetaxel was used as an antitumor angiogenesis drug to fabricate GC target
NPs. The physical characterization was analyzed, the sustained release performance was further analyzed, and the anticancer performance was tested from in vitro and in vivo perspectives. After the NPs were transfected into GC cells, Prdx6 protein level in the cancer cells was
determined by western blotting, and the survival rate of GC cells was determined by cholecystokinin octapeptide (CCK-8). Experiments showed that the encapsulation efficiency and drug loading rate of GC-targeted NPs reached 51.8% and 24.3%, respectively. The average particle size was 148.7
nm, and the surface showed smooth and homogeneous aggregation. docetaxel in the NPs belongs to pH-responsive sustained release, and the drug diffusion type belongs to non-Fickian diffusion. in vitro tests showed that GX1 can improve the uptake rate of the NPs by gastric vascular endothelial
cells, and in vivo tests showed that the NPs can greatly limit the growth rate of GC tumors in nude mice (P < 0.01). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) results of tumor sections showed that NPs could induce a large amount of tumor
cell apoptosis. The expression of Prdx6 protein in GC cells was decreased after transfection with NPs (P < 0.05), and NPs notably inhibited the proliferation of GC cells (P < 0.01).
研究领域:
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
DOI
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2026
·
IF 3.5
Yurou Li,Zhenzhen Yan,Wanrong Zhang,Xin Zheng,Zhengping Wu,Yinjie Jiang,Jie Zhou
Sodium aescinate (SA), a triterpenoid saponin derived from Aesculus hippocastanum seeds, is widely used clinically but has been linked to hepatotoxicity, nephrotoxicity, and phlebitis. We previously reported that SA triggers hepatocyte ferroptosis, and enhancing GSH synthesis via the CTH/cysteine axis activation only partially mitigates liver injury. In this study, we showed that SA disrupted redox homeostasis, promoted lipid peroxidation (LPO), and induced ferroptosis in hepatocytes, concomitant with suppressed Nrf2/PRDX6/GPX4 pathway activity. Mechanistically, SA downregulated the expression and transcriptional activity of Nrf2, reducing its binding to antioxidant response elements (AREs) in the promoters of PRDX6 and GPX4, thereby decreasing their expression. Nrf2 overexpression restored PRDX6 and GPX4 levels, enhanced antioxidant capacity, and attenuated SA-induced ferroptosis. Notably, PRDX6 regulated GPX4 expression and activity by modulating selenium utilization and selenoprotein biosynthesis during SA-induced hepatotoxicity. Both PRDX6 overexpression and selenium supplementation rescued GPX4 and protected against SA-induced ferroptotic damage. The protection conferred by Nrf2/PRDX6 overexpression or selenium supplementation was fully abrogated upon GPX4 knockdown or inhibition with RSL3. Collectively, SA induced ferroptotic liver injury by disrupting the Nrf2/PRDX6/GPX4 axis, culminating in GPX4 deficiency and redox collapse. This study suggests that this cascade represents a promising therapeutic target for SA-induced hepatotoxicity.
✓ 已验证
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2023
·
IF 6.9
Heran Cao,Zhenpeng Li,Tianqi Jin,Shuyang He,Shujuan Liu,Long Li,Yang Wang,Ye Gong,Gang Wang,Fangxia Yang,Wuzi Dong
Chinese forest musk deer (FMD), an endangered species, have exhibited low reproductive rates even in captivity due to stress conditions. Investigation revealed the presence of di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, in the serum and skin of captive FMDs. Feeding FMDs with maslinic acid (MA) has been observed to alleviate the stress response and improve reproductive rates, although the precise molecular mechanisms remain unclear. Therefore, this study aims to investigate the molecular mechanisms underlying the alleviation of DEHP-induced oxidative stress and cell apoptosis in primary peritubular myoid cells (PMCs) through MA intake. Primary PMCs were isolated and exposed to DEHP in vitro . The results demonstrated that DEHP significantly suppressed antioxidant levels and promoted cell apoptosis in primary PMCs. Moreover, interfering with the expression of PRDX6 was found to induce excessive reactive oxygen species (ROS) production and cell apoptosis in primary PMCs. Supplementation with MA significantly upregulated the expression of PRDX6, thereby attenuating DEHP-induced oxidative stress and cell apoptosis in primary PMCs. These findings provide a theoretical foundation for mitigating stress levels and enhancing reproductive capacity of in captive FMDs.
研究领域:
内分泌学
·
生殖生物学
·
环境毒理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）