PMID- 36241072
OWN - NLM
STAT- MEDLINE
DCOM- 20221212
LR  - 20221212
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 193
IP  - Pt 1
DP  - 2022 Nov 20
TI  - Exosomal thioredoxin-1 from hypoxic human umbilical cord mesenchymal stem cells 
      inhibits ferroptosis in doxorubicin-induced cardiotoxicity via mTORC1 signaling.
PG  - 108-121
LID - S0891-5849(22)00898-X [pii]
LID - 10.1016/j.freeradbiomed.2022.10.268 [doi]
AB  - Doxorubicin (DOX), a clinical chemotherapeutic drug, is often annoyed by its 
      cardiotoxicity which involves ferroptosis in its pathological progress. Human 
      umbilical cord mesenchymal stem cells (HucMSCs)-derived exosomes (HucMSCs-Exo) 
      are proven effective in treating cardiovascular diseases. This study aimed to 
      compare the therapeutic effects between normoxic HucMSCs-Exo (Exo) and hypoxic 
      HucMSCs-Exo (Hypo-Exo) on DOX-induced ferroptosis and explore the underlying 
      mechanisms. An acute cardiotoxicity model was successfully constructed by 
      administrating two doses intraperitoneal injections of DOX (25 mg/kg in total). 
      Exo and Hypo-Exo were extracted by ultracentrifugation and characterized. 
      Compared with Exo, Hypo-Exo and Ferrostatin-1 (Fer-1) exerted superior effects on 
      inhibiting DOX-induced ferroptosis, as evidenced by decreasing malondialdehyde 
      (MDA), iron content and increasing glutathione (GSH) level as well as 
      ferroptosis-related genes expression including prostaglandin-endoperoxide 
      synthase 2 (Ptgs2) mRNA level and glutathione peroxidase 4 (GPX4) protein level. 
      Based on quantitative proteomics analysis, we found that thioredoxin1 (Trx1) was 
      remarkably upregulated in Hypo-Exo and exhibited anti-ferroptosis activity via 
      activating the mechanistic target of rapamycin complex 1 (mTORC1) in neonatal rat 
      cardiomyocytes (NRCMs). Trx1 knockdown and rapamycin (an mTORC1 inhibitor) 
      partially abolished the protective effects of Hypo-Exo. Furthermore, our data 
      indicated that solute carrier family 7 member 11 (SLC7A11) was critical for GPX4 
      protein synthesis. In conclusion, Hypo-Exo exhibited a better suppression of 
      ferroptosis in DOX-induced cardiotoxicity. Trx1-mediated mTORC1 activation is 
      critical for the Hypo-Exo anti-ferroptosis process, which involves increased GPX4 
      protein synthesis and decreased iron overload. This study indicated that Hypo-Exo 
      may present a potential strategy against ferroptosis in DOX-induced 
      cardiotoxicity.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Yu, Yue
AU  - Yu Y
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Wu, Tianyu
AU  - Wu T
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Lu, Yao
AU  - Lu Y
AD  - Department of Cardiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital 
      of Nanjing Medical University, Xuzhou, 221009, Jiangsu, China.
FAU - Zhao, Wei
AU  - Zhao W
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Zhang, Jian
AU  - Zhang J
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Chen, Qiushi
AU  - Chen Q
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Ge, Gaoyuan
AU  - Ge G
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Hua, Yan
AU  - Hua Y
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Chen, Kaiyan
AU  - Chen K
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Ullah, Inam
AU  - Ullah I
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China.
FAU - Zhang, Fengxiang
AU  - Zhang F
AD  - Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, 210029, Jiangsu, China. Electronic address: 
      njzfx6@njmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221012
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
RN  - 52500-60-4 (Thioredoxins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Rats
MH  - Apoptosis/genetics
MH  - *Cardiotoxicity
MH  - Doxorubicin/toxicity
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Phospholipid Hydroperoxide Glutathione Peroxidase
MH  - Thioredoxins/metabolism
MH  - Umbilical Cord/cytology
OTO - NOTNLM
OT  - Doxorubicin
OT  - Exosomes
OT  - Ferroptosis
OT  - Glutathione peroxidase 4 (GPX4)
OT  - Mechanistic target of rapamycin complex 1 (mTORC1)
OT  - Mesenchymal stem cells
OT  - Thioredoxin1 (Trx1)
EDAT- 2022/10/15 06:00
MHDA- 2022/12/07 06:00
CRDT- 2022/10/14 19:33
PHST- 2022/07/21 00:00 [received]
PHST- 2022/10/06 00:00 [revised]
PHST- 2022/10/07 00:00 [accepted]
PHST- 2022/10/15 06:00 [pubmed]
PHST- 2022/12/07 06:00 [medline]
PHST- 2022/10/14 19:33 [entrez]
AID - S0891-5849(22)00898-X [pii]
AID - 10.1016/j.freeradbiomed.2022.10.268 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2022 Nov 20;193(Pt 1):108-121. doi: 
      10.1016/j.freeradbiomed.2022.10.268. Epub 2022 Oct 12.