PMID- 36586206
OWN - NLM
STAT- MEDLINE
DCOM- 20230130
LR  - 20230201
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 110
DP  - 2023 Feb
TI  - Neocryptotanshinone protects against myocardial ischemia-reperfusion injury by 
      promoting autolysosome degradation of protein aggregates via the 
      ERK1/2-Nrf2-LAMP2 pathway.
PG  - 154625
LID - S0944-7113(22)00712-7 [pii]
LID - 10.1016/j.phymed.2022.154625 [doi]
AB  - BACKGROUND: Aggrephagy is a critical compensatory mechanism for the elimination 
      of misfolded proteins resulting from stress and depends on the autolysosome 
      degradation of protein aggregates. However, there have been few mechanism 
      research related to aggrephagy in myocardial ischemia/reperfusion (I/R) injury. 
      Neocryptotanshinone (NCTS) is a fat-soluble active compound extracted from Salvia 
      miltiorrhiza, and may be cardioprotective against I/R. However, the efficacy and 
      specific mechanism of NCTS on I/R have not been studied. PURPOSE: The current 
      study aimed to investigate the molecular mechanism of NCTS involved in the 
      therapeutic effect on I/R, with a special emphasis on the up-regulation of the 
      ERK1/2-Nrf2-LAMP2 pathway to increase autolysosomal degradation during 
      aggrephagy. METHODS: A rat model of myocardial I/R injury was constructed by left 
      anterior descending (LAD) ligation-reperfusion. To verify cardiac protection, 
      autolysosome clearance of protein aggregates, and their intracellular biological 
      mechanism, an oxygen-glucose deprivation/recovery (OGD/R)-induced H9c2 
      cardiomyocyte model was created. RESULTS: NCTS was found to have a significant 
      cardioprotective effect in I/R rats as evidenced by remarkably improved 
      pathological anatomy, decreased myocardial damage indicators, and substantially 
      enhanced cardiac performance. Mechanistically, NCTS might boost the levels of 
      LAMP2 mRNA and protein, total and Ser40 phosphorylated Nrf2, and 
      (Thr202/Tyr204)p-ERK1/2 protein. Simultaneously, the cytoplasmic Nrf2 level was 
      reduced after NCTS administration, which was contrary to the total Nrf2 content. 
      However, these beneficial changes were reversed by the co-administration with 
      ERK1/2 inhibitor, PD98059. NCTS therapy up-regulated Rab7 protein content, 
      Cathepsin B activity, and lysosomal acidity, while down-regulating autophagosome 
      numbers, Ubiquitin (Ub), and autophagosome marker protein accumulations through 
      the above signaling pathway. This might indicate that NCTS enhanced lysosomal 
      fusion and hydrolytic capacity. It was also found that NCTS intervention limited 
      oxidative stress and cellular apoptosis both in vivo and in vitro. CONCLUSIONS: 
      We reported for the first time that NCTS promoted the autolysosome removal of 
      protein aggregation both in vivo and in vitro, to exert the therapeutic 
      advantages of myocardial I/R injury. This was reliant on the up-regulation of the 
      ERK1/2-Nrf2-LAMP2 signaling pathway.
CI  - Copyright (c) 2022 Elsevier GmbH. All rights reserved.
FAU - Yang, Ye
AU  - Yang Y
AD  - Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, 
      China; Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China.
FAU - Shao, Mingyan
AU  - Shao M
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Yao, Junkai
AU  - Yao J
AD  - Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, 
      China; Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China.
FAU - Yang, Shuangjie
AU  - Yang S
AD  - School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 
      100029, China.
FAU - Cheng, Wenkun
AU  - Cheng W
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Ma, Lin
AU  - Ma L
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Life Sciences, 
      Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Li, Weili
AU  - Li W
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Life Sciences, 
      Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Cao, Jing
AU  - Cao J
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Zhang, Yawen
AU  - Zhang Y
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Hu, Yueyao
AU  - Hu Y
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
FAU - Li, Chun
AU  - Li C
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; Modern Research Center 
      for Traditional Chinese Medicine, Beijing University of Chinese Medicine, 
      Beijing, China. Electronic address: lichun19850204@163.com.
FAU - Wang, Yong
AU  - Wang Y
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; School of Chinese 
      Medicine, Beijing University of Chinese Medicine, Beijing 100029, China. 
      Electronic address: doctor_wangyong@163.com.
FAU - Wang, Wei
AU  - Wang W
AD  - Key Laboratory of TCM Syndrome and Formula (Beijing University of Chinese 
      Medicine), Ministry of Education, Beijing 100700, China; Guangzhou University of 
      Chinese Medicine, Guangzhou 510006, China. Electronic address: 
      wangwei26960@126.com.
LA  - eng
PT  - Journal Article
DEP - 20221224
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Protein Aggregates)
RN  - 0 (Nfe2l2 protein, rat)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
SB  - IM
MH  - Animals
MH  - Rats
MH  - Apoptosis
MH  - Lysosomes/metabolism
MH  - MAP Kinase Signaling System
MH  - *Myocardial Reperfusion Injury/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - NF-E2-Related Factor 2/metabolism
MH  - Oxidative Stress
MH  - Protein Aggregates
MH  - Lysosomal-Associated Membrane Protein 2
OTO - NOTNLM
OT  - Aggrephagy
OT  - Autolysosme
OT  - ERK1/2-Nrf2
OT  - LAMP2
OT  - Myocardial I/R injury
OT  - Neocryptotanshinone
COIS- Declaration of Competing Interest The authors have no conflict of interest to 
      declare.
EDAT- 2023/01/01 06:00
MHDA- 2023/01/25 06:00
CRDT- 2022/12/31 18:09
PHST- 2022/07/21 00:00 [received]
PHST- 2022/12/04 00:00 [revised]
PHST- 2022/12/23 00:00 [accepted]
PHST- 2023/01/01 06:00 [pubmed]
PHST- 2023/01/25 06:00 [medline]
PHST- 2022/12/31 18:09 [entrez]
AID - S0944-7113(22)00712-7 [pii]
AID - 10.1016/j.phymed.2022.154625 [doi]
PST - ppublish
SO  - Phytomedicine. 2023 Feb;110:154625. doi: 10.1016/j.phymed.2022.154625. Epub 2022 
      Dec 24.