PMID- 33285470
OWN - NLM
STAT- MEDLINE
DCOM- 20210208
LR  - 20240226
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 81
DP  - 2021 Jan
TI  - Physcion, a tetra-substituted 9,10-anthraquinone, prevents homocysteine-induced 
      endothelial dysfunction by activating Ca(2+)- and Akt-eNOS-NO signaling pathways.
PG  - 153410
LID - S0944-7113(20)30241-5 [pii]
LID - 10.1016/j.phymed.2020.153410 [doi]
AB  - BACKGROUND: Homocysteine (Hcy) induced vascular endothelial dysfunction is known 
      to be closely associated with oxidative stress and impaired NO system. 
      1,8-Dihydroxy-3-methoxy-6-methylanthracene-9,10-dione (physcion) has been known 
      to has antioxidative and anti-inflammatory properties. PURPOSE: The purpose of 
      the present study was to define the protective effect of physcion on Hcy-induced 
      endothelial dysfunction and its mechanisms involved. STUDY DESIGN AND METHODS: 
      Hyperhomocysteinemia (HHcy) rat model was induced by feeding 3% methionine. A rat 
      thoracic aortic ring model was used to investigate the effects of physcion on 
      Hcy-induced impairment of endothelium-dependent relaxation. Two doses, low (L, 30 
      mg/kg/day) and high (H, 50 mg/kg/day) of physcion were used in the present study. 
      To construct Hcy-injured human umbilical vein endothelial cells (HUVECs) model, 
      the cells treated with 3 mM Hcy. The effects of physcion on Hcy-induced HUVECs 
      cytotoxicity and apoptosis were studied using MTT and flow cytometry. Confocal 
      analysis was used to determine the levels of intracellular Ca(2+). The levels of 
      protein expression of the apoptosis-related markers Bcl-2, Bax, caspase-9/3, and 
      Akt and endothelial nitric oxide synthase (eNOS) were evaluated by western blot. 
      RESULTS: In the HHcy rat model, plasma levels of Hcy and malondialdehyde (MDA) 
      were elevated (20.45 +/- 2.42 vs. 4.67 +/- 1.94 muM, 9.42 +/- 0.48 vs. 3.47 +/- 0.59 nM, p 
      < 0.001 for both), whereas superoxide dismutase (SOD) and nitric oxide (NO) 
      levels were decreased (77.11 +/- 4.78 vs. 115.02 +/- 5.63 U/ml, 44.51 +/- 4.45 vs. 
      64.18 +/- 5.34 muM, p < 0.001 and p < 0.01, respectively). However, treatment with 
      physcion significantly reversed these changes (11.82 +/- 2.02 vs. 20.45 +/- 2.42 muM, 
      5.97 +/- 0.72 vs. 9.42 +/- 0.48 nM, 108.75 +/- 5.65 vs. 77.11 +/- 4.78 U/ml, 58.14 +/- 6.02 
      vs. 44.51 +/- 4.45 muM, p < 0.01 for all). Physcion also prevented Hcy-induced 
      impairment of endothelium-dependent relaxation in HHcy rats (1.56 +/- 0.06 vs. 
      15.44 +/- 2.53 nM EC(50) for ACh vasorelaxation, p < 0.05 vs. HHcy). In Hcy-injured 
      HUVECs, physcion inhibited the impaired viability, apoptosis and reactive oxygen 
      species. Hcy treatment significantly increased the protein phosphorylation levels 
      of p38 (2.26 +/- 0.20 vs. 1.00 +/- 0.12, p <0.01), ERK (2.11 +/- 0.21 vs. 1.00 +/- 0.11, 
      p <0.01) and JNK. Moreover, physcion reversed the Hcy-induced apoptosis related 
      parameter changes such as decreased mitochondrial membrane potential (MMP) and 
      Bcl-2/Bax protein ratio, and increased protein expression of caspase-9/3 in 
      HUVECs. Furthermore, the downregulation of Ca(2+), Akt, eNOS and NO caused by Hcy 
      were recovered with physcion treatment in HUVECs. CONCLUSION: Physcion prevents 
      Hcy-induced endothelial dysfunction by activating Ca(2+)- and Akt-eNOS-NO 
      signaling pathways. This study provides the first evidence that physcion might be 
      a candidate agent for the prevention of cardiovascular disease induced by Hcy.
CI  - Copyright (c) 2020. Published by Elsevier GmbH.
FAU - Ji, Xiao Wei
AU  - Ji XW
AD  - School of Pharmacy, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China.
FAU - Lyu, Hang Ji
AU  - Lyu HJ
AD  - Graduate department, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China.
FAU - Zhou, Guang Hai
AU  - Zhou GH
AD  - Institute of Cardiovascular Endocrinology, Key Laboratory of Atherosclerosis in 
      Universities of Shandong, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271000, China.
FAU - Wu, Bo
AU  - Wu B
AD  - School of Pharmacy, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China.
FAU - Zhu, Yuan Yuan
AU  - Zhu YY
AD  - School of Pharmacy, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China.
FAU - Wu, Tian Hua
AU  - Wu TH
AD  - School of Pharmacy, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China.
FAU - Zhang, Feng
AU  - Zhang F
AD  - Institute of Cardiovascular Endocrinology, Key Laboratory of Atherosclerosis in 
      Universities of Shandong, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271000, China.
FAU - Jin, Song Nan
AU  - Jin SN
AD  - School of Pharmacy, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271016, China. Electronic address: 
      snjin0504@aliyun.com.
FAU - Cho, Kyung Woo
AU  - Cho KW
AD  - Institute of Cardiovascular Endocrinology, Key Laboratory of Atherosclerosis in 
      Universities of Shandong, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271000, China.
FAU - Wen, Jin Fu
AU  - Wen JF
AD  - Institute of Cardiovascular Endocrinology, Key Laboratory of Atherosclerosis in 
      Universities of Shandong, Shandong First Medical University & Shandong Academy of 
      Medical Sciences, Taian, Shandong, 271000, China. Electronic address: 
      jfwen0603@aliyun.com.
LA  - eng
PT  - Journal Article
DEP - 20201118
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
RN  - 0 (Protective Agents)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (NOS3 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.22.- (CASP9 protein, human)
RN  - EC 3.4.22.- (Caspase 9)
RN  - H6PT94IV61 (physcione)
RN  - KA46RNI6HN (Emodin)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Calcium/*metabolism
MH  - Caspase 9/metabolism
MH  - Emodin/*analogs & derivatives/pharmacology
MH  - Endothelium, Vascular/*drug effects/metabolism/physiopathology
MH  - Homocysteine/*metabolism
MH  - Human Umbilical Vein Endothelial Cells/drug effects
MH  - Humans
MH  - Hyperhomocysteinemia/*drug therapy/metabolism
MH  - Male
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Protective Agents/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats, Sprague-Dawley
MH  - Vasodilation/drug effects
MH  - Rats
OTO - NOTNLM
OT  - Akt
OT  - Calcium
OT  - Endothelial cell
OT  - Homocysteine
OT  - Nitric oxide
OT  - Physcion
EDAT- 2020/12/08 06:00
MHDA- 2021/02/09 06:00
CRDT- 2020/12/07 20:12
PHST- 2020/06/26 00:00 [received]
PHST- 2020/11/11 00:00 [revised]
PHST- 2020/11/14 00:00 [accepted]
PHST- 2020/12/08 06:00 [pubmed]
PHST- 2021/02/09 06:00 [medline]
PHST- 2020/12/07 20:12 [entrez]
AID - S0944-7113(20)30241-5 [pii]
AID - 10.1016/j.phymed.2020.153410 [doi]
PST - ppublish
SO  - Phytomedicine. 2021 Jan;81:153410. doi: 10.1016/j.phymed.2020.153410. Epub 2020 
      Nov 18.