Paeonia lactifloraExtract Attenuating Cerebral Ischemia and Arterial Intimal Hyperplasia Is Mediated by Paeoniflorin via Modulation of VSMC Migration and Ras/MEK/ERK Signaling Pathway

Paeonia lactiflorais a well-known traditional Chinese medicine. Paeoniflorin is an active component found inPaeonia lactiflora, which is used to treat smooth muscle spasms and pain and to protect the cardiovascular system. The objective of this study was to determine ifPaeonia lactiflorawould be protective in rodent models of cerebral ischemia and arterial intimal hyperplasia.Paeonia lactifloraextract (PLex) and paeoniflorin (PF) significantly attenuated cerebral infarction in ischemia/reperfusion injury rats and the severity of intimal hyperplasia in mice where the carotid artery was ligated. PLex and PF reduced PDGF-stimulated VSMC proliferation and migration in a dose-dependent manner by MTT, wound healing, and transwell assays. PF significantly reduced protein levels of Ras, MEK, p-MEK and p-ERK, but not MMP-2 and MMP-9. In summary,Paeonia lactiflorareduced cerebral ischemia and arterial intimal hyperplasia which were mainly made via the intermediary of PF. The protective effect of PF was related to the modulation of the Ras/MEK/ERK signaling pathway.

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The Autophagy Signaling Pathway in Necroptosis-Dependent Cerebral Ischemia/Reperfusion Injury

Neurochemical Journal ◽

10.1134/s1819712421030132 ◽

2021 ◽

Vol 15 (3) ◽

pp. 247-253

Author(s):

Yang Xu ◽

Yingying Zhou ◽

Dijing Yu ◽

Wenjie Hu ◽

Xiaodong Wu ◽

...

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

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Abstract 1394: Sublethal Levels of Aldehydes Augmented Cardiac Anti-Oxidant Defense through Activation of eIF2 α -ATF4 Pathway via GCN2 Kinase

Circulation ◽

10.1161/circ.118.suppl_18.s_320 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Takaharu Katayama ◽

Motoaki Sano ◽

Jin Endo ◽

Kentaro Hayashida ◽

Tomohiro Matsuhashi ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Special Importance ◽

Dependent Manner ◽

Protein Levels

[Introduction] Despite an increase in the levels of aldehydes, the heart from aldehyde dehydrogenase ( ALDH ) 2*2 -transgenic (Tg) mice, loss of function model of ALDH, exhibited a greater tolerance to oxidative stress via activation of amino acid metabolism leading to glutathione biosynthesis. This study was designed to identify the signaling cascades responsible for the activation of amino acid metabolism by aldehydes. [Methods & Results] (1) Phosphorylation of α -subunit of eukaryotic translation initiation factor 2 (eIF2 α ) and subsequent translational activation of ATF4 have been shown to induce amino acid metabolism as a common response to a wide variety of stressors. Consistent with this, phosphorylation levels of eIF2 α and protein expression of ATF4 were increased in ALDH2*2 -Tg hearts. (2) Among four eIF2 α kinases, general control non-depressible (GCN)2 kinase, a sensor for amino acid insufficiency, was activated in ALDH2*2 -Tg heart. (3) Quantification of intracellular amino acid demonstrated that free histidine concentration in ALDH2*2 -Tg heart was selectively reduced by 50% compared to that in non-Tg littermates. (4) To clarify the functional significance of observed reduction in histidine, ALDH2*2 -Tg mice were fed a high histidine diet. The phosphorylation levels of eIF2 α and the protein levels of ATF4 were diminished by 50% in ALDH2*2 -Tg mice fed the high histidine diet, in agreement with the normalization of histidine concentration. Accordingly, both enhanced tolerance to ischemia-reperfusion injury and elevated levels of glutathione were partially diminished in the heart from ALDH2*2 -Tg mice fed the high histidine diet compared to ALDH2*2 -Tg mice fed normal chow. (5) In culture, exposure to 4-hydroxy-2-nonenal (4-HNE) phosphorylated GCN2 and eIF2 α and increased protein levels of ATF4 in a time-dependent manner. (6) siRNA-mediated knockdown of GCN2 abrogated 4-HNE-induced induction of amino acid metabolic genes. [Conclusions] Activation of eIF2 α -ATF4 pathway via GCN2 kinase might be of special importance in the transcriptional control that coordinately promotes amino acid metabolism in response to aldehydes. Intracellular depletion of free histidine is at least partly involved in the activation of GCN2 kinase by aldehydes.

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