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      Neuroprotective Effect of Scutellarin on Ischemic Cerebral Injury by Down-Regulating the Expression of Angiotensin-Converting Enzyme and AT1 Receptor

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          Abstract

          Background and Purpose

          Previous studies have demonstrated that angiotensin-converting enzyme (ACE) is involved in brain ischemic injury. In the present study, we investigated whether Scutellarin (Scu) exerts neuroprotective effects by down-regulating the Expression of Angiotensin-Converting Enzyme and AT1 receptor in a rat model of permanent focal cerebral ischemia.

          Methods

          Adult Sprague–Dawley rats were administrated with different dosages of Scu by oral gavage for 7 days and underwent permanent middle cerebral artery occlusion (pMCAO). Blood pressure was measured 7 days after Scu administration and 24 h after pMCAO surgery by using a noninvasive tail cuff method. Cerebral blood flow (CBF) was determined by Laser Doppler perfusion monitor and the neuronal dysfunction was evaluated by analysis of neurological deficits before being sacrificed at 24 h after pMCAO. Histopathological change, cell apoptosis and infarct area were respectively determined by hematoxylin–eosin staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis and 2,3,5-triphenyltetrazolium chloride staining. Tissue angiotensin II (Ang II) and ACE activity were detected by enzyme-linked immunosorbent assays. The expression levels of ACE, Ang II type 1 receptor (AT1R), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by Western blot and real-time PCR. ACE inhibitory activity of Scu in vitro was detected by the photometric determination.

          Results

          Scu treatment dose-dependently decreased neurological deficit score, infarct area, cell apoptosis and morphological changes induced by pMCAO, which were associated with reductions of ACE and AT1R expression and the levels of Ang II, TNF-α, IL-6, and IL-1β in ischemic brains. Scu has a potent ACE inhibiting activity.

          Conclusion

          Scu protects brain from acute ischemic injury probably through its inhibitory effect on the ACE/Ang II/AT1 axis, CBF preservation and proinflammation inhibition.

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          Most cited references47

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          The complexity of neurobiological processes in acute ischemic stroke.

          There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches. In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood-brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells.
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            The angiotensin-converting enzyme gene family: genomics and pharmacology.

            Modulation of the renin-angiotensin system (RAS), and particularly inhibition of angiotensin-converting enzyme (ACE), a zinc metallopeptidase, has long been a prime strategy in the treatment of hypertension. However, other angiotensin metabolites are gaining in importance as our understanding of the RAS increases. Recently, genomic approaches have identified the first human homologue of ACE, termed ACEH (or ACE2). ACEH differs in specificity and physiological roles from ACE, which opens a potential new area for discovery biology. The gene that encodes collectrin, a homologue of ACEH, is upregulated in response to renal injury. Collectrin lacks a catalytic domain, which indicates that there is more to ACE-like function than simple peptide hydrolysis.
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              Targeting apoptosis pathways in cancer by Chinese medicine.

              The traditional Chinese medicine (TCM) uses a combination of different natural products based on practical experiences. To better understand the therapeutic functions of TCM, large efforts have been made to identify the principle constituents of TCM and to unravel the molecular mechanisms behind the efficacy observed. This review aims to summarize research results obtained from the most intensively studied TCM phytochemical compounds namely the alkaloids Berberine, Evodiamine; anthraquinones Emodin, Aloe-emodin, Rhein; the terpenoids Artemisinin, Celastrol, Triptolide; the flavones Apigenin, Chrysin, Wogonin, Baicalein; and the cyclopenta[b]benzofuran derivatives Rocaglamide. Most of them have been originally identified as anti-inflammatory and anti-viral reagents and are now known to also possess anti-tumor activities by targeting the apoptosis pathways in cancer. This review also intends to give an overview of the mechanisms of action identified so far. These breakthrough findings may have important implications for targeted-cancer therapy and for modernization of TCM. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 January 2016
                2016
                : 11
                : 1
                : e0146197
                Affiliations
                [1 ]Pharmacy School, Shihezi University, Shihezi, China
                [2 ]Department of Pharmacy, the First Division Hospital of Xinjiang Production and Construction Corps, Aksu, Xinjiang, China
                [3 ]College of Life Sciences, Northwest A&F University, Yangling, Shanxi, China
                [4 ]Binzhou Medical University, Yantai, China
                [5 ]Institute of Neurological Disease, Zhanjiang Medical College, Zhanjiang, Guangdong, China
                [6 ]Weifang Medical University, Weifang, China
                Indian Institute of Integrative Medicine, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WW XM. Performed the experiments: WW XM MZ HR JH QP. Analyzed the data: WW XM QP QZ. Contributed reagents/materials/analysis tools: WW XM QP QZ. Wrote the paper: WW XM CZ QZ.

                Article
                PONE-D-15-06811
                10.1371/journal.pone.0146197
                4711585
                26730961
                ed33cdc9-8016-4284-a6fe-4d302bad9ed6
                © 2016 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 21 February 2015
                : 14 December 2015
                Page count
                Figures: 8, Tables: 1, Pages: 17
                Funding
                This study was supported by the National Natural Science Foundation of China (No. 31471338) to Zheng QS. The authors are especially thankful for funds from the Xinjiang Production and Construction Corps for innovation team in key areas (2015BD005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Research Article
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                All relevant data are within the paper and its Supporting Information files.

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