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      The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy

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          Abstract

          Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

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          Autophagy maintains the metabolism and function of young and old (hematopoietic) stem cells

          Theodore Ho, Matthew Warr, Emmalee Adelman … (2017)
          With age, hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting HSCs from metabolic stress. Here, we show that loss of autophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs HSC self-renewal activity and regenerative potential. Strikingly, the majority of HSCs in aged mice share these altered metabolic and functional features. However, ~ 1/3 of aged HSCs exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young HSCs. Our results demonstrate that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old HSCs.
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            ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy.

            Zheng Wang, Liang Qin, Yun Wang … (2010)
            Disturbance to endoplasmic reticulum (ER) homeostasis that cannot be rescued by the unfolded protein response (UPR) results in autophagy and cell death, but the precise mechanism was largely unknown. Here we demonstrated that ER stress-induced cell death was mediated by autophagy which was partly attributed to the inactivation of the mammalian target of rapamycin (mTOR). Three widely used ER stress inducers including tunicamycin, DTT and MG132 led to the conversion of LC3-I to LC3-II , a commonly used marker of autophagy, as well as the downregulation of mTOR concurrently. TSC -deficient cells with constitutive activation of mTOR exhibited more resistance to ER stress-induced autophagy, compared with their wild-type counterparts. Furthermore, our studies showed that ER stress-induced deactivation of mTOR was attributed to the downregulation of AKT/TSC /mTOR pathway. Phosphatase and tensin homolog (PTEN) and AMP-activated protein kinase (AMPK) as two regulators in this pathway seemed to be absent in this regulation. As a chemical chaperone helping the correct folding of proteins, 4-phenylbutyric acid (4-PBA) partly rescued the AKT/TSC/mTOR pathway in drug-induced acute ER stress. Moreover, constitutively-activated mTOR-induced long-term ER stress attenuated the RTK/PI3K/AKT signaling pathway in response to the stimulation by various growth factors, which could also be partly restored by 4-PBA.
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              The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis.

              Megan Goodall, Brent E Fitzwalter, Shadi Zahedi … (2016)
              Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 13 May 2019
                Publication date Collection: May 2019
                Volume: 24
                Issue: 9
                Electronic Location Identifier: 1838
                Affiliations
                Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang 050200, China; 734910343@ 123456163.com (Y.Z.); yingzhang2810@ 123456163.com (Y.Z.); jxf1655@ 123456163.com (X.-f.J.); zxh19703@ 123456163.com (X.-h.Z.); dongxianhuitj@ 123456126.com (X.-h.D.); ywtawen@ 123456163.com (W.-t.Y.)
                Author notes
                [* ]Correspondence: gwj6088@ 123456163.com ; Tel.: +86-311-8992-6007
                Article
                Publisher ID: molecules-24-01838
                DOI: 10.3390/molecules24091838
                PMC ID: 6539971
                PubMed ID: 31086091
                SO-VID: 7d166f32-8f72-424e-b72b-2952beefe6ad
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 02 April 2019
                Date accepted : 08 May 2019
                Categories
                Subject: Article

                Keywords: astragaloside iv,cerebral ischemia/reperfusion injury,autophagy,apoptosis,mechanism
                Data availability:
                Keywords: astragaloside iv, cerebral ischemia/reperfusion injury, autophagy, apoptosis, mechanism

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