Oxidative stress in keratinocytes induces cytoprotective events, such as autophagy and cellular senescence. The present study investigated whether an induction of autophagy and cellular senescence can be observed in oxidative-stressed keratinocytes to allow those cells to maintain a cytoprotecitve state.

We examined that the effect of various inhibitors on the induction of both autophagy and senescence in H 2 O 2 -treated HaCaT cells via Western blotting and immunocytochemical assays.

H 2 O 2 -treated cells exhibited increased expression of the senescent markers, p21 and Decades Dec1 , in addition to increased and decreased numbers of senescence-associated β-galactosidase SA-β-gal — and Ki—positive cells, respectively.

These senescent cells also displayed upregulation of the autophagy marker, LC3-II. Attenuation of LC3-II expression using 3-methyladenin inhibited H 2 O 2 - autophagy and cellular senescence.

Our Western blotting results revealed that H 2 O 2 -induced autophagy was regulated independently by the negative feedback pathway of a mammalian target of rapamycin. By contrast, H 2 O 2 -induced autophagy and cellular senescence depended on the activation of the p38 mitogen-activated protein kinase α MAPKα pathway mediated by the intracellular reactive oxygen species ROS production.

Furthermore, a suppression of autophagy by 3-methyladenine promoted an induction of apoptosis in H 2 O 2 -treated cells, suggesting that autophagy, in association with the cellular senescence, may induce the cytoprotection under the oxidative stress.

Our findings suggest that the acceleration of both events may allow stressed cells to maintain the cytoprotective effects and may be regulated, in part, by p38 MAPK activation through the intracellular production of ROS. Already have an account?

Sign in here. Journal of Hard Tissue Biology. demonstrated that nitrogen-doped carbon nanocages enhanced the therapeutic effects of hUMSCs on cerebral infarction and inhibited the microglia reactivation and neuroinflammation Zhai et al.

Besides, Huang and his group coated palmitic acid peptide onto the cell membrane of MSCs and thus increased the number of transplanted cells in the ischemic lesion Huang et al. Generally, these approaches used to modify MSCs might generate a potential therapeutic strategy for stroke management.

That MSC-derived EVs can be advantageous over MSCs in the field of stroke therapy is partly dependent on the EV-mediated molecular transfer. EVs always serve as molecular cargoes, such as membrane receptors, proteins, lipids, and various forms of RNA molecules Otero-Ortega et al.

Among the contents of EVs, miRNAs, endogenously expressed RNA molecules that function to inhibit messenger RNA mRNA translation, have been shown to govern important processes that are responsible for ischemic stroke injuries Khoshnam et al.

Therefore, EV-mediated miRNA transfer provides an attractive candidate for the treatment of cerebral ischemic injury. Recently, a number of studies have confirmed the therapeutic effectiveness of EV-mediated miRNA delivery in ischemic stroke.

Plenty of miRNAs were involved in these processes, such as miRNAb-3p and miRNAb-5p Hou et al. However, more researchers used miRNAs to modify MSCs for producing more robust EVs.

In their investigations, EVs from MSCs primed with miRNA, miRNAp, miRNAp, miRNAb, and miRNAp showed stronger neuroprotection effects than EVs lacking additional miRNA. Those miRNAs mainly participated in the reduction in neuroinflammation, ROS production, as well as BBB dysfunction, and promotion of angiogenesis Xin et al.

Intriguingly, Xin et al. Moreover, other teams designed to modify MSCs in other ways to enhance the therapeutic potential of their EVs.

A recent study showed that pretreatment of MSCs with lithium significantly upregulated the expression level of miRNA in MSC-derived EVs, thereby enhancing the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury and reducing the levels of poststroke cerebral inflammation, and this process was connected with miRNA inhibition of TLR4 abundance Haupt et al.

Kim et al. There was also a report on the effective inhibition of ROS and inflammatory activity following cerebral ischemia by combined nanoformulation of curcumin and embryonic stem-cell-derived exosomes Kalani et al.

Despite that studies on MSC-based therapies that target pyroptosis are relatively few in ischemic stroke, eminent outcome has also been observed.

In vitro , the inhibitory effect of BMSC-derived exosomes on pyroptosis in PC12 cells was comparable to the NLRP3 inhibitor and was reversed by NLRP3 overexpression Zeng et al. Meanwhile, that human umbilical cord blood mononuclear cells cbMNCs inhibited the activation of NLRP3 inflammasome in vivo has also been documented Liu et al.

Another in vivo investigation demonstrated that lymphocytes cocultured with human cord blood-derived multipotent stem cells HCB-SCs attenuated inflammasome activity in middle cerebral artery occlusion MCAO rats by suppressing NLRP3 inflammasome activation and promoting Tregs differentiation Zhao et al.

In addition, a study on microglia revealed that hypoxia-preconditioned OM-MSCs suppressed pyroptotic death of microglia caused by cerebral ischemia—reperfusion insult by activating HIF-1α Huang et al.

The mechanism by which MSCs and secretome inhibit pyroptosis has been more deeply studied in other disease models. Several new findings showed that MSCs exosomes inhibited NLRP3 expression and pyroptosis of cardiomyocytes and myocardial infarction by delivering miRNAb or long non-coding RNA lncRNA KLF3-AS1 Mao et al.

Liu et al. Besides, Kong and his group transplanted IL gene-modified MSCs into rats model of intestinal ischemia—reperfusion injury and found that the expression of NLRP3 and downstream targets cleaved caspase-1, IL-1β, and IL were observably lessened Kong et al.

Overall, the underlying mechanism regarding multiple molecular pathways involved in the role of MSCs and secretome in other diseases are expected to further elucidate in ischemic stroke.

Different from the direct inhibition of oxidative stress level and inflammatory activity, MSCs have two-sided effects on autophagy in ischemic stroke. Accumulating evidence have implied that MSCs were able to suppress autophagy through numerous molecular pathways and then promoted functional recovery after ischemic injury.

Among these researches, Li et al. Second, exosome-mediated miRNAs delivery also took part in the regulatory process. miRNAa in exosomes from hUMSCs directly binds to beclin-1 and inhibits its expression, thereby inhibiting autophagic flux in ischemia—reperfusion-induced injury Zhang et al.

Third, a recent study suggested that the protective role of transplanted MSCs in a murine model of ischemic stroke was associated with their promotion of the molecular switch from autophagy to ubiquitin—proteasome system UPS Tadokoro et al. By contrast, some other investigations declared that MSCs combated ischemic injury by enhancing autophagy Huang et al.

Likewise, in most studies, MSCs play a role by targeting mTOR-mediated autophagy pathway. In PC12 cells treated with OGD insult, BMSC exosomes attenuated the pyroptosis mediated by NLRP3 inflammasome by promoting AMPK-dependent autophagy flux Zeng et al.

Besides, heme oxygenase-1 HO-1 -mediated autophagy could also be modulated by MSCs in ischemic injury models Wang et al. Collectively, the regulatory role of MSCs in autophagy following ischemic stroke is still under dispute.

Even in the same cell or animal models of cerebral ischemic injury, MSCs can exhibit diametrically opposite effects on the modulation of autophagy, which is believed to be related to multiple factors, such as the length of modeling time and the time nodes of MSCs intervention.

From another point of view, the beneficial or detrimental impacts on ischemic brain tissue depend on the intensity of autophagy, and the transplanted MSCs exert neuroprotection effects through modulating their functions adaptively according to the state of autophagy.

The applicable therapeutic strategy to reduce or prevent the cerebral ischemic injury is still largely lacking.

Abundant data implicated intricate rather than a single signaling pathway to frequently work together to undermine the cells in the setting of cerebral ischemia—reperfusion. The crosstalk among oxidative stress, inflammatory activity, and autophagy dysfunction may raise the need of deeply taking into consideration these pathways in ischemic stroke.

Nowadays, the pleiotropic ability of MSCs to exhibit antioxidative stress, reduce neuroinflammation, and regulate autophagy in experimental ischemic stroke has been recognized, most of which benefit from its robust paracrine activities Figure 2.

More importantly, the low immunogenicity, ability to cross the BBB, capacity of targeted delivering gene drugs, and similar properties as MSCs seem to make MSC-derived EVs a better clinical application candidate relative to MSCs.

In summary, MSCs and secretome hold great promise in the clinical treatment of ischemic stroke. Figure 2. MSCs rescue ischemic brain tissue and promote recovery by inhibiting oxidative stress as well as inflammatory activity and modulation autophagy.

MSCs, mesenchymal stem cells; TNTs, tunneling nanotubes; EVs, extracellular vesicles; ROS, reactive oxygen species; RNS, reactive nitrogen species; BBB, blood—brain barrier; UPS, ubiquitin-proteasome system; HO-1, heme oxygenase ZH and HX acquired the funding.

JH attended in literature review and drafting the manuscript. JL and YH participated in literature review. XT and ZH supervised the project. All authors read and approved the final manuscript. This work was supported by the National Natural Science Foundation of China grant numbers and and the Natural Science Foundation of Hunan Province, China grant number JJ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acquistapace, A. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 29, — doi: PubMed Abstract CrossRef Full Text Google Scholar.

Albers, G. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. Alhazzani, A. Cells Allen, C. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Stroke 4, — Anderson, C. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke ENCHANTED : an international, randomised, open-label, blinded-endpoint, phase 3 trial.

Lancet , — CrossRef Full Text Google Scholar. Anrather, J. Inflammation and stroke: an overview. Neurotherapeutics 13, — Babenko, V. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells MMSC to neural cells and improves the efficacy of cell recovery.

Molecules Improving the post-stroke therapeutic potency of mesenchymal multipotent stromal cells by cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Transl. Bao, Q. Simultaneous blood-brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles.

ACS Nano 12, — Bergendi, L. Chemistry, physiology and pathology of free radicals. Life Sci. Bernardo, M. Mesenchymal stromal cells: sensors and switchers of inflammation.

Cell Stem Cell 13, — Boltze, J. Stem cells as an emerging paradigm in stroke 4: advancing and accelerating preclinical research. Stroke 50, — Boshuizen, M. Stem cell—based immunomodulation after stroke. Stroke 49, — Calio, M. Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model.

Free Radic Biol. Campbell, B. Ischaemic stroke. Primers Carbone, F. Pathophysiology and treatments of oxidative injury in ischemic stroke: focus on the phagocytic NADPH Oxidase 2. Castets, P.

Cecconi, F. The role of autophagy in mammalian development: cell makeover rather than cell death. Cell 15, — Cespedes, A. Energy-Sensing pathways in ischemia: the counterbalance between AMPK and mTORC. Chamorro, Á, Dirnagl, U.

Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. Chen, H. Chen, S. Targeting Myeloperoxidase MPO mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds.

Acta Pharmacol. Chen, K. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells ADMSC and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke.

Oncotarget 7, — Chen, X. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury. Cheng, Z. Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice. Chong, Z. The rationale of targeting mammalian target of rapamycin for ischemic stroke.

Cell Signal. Cunningham, C. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. Blood Flow Metab. Systemic conditioned medium treatment from interleukin-1 primed mesenchymal stem cells promotes recovery after stroke.

Stem Cell Res. Darroudi, S. Biofactors 46, 55— Deans, R. Mesenchymal stem cells: biology and potential clinical uses. Deng, Y. Exosomes derived from microRNAp-overexpressing bone marrow-derived mesenchymal stem cells confer neuroprotection to astrocytes following ischemic stroke via inhibition of LCN2.

Elsner, V. Therapeutic effectiveness of a single exercise session combined with WalkAide functional electrical stimulation in post-stroke patients: a crossover design study. Feng, J. Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke.

Expert Opin. Targets 21, — Ferreira, J. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning.

Fu, B. Cell Longev. Furuhashi, M. New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. GBD Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries and territories, a systematic analysis for the Global Burden of Disease Study Gelderblom, M.

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40, — George, P. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87, — Gong, X. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction.

Cell Physiol. Granger, D. Reperfusion injury and reactive oxygen species: the evolution of a concept. Guan, R. Mitophagy, a potential therapeutic target for stroke.

Guan, Y. Stem Cells Int. Guo, Q. ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress. EMBO J. Guo, Z. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. Tissue Eng. Guruswamy, R. Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions.

Haupt, M. Lithium modulates miR levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation. Cells Transl. CrossRef Full Text PubMed Abstract Google Scholar. He, H. Brain Res. He, J.

Cell Dev. Hendouei, N. Alterations in oxidative stress markers and its correlation with clinical findings in schizophrenic patients consuming perphenazine, clozapine and risperidone. Hong, Y. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats.

Hou, K. Bone mesenchymal stem cell-derived exosomal microRNAb-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway.

The progress of neuronal autophagy in cerebral ischemia stroke: mechanisms, roles and research methods. Hu, Z. Mechanism and regulation of autophagy and its role in neuronal diseases.

Huang, B. Peptide modified mesenchymal stem cells as targeting delivery system transfected with miRb for the treatment of cerebral ischemia. Huang, X. Exosomes derived from PEDF modified adipose-derived mesenchymal stem cells ameliorate cerebral ischemia-reperfusion injury by regulation of autophagy and apoptosis.

Cell Res. Huang, Y. Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation. Theranostics 8, — Aging Albany NY 12, — Iadecola, C.

The immunology of stroke: from mechanisms to translation. Jayaraj, R. Neuroinflammation: friend and foe for ischemic stroke. Jiang, Q. Hypoxia Inducible Factor-1alpha HIF-1alpha mediates NLRP3 inflammasome-dependent-pyroptotic and apoptotic cell death following ischemic stroke. Neuroscience , — Jiang, T.

Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Daniel J, Klionsky DJ, Cuervo AM, Segle PO Methods for monitoring autophagy from yeast to human.

Autophagy 3 3 — Deretic V, Levine B Autophagy balances inflammation in innate immunity. Autophagy — Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, Pagliarini V, Matteoni S, Fuoco C, Giunta L The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy.

Djavaheri-Mergny M, Amelotti M, Mathieu J NF- kappa B activation represses tumor necrosis factor-alpha-induced autophagy. J Biol Chem — Biochim Et Biophys Acta — Fortun J, Dunn WA Jr, Joy S, Li J, Notterpek L Emerging role for autophagy in the removal of aggresomes in Schwann cells.

J Neurosci — Gatica D, Chiong M, Lavandero S, Klionsky DJ Molecular mechanisms of autophagy in the cardiovascular system. Circ Res — Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.

Genes Dev — Harris J Autophagy and cytokines. Cytokine — Hartleben B, Gödel M, Schwesinger CM, Liu S, Ulrich T, Köbler S Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice.

J Clin Invest — Henderson P, Stevens C The role of autophagy in Crohns disease. Cells — Iida T, Onodera K, Nakase H Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 23 11 — Isakson P, Holland P, Simonsen A The role of ALFY in selective autophagy.

Cell Death Differ — Itakura E, Mizushima N Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Jiang S, Wells CD, Roach PJ Starch-binding domain-containing protein 1 Stbd1 and glycogen metabolism: identification of the Atg8 family interacting motif AIM in Stbd1 required for interaction with GABARAPL1.

Biol Chem Res Commun — Johansen T, Lamark T Selective autophagy mediated by autophagic adapter proteins. Jung HS, Lee MS Role of autophagy in diabetes and mitochondria.

Ann N Y Acad Sci — Kanki T Nix: a receptor protein for mitophagy in mammals. Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, Namba T Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol — Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.

Mol Cell — Klionsky DJ Protein transport from the cytoplasm into vacuole. J Memb Biol — Klionsky DJ Autophagy: from phenomenology to molecular understanding in less than a decade.

Nat Rev Mol Cell Biol — Klionsky DJ, Cregg JM, Dunn WA, Emr SD, SakaiY SIV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y A unified nomenclature for yeast autophagy-related genes. Dev Cell — Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.

Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature — ubiquitin protease. Nat Cell Biol 10 5 — Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T The role of autophagy during the early neonatal starvation period.

Essays Biochem — Lapaquette P, Guzzo J, Bretillon L, Bringer MA Cellular and molecular connections between autophagy and inflammation. Mediat Inflamm Laplante M, Sabatini DM mTOR signaling in growth control and disease.

Cell — Mathew R, Karantza-Wadsworth V, White E Role of autophagy in cancer. Nat Rev Cancer — Mijaljica D, Prescot M, Devenish RJ The intricacy of nuclear membrane dynamics during nucleophagy. Nucleus — Mizushima N Autophagy: process and function. Nakatogawa H Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy.

Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K The role of autophagy in the heart. Nixon RA Autophagy, Amyloidogenesis and Alzheimer disease. Onodera J, Ohsumi Y Autophagy is required for maintenance of aminoacid levels and protein synthesis under nitrogen starvation.

Otomo C, Metlagel Z, Takaesu G, Otomo T Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.

Nat Struct Mol Biol — Overbye A, Fengsrud M, Seglen PO Proteomic analysis of membrane-associated proteins from rat liver autophagosomes.

J Mol Biol — Pattingre S, Tassa A, Qu X, Garuti R, Linag XH, Mizushima N Bcl-2 anti-apoptotic proteins inhibit Beclin 1-dependent autophagy.

Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M Interplay between ROSand autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol — Polson HE, De Lartigue J, Rigden DJ, Reedijk M, Urbe S, Clague MJ, Tooze SA Mammalian Atg18 WIPI2 localizes to omegasome-anchoredphagophores and positively regulates LC3 lipidation.

Qian M, Fang X, Wang X Autophagy and inflammation. Clin Transl Med — Qu X, Yu J, Bhagat G Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.

Quan W, Lim YM, Lee MS Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells. Exp Mol Med — Ravikumar B, Stewart A, Kita H, Kato K, Duden R, Rubinsztein DC Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy.

Hum Mol Genet — Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Sato M, Sato K Degradation of paternal mitochondria by fertilization-triggered autophagy in C.

elegans embryos. Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, Inagaki F The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy.

Matoba K, Kotani T, Tsutsumi A, Tsuji T, Mori T, Noshiro D, Sugita Y, Nomura N, Iwata S, Ohsumi Y, et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion.

Nat Struct Mol Biol. Sawa-Makarska J, Baumann V, Coudevylle N, von Bulow S, Nogellova V, Abert C, Schuschnig M, Graef M, Hummer G, Martens S. Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation.

Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA, Maiolica A, Hansmann I, Pfaffenwimmer T, Kijanska M, Stoffel I, et al.

Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Otomo C, Metlagel Z, Takaesu G, Otomo T. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z.

EMBO J. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. Metlagel Z, Otomo C, Takaesu G, Otomo T. Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG Proc Natl Acad Sci U S A.

Yu L, Chen Y, Tooze SA. Autophagy pathway: cellular and molecular mechanisms. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, Mizushima N. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz LM, Li J, Vivona S, et al.

ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Ung L, Pattamatta U, Carnt N, Wilkinson-Berka JL, Liew G, White AJR. Oxidative stress and reactive oxygen species: a review of their role in ocular disease.

Clin Sci Lond. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. CAS PubMed Central Google Scholar. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases.

Vascul Pharmacol. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A.

Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. Liu PF, Farooqi AA, Peng SY, Yu TJ, Dahms HU, Lee CH, Tang JY, Wang SC, Shu CW, Chang HW.

Regulatory effects of noncoding RNAs on the interplay of oxidative stress and autophagy in cancer malignancy and therapy. Semin Cancer Biol. Article PubMed PubMed Central Google Scholar.

Filomeni G, Desideri E, Cardaci S, Rotilio G, Ciriolo MR. Under the ROS: thiol network is the principal suspect for autophagy commitment. Autophagy , 6 7 — Cao J, Schulte J, Knight A, Leslie NR, Zagozdzon A, Bronson R, Manevich Y, Beeson C, Neumann CA.

Su Q, Zheng B, Wang CY, Yang YZ, Luo WW, Ma SM, Zhang XH, Ma D, Sun Y, Yang Z, et al. Oxidative stress induces neuronal apoptosis through suppressing transcription factor EB phosphorylation at Ser Cell Physiol Biochem.

Kimball SR, Gordon BS, Moyer JE, Dennis MD, Jefferson LS. Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal. Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S.

Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Velasco-Miguel S, Buckbinder L, Jean P, Gelbert L, Talbott R, Laidlaw J, Seizinger B, Kley N.

PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes.

Shin BY, Jin SH, Cho IJ, Ki SH. Nrf2-ARE pathway regulates induction of Sestrin-2 expression. Free Radic Biol Med. Shi X, Doycheva DM, Xu L, Tang J, Yan M, Zhang JH. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

Neurobiol Dis. Zhang XY, Wu XQ, Deng R, Sun T, Feng GK, Zhu XF. Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells. Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, Schwartz TU, Sabatini DM.

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Kim H, An S, Ro SH, Teixeira F, Park GJ, Kim C, Cho CS, Kim JS, Jakob U, Lee JH, et al. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains.

Nat Commun. Cordani M, Sanchez-Alvarez M, Strippoli R, Bazhin AV, Donadelli M. Sestrins at the interface of ROS control and autophagy regulation in health and disease. Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, Komatsu M, Oh YJ, Zhao Y, Yue Z. PLoS Genet. Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, et al.

Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. Orenstein SJ, Cuervo AM.

Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol. Zhang L, Wang H, Xu J, Zhu J, Ding K.

Toxicol Lett. Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, Tee AR, Tait-Mulder J, Di Nardo A, Han JM, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.

Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, et al. TFEB links autophagy to lysosomal biogenesis. Wu JJ, Quijano C, Chen E, Liu H, Cao L, Fergusson MM, Rovira II, Gutkind S, Daniels MP, Komatsu M, et al.

Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling.

Proc Natl Acad Sci USA. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. Gao Q. Oxidative stress and autophagy. Adv Exp Med Biol. Chen Y, Azad MB, Gibson SB. Superoxide is the major reactive oxygen species regulating autophagy.

Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal. Ribas V, Garcia-Ruiz C, Fernandez-Checa JC. Glutathione and mitochondria.

Front Pharmacol. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling.

Circ Res. Yang S, Xia C, Li S, Du L, Zhang L, Zhou R. Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species ROS -induced nod-like receptor 3 NLRP3 dependent proinflammatory response and aggravates lipotoxicity.

Redox Biol. Kurihara Y, Kanki T, Aoki Y, Hirota Y, Saigusa T, Uchiumi T, Kang D. Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast.

J Biol Chem. Wang Y, Nartiss Y, Steipe B, McQuibban GA, Kim PK. Ge P, Dawson VL, Dawson TM. Mol Neurodegener. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.

Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Rose CM, Isasa M, Ordureau A, Prado MA, Beausoleil SA, Jedrychowski MP, Finley DJ, Harper JW, Gygi SP.

Highly multiplexed quantitative mass spectrometry analysis of ubiquitylomes. Cell Syst. Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW. Eiyama A, Okamoto K. Xiao B, Deng X, Lim GGY, Xie S, Zhou ZD, Lim KL, Tan EK. Cell Death Dis. Xiao B, Goh JY, Xiao L, Xian H, Lim KL, Liou YC.

Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.

Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIFdependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.

Cancer Res. Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. Bonekamp NA, Volkl A, Fahimi HD, Schrader M. Reactive oxygen species and peroxisomes: struggling for balance.

Fransen M, Nordgren M, Wang B, Apanasets O. Biochim Biophys Acta. Schrader M, Fahimi HD. Peroxisomes and oxidative stress. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress. Ditch S, Paull TT.

The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Guo Z, Deshpande R, Paull TT. ATM activation in the presence of oxidative stress.

Cell Cycle. Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL, Wogan GN. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1.

Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, Dere R, Tait-Mulder J, Lee JH, Paull TT, et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Kamsler A, Daily D, Hochman A, Stern N, Shiloh Y, Rotman G, Barzilai A. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice.

Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia. Chaperone-mediated autophagy: a unique way to enter the lysosome world.

Trends Cell Biol. Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone-mediated autophagy during oxidative stress. Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Callahan MK, Chaillot D, Jacquin C, Clark PR, Menoret A.

Differential acquisition of antigenic peptides by Hsp70 and Hsc70 under oxidative conditions. Lee JJ, Ishihara K, Notomi S, Efstathiou NE, Ueta T, Maidana D, Chen X, Iesato Y, Caligiana A, Vavvas DG. Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Biochem Biophys Res Commun. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM. Consequences of the selective blockage of chaperone-mediated autophagy. Suzuki T, Yamamoto M. Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress.

Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S, Suda H, et al. Molecular mechanism of cellular oxidative stress sensing by Keap1.

Cell Rep. Friling RS, Bergelson S, Daniel V. Two adjacent APlike binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. Rushmore TH, Morton MR, Pickett CB.

The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. Telakowski-Hopkins CA, King RG, Pickett CB.

Glutathione S-transferase Ya subunit gene: identification of regulatory elements required for basal level and inducible expression. Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML, Van Leuven F, Rabano A, Yamamoto M, Rojo AI, Cuadrado A.

Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A, McMahon M, Hayes JD, Johansen T. Kaspar JW, Niture SK, Jaiswal AK. Nrf 2:INrf2 Keap1 signaling in oxidative stress. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, et al.

Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Kageyama S, Gudmundsson SR, Sou YS, Ichimura Y, Tamura N, Kazuno S, Ueno T, Miura Y, Noshiro D, Abe M, et al.

Kumar RR, Narasimhan M, Shanmugam G, Hong J, Devarajan A, Palaniappan S, Zhang J, Halade GV, Darley-Usmar VM, Hoidal JR, et al. Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress.

J Transl Med. Georgakopoulos ND, Frison M, Alvarez MS, Bertrand H, Wells G, Campanella M. Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy. Sci Rep.

Murata H, Takamatsu H, Liu S, Kataoka K, Huh NH, Sakaguchi M. NRF2 regulates PINK1 expression under oxidative stress conditions. PLoS ONE. Yamada T, Murata D, Adachi Y, Itoh K, Kameoka S, Igarashi A, Kato T, Araki Y, Huganir RL, Dawson TM, et al.

Mitochondrial stasis reveals pmediated ubiquitination in parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab. Bialik S, Dasari SK, Kimchi A. Autophagy-dependent cell death—where, how and why a cell eats itself to death. Google Scholar.

Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells.

Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species.

Ha S, Ryu HY, Chung KM, Baek SH, Kim EK, Yu SW. Regulation of autophagic cell death by glycogen synthase kinase-3beta in adult hippocampal neural stem cells following insulin withdrawal.

Mol Brain. Law BYK, Michelangeli F, Qu YQ, Xu SW, Han Y, Mok SWF, Dias I, Javed MU, Chan WK, Xue WW, et al. Quigley HA, Broman AT. The number of people with glaucoma worldwide in and Br J Ophthalmol.

Nettesheim A, Dixon A, Shim MS, Coyne A, Walsh M, Liton PB. Autophagy in the aging and experimental ocular hypertensive mouse model. Invest Ophthalmol Vis Sci. Lin WJ, Kuang HY. Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells.

Amankwa CE, Gondi SR, Dibas A, Weston C, Funk A, Nguyen T, Nguyen KT, Ellis DZ, Acharya S. Novel thiol containing hybrid antioxidant-nitric oxide donor small molecules for treatment of glaucoma. Izzotti A, Bagnis A, Sacca SC. The role of oxidative stress in glaucoma. Mutat Res.

Shim MS, Nettesheim A, Dixon A, Liton PB. Zuo L, Khan RS, Lee V, Dine K, Wu W, Shindler KS. SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Kang LH, Zhang S, Jiang S, Hu N. Activation of autophagy in the retina after optic nerve crush injury in rats.

Int J Ophthalmol. Zhan Z, Wu Y, Liu Z, Quan Y, Li D, Huang Y, Yang S, Wu K, Huang L, Yu M. Reduced dendritic spines in the visual cortex contralateral to the optic nerve crush eye in adult mice.

Kim SH, Munemasa Y, Kwong JM, Ahn JH, Mareninov S, Gordon LK, Caprioli J, Piri N. Activation of autophagy in retinal ganglion cells.

J Neurosci Res. Knoferle J, Koch JC, Ostendorf T, Michel U, Planchamp V, Vutova P, Tonges L, Stadelmann C, Bruck W, Bahr M, et al. Mechanisms of acute axonal degeneration in the optic nerve in vivo. Rodriguez-Muela N, Germain F, Marino G, Fitze PS, Boya P.

Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. Porter K, Hirt J, Stamer WD, Liton PB. Autophagic dysregulation in glaucomatous trabecular meshwork cells. Kitaoka Y, Sase K, Tsukahara C, Fujita N, Tokuda N, Kogo J, Takagi H.

Axonal protection by a small molecule SIRT1 activator, SRT, with alteration of autophagy in TNF-induced optic nerve degeneration. Jpn J Ophthalmol. Yazdankhah M, Ghosh S, Shang P, Stepicheva N, Hose S, Liu H, Chamling X, Tian S, Sullivan MLG, Calderon MJ, et al.

BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. Beckers A, Vanhunsel S, Van Dyck A, Bergmans S, Masin L, Moons L. Injury-induced autophagy delays axonal regeneration after optic nerve damage in adult zebrafish.

Rodriguez-Muela N, Boya P. Axonal damage, autophagy and neuronal survival. Ying H, Yue BY. Optineurin: the autophagy connection. Exp Eye Res. Zhang S, Shao Z, Liu X, Hou M, Cheng F, Lei D, Yuan H.

The E50K optineurin mutation impacts autophagy-mediated degradation of TDP and leads to RGC apoptosis in vivo and in vitro. Cell Death Discov. Losiewicz MK, Elghazi L, Fingar DC, Rajala RVS, Lentz SI, Fort PE, Abcouwer SF, Gardner TW.

mTORC1 and mTORC2 expression in inner retinal neurons and glial cells. Russo R, Berliocchi L, Adornetto A, Amantea D, Nucci C, Tassorelli C, Morrone LA, Bagetta G, Corasaniti MT. In search of new targets for retinal neuroprotection: is there a role for autophagy? Curr Opin Pharmacol. Russo R, Varano GP, Adornetto A, Nazio F, Tettamanti G, Girardello R, Cianfanelli V, Cavaliere F, Morrone LA, Corasaniti MT, et al.

Bell K, Rosignol I, Sierra-Filardi E, Rodriguez-Muela N, Schmelter C, Cecconi F, Grus F, Boya P. Age related retinal Ganglion cell susceptibility in context of autophagy deficiency. Kauppinen A. Introduction to the multi-author review on macular degeneration.

Cell Mol Life Sci. Fleckenstein M, Keenan TDL, Guymer RH, Chakravarthy U, Schmitz-Valckenberg S, Klaver CC, Wong WT, Chew EY. Age-related macular degeneration. Nat Rev Dis Primers. Chan CM, Huang DY, Sekar P, Hsu SH, Lin WW. Reactive oxygen species-dependent mitochondrial dynamics and autophagy confer protective effects in retinal pigment epithelial cells against sodium iodate-induced cell death.

J Biomed Sci. Zhang ZY, Bao XL, Cong YY, Fan B, Li GY. Autophagy in age-related macular degeneration: a regulatory mechanism of oxidative stress. Wang S, Ji LY, Li L, Li JM. Oxidative stress, autophagy and pyroptosis in the neovascularization of oxygeninduced retinopathy in mice.

Mol Med Rep. Song C, Mitter SK, Qi X, Beli E, Rao HV, Ding J, Ip CS, Gu H, Akin D, Dunn WA Jr, et al. Blasiak J, Szczepanska J, Fila M, Pawlowska E, Kaarniranta K. Potential of telomerase in age-related macular degeneration-involvement of Senescence, DNA damage response and autophagy and a key role of PGC-1alpha.

Yang X, Pan X, Zhao X, Luo J, Xu M, Bai D, Hu Y, Liu X, Yu Q, Gao D. Autophagy and age-related eye diseases. Biomed Res Int. George SM, Lu F, Rao M, Leach LL, Gross JM. The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems.

Prog Retin Eye Res. Kaarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J. Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration. Cell Biol Toxicol. Liu J, Copland DA, Theodoropoulou S, Chiu HA, Barba MD, Mak KW, Mack M, Nicholson LB, Dick AD.

Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis. Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH.

Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration. Rodriguez-Muela N, Koga H, Garcia-Ledo L, de la Villa P, de la Rosa EJ, Cuervo AM, Boya P. Balance between autophagic pathways preserves retinal homeostasis.

Aging Cell. Mitter SK, Song C, Qi X, Mao H, Rao H, Akin D, Lewin A, Grant M, Dunn W Jr, Ding J, et al. Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Golestaneh N, Chu Y, Xiao YY, Stoleru GL, Theos AC.

Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Szatmari-Toth M, Kristof E, Vereb Z, Akhtar S, Facsko A, Fesus L, Kauppinen A, Kaarniranta K, Petrovski G.

Clearance of autophagy-associated dying retinal pigment epithelial cells—a possible source for inflammation in age-related macular degeneration. Szatmari-Toth M, Ilmarinen T, Mikhailova A, Skottman H, Kauppinen A, Kaarniranta K, Kristof E, Lytvynchuk L, Vereb Z, Fesus L, et al.

Human embryonic stem cell-derived retinal pigment epithelium-role in dead cell clearance and inflammation. Sheu SJ, Chen JL, Bee YS, Lin SH, Shu CW. ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress. Chang KC, Snow A, LaBarbera DV, Petrash JM.

Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells. Chem Biol Interact. Yao J, Tao ZF, Li CP, Li XM, Cao GF, Jiang Q, Yan B.

Regulation of autophagy by high glucose in human retinal pigment epithelium. Piano I, Novelli E, Della Santina L, Strettoi E, Cervetto L, Gargini C.

Involvement of autophagic pathway in the progression of retinal degeneration in a mouse model of diabetes. Front Cell Neurosci. Coucha M, Elshaer SL, Eldahshan WS, Mysona BA, El-Remessy AB. Molecular mechanisms of diabetic retinopathy: potential therapeutic targets. Middle East Afr J Ophthalmol.

Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, Nogueira-Machado JA. Cellular death, reactive oxygen species ROS and diabetic complications. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Rosa MD, Distefano G, Gagliano C, Rusciano D, Malaguarnera L.

Autophagy in diabetic retinopathy. Curr Neuropharmacol. Fu D, Wu M, Zhang J, Du M, Yang S, Hammad SM, Wilson K, Chen J, Lyons TJ. Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Aihara M. Prostanoid receptor agonists for glaucoma treatment.

Skov AG, Rives AS, Freiberg J, Virgili G, Azuara-Blanco A, Kolko M: Comparative efficacy and safety of preserved versus preservative-free beta-blockers in patients with glaucoma or ocular hypertension: a systematic review. Acta Ophthalmol Nocentini A, Supuran CT. Adrenergic agonists and antagonists as antiglaucoma agents: a literature and patent review — Expert Opin Ther Pat.

Jansook P, Hnin HM, Loftsson T, Stefansson E. Cyclodextrin-based formulation of carbonic anhydrase inhibitors for ocular delivery—a review. Int J Pharm. Al-Humimat G, Marashdeh I, Daradkeh D, Kooner K. Investigational Rho kinase inhibitors for the treatment of glaucoma. J Exp Pharmacol.

Faiq MA, Wollstein G, Schuman JS, Chan KC. Cholinergic nervous system and glaucoma: from basic science to clinical applications.

Toteberg-Harms M, Meier-Gibbons F. Is laser trabeculoplasty the new star in glaucoma treatment? Curr Opin Ophthalmol. Wolters JEJ, van Mechelen RJS, Al Majidi R, Pinchuk L, Webers CAB, Beckers HJM, Gorgels T. History, presence, and future of mitomycin C in glaucoma filtration surgery. Riva I, Roberti G, Katsanos A, Oddone F, Quaranta L.

A Review of the ahmed glaucoma valve implant and comparison with other surgical operations. Adv Ther. Kan JT, Betzler BK, Lim SY, Ang BCH. Anterior segment imaging in minimally invasive glaucoma surgery—a systematic review.

Acta Ophthalmol. Article PubMed Google Scholar. Chang KC, Sun C, Cameron EG, Madaan A, Wu S, Xia X, Zhang X, Tenerelli K, Nahmou M, Knasel CM, et al. Opposing effects of growth and differentiation factors in cell-fate specification.

Curr Biol. Zhang X, Tenerelli K, Wu S, Xia X, Yokota S, Sun C, Galvao J, Venugopalan P, Li C, Madaan A, et al.

Cell transplantation of retinal ganglion cells derived from hESCs. Restor Neurol Neurosci. Fligor CM, Langer KB, Sridhar A, Ren Y, Shields PK, Edler MC, Ohlemacher SK, Sluch VM, Zack DJ, Zhang C, et al.

Three-dimensional retinal organoids facilitate the investigation of retinal ganglion cell development, organization and neurite outgrowth from human pluripotent stem cells. Sluch VM, Chamling X, Liu MM, Berlinicke CA, Cheng J, Mitchell KL, Welsbie DS, Zack DJ. Enhanced stem cell differentiation and immunopurification of genome engineered human retinal ganglion cells.

Stem Cells Transl Med. Luo Z, Xian B, Li K, Li K, Yang R, Chen M, Xu C, Tang M, Rong H, Hu D, et al. scaffolds facilitate epiretinal transplantation of hiPSC-derived retinal neurons in nonhuman primates. Acta Biomater. Miltner AM, La Torre A. Retinal ganglion cell replacement: current status and challenges ahead.

Dev Dyn. Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP, Goldberg JL. KLF family members regulate intrinsic axon regeneration ability.

Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, et al. Chang KC, Bian M, Xia X, Madaan A, Sun C, Wang Q, Li L, Nahmou M, Noro T, Yokota S, et al. Posttranslational modification of Sox11 regulates RGC survival and axon regeneration.

Xie L, Yin Y, Benowitz L. Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy. Patel AK, Broyer RM, Lee CD, Lu T, Louie MJ, La Torre A, Al-Ali H, Vu MT, Mitchell KL, Wahlin KJ, et al. Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons.

Williams PR, Benowitz LI, Goldberg JL, He Z. Axon regeneration in the mammalian optic nerve. Annu Rev Vis Sci. Matloob S, Fan JC, Danesh-Meyer HV. Multifocal malignant optic glioma of adulthood presenting as acute anterior optic neuropathy. J Clin Neurosci. Tooley AA, Rasool N, Campbell A, Kazim M.

Acute angle plication of optic nerve glioma as a mechanism of rapidly progressive visual loss. Pan Y, Hysinger JD, Barron T, Schindler NF, Cobb O, Guo X, Yalcin B, Anastasaki C, Mulinyawe SB, Ponnuswami A, et al.

NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Brown EE, DeWeerd AJ, Ildefonso CJ, Lewin AS, Ash JD. Mitochondrial oxidative stress in the retinal pigment epithelium RPE led to metabolic dysfunction in both the RPE and retinal photoreceptors.

Skrzypczak T, Jany A, Bugajska-Abramek E, Boguslawska J, Kowal-Lange A. A comparative study of ranibizumab and aflibercept for neovascular age-related macular degeneration: month outcomes of Polish therapeutic program in non-tertiary institution. Banaee T, Alwan S, Kellogg C, Kornblau I, El-Annan J.

PRN treatment of neovascular AMD with cycles of three monthly injections. J Ophthalmic Vis Res. Parravano M, Costanzo E, Scondotto G, Trifiro G, Virgili G. Anti-VEGF and other novel therapies for neovascular age-related macular degeneration: an update.

Chichan H, Maus M, Heindl LM. Subthreshold nanosecond laser, from trials to real-life clinical practice: a cohort study. Clin Ophthalmol. Gao Y, Yu T, Zhang Y, Dang G. Anti-VEGF monotherapy versus photodynamic therapy and anti-VEGF combination treatment for neovascular age-related macular degeneration: a meta-analysis.

Bikbov MM, Orenburkina OI, Babushkin AE, Burkhanov YK. Use of macular lenses in patients with age-related macular degeneration. Vestn Oftalmol. Arrigo A, Bandello F. Molecular features of classic retinal drugs, retinal therapeutic targets and emerging treatments.

Berrocal MH, Acaba-Berrocal L. Early pars plana vitrectomy for proliferative diabetic retinopathy: update and review of current literature. Chang KC, Petrash JM. Aldo-Keto reductases: multifunctional proteins as therapeutic targets in diabetes and inflammatory disease.

Sonowal H, Ramana KV. Development of aldose reductase inhibitors for the treatment of inflammatory disorders and cancer: current drug design strategies and future directions.

Curr Med Chem. Suzen S, Buyukbingol E. Recent studies of aldose reductase enzyme inhibition for diabetic complications. Gabbay KH. Aldose reductase inhibition in the treatment of diabetic neuropathy: where are we in ?

Curr Diab Rep. Ishikawa M, Takaseki S, Yoshitomi T, Covey DF, Zorumski CF, Izumi Y. Sbardella D, Tundo GR, Coletta M, Manni G, Oddone F. Dexamethasone downregulates autophagy through accelerated turn-over of the Ulk-1 complex in a trabecular meshwork cells strain: insights on steroid-induced glaucoma pathogenesis.

Hamano T, Shirafuji N, Yen SH, Yoshida H, Kanaan NM, Hayashi K, Ikawa M, Yamamura O, Fujita Y, Kuriyama M, et al. Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiol Aging. Kitaoka Y, Sase K, Tsukahara C, Kojima K, Shiono A, Kogo J, Tokuda N, Takagi H.

Axonal protection by ripasudil, a rho kinase inhibitor, via modulating autophagy in TNF-induced optic nerve degeneration. Zhang J, Bai Y, Huang L, Qi Y, Zhang Q, Li S, Wu Y, Li X. Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration.

Ran Z, Zhang Y, Wen X, Ma J. Su W, Li Z, Jia Y, Zhuo Y. Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model. Dai Y, Zheng K, Clark J, Swerdlow RH, Pulst SM, Sutton JP, Shinobu LA, Simon DK.

Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation. Hum Mol Genet. Cinik R, Yuksel N, Pirhan D, Aslan MS, Subasi C, Karaoz E.

The effect of everolimus on scar formation in glaucoma filtering surgery in a rabbit model. Curr Eye Res. Matsuki M, Adachi Y, Ozawa Y, Kimura T, Hoshi T, Okamoto K, Tohyama O, Mitsuhashi K, Yamaguchi A, Matsui J, et al.

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci.

Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. Uchida J, Iwai T, Nakatani T. Introduction of everolimus in kidney transplant recipients at a late posttransplant stage.

World J Transpl. Touhami S, Arzouk N, Darugar A, Heron E, Clarencon F, Bodaghi B, LeHoang P, Barrou B, Touitou V. Everolimus-induced posterior reversible encephalopathy syndrome and bilateral optic neuropathy after kidney transplantation.

Canovai E, Cassiman C, Ceulemans LJ, Demaerel P, Sainz-Barriga M, Jochmans I, Monbaliu D, Pirenne J, Vanuytsel T. Tacrolimus-induced optic neuropathy after multivisceral transplantation. Transpl Direct. Liegl R, Koenig S, Siedlecki J, Haritoglou C, Kampik A, Kernt M. Temsirolimus inhibits proliferation and migration in retinal pigment epithelial and endothelial cells via mTOR inhibition and decreases VEGF and PDGF expression.

Jacot JL, Sherris D. J Ophthalmol. Kourelis TV, Siegel RD. Metformin and cancer: new applications for an old drug. Med Oncol. Brown EE, Ball JD, Chen Z, Khurshid GS, Prosperi M, Ash JD. The common antidiabetic drug metformin reduces odds of developing age-related macular degeneration.

Lin HC, Stein JD, Nan B, Childers D, Newman-Casey PA, Thompson DA, Richards JE. Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus. JAMA Ophthalmol. Kim YS, Kim M, Choi MY, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Kim SJ, Yoo JM, et al.

Metformin protects against retinal cell death in diabetic mice. Motoi Y, Shimada K, Ishiguro K, Hattori N. Lithium and autophagy. ACS Chem Neurosci. Sun XB, Lu HE, Chen Y, Fan XH, Tong B. Zeilbeck LF, Muller B, Knobloch V, Tamm ER, Ohlmann A.

Differential angiogenic properties of lithium chloride in vitro and in vivo. Ruiz-Pesini E, Emperador S, Lopez-Gallardo E, Hernandez-Ainsa C, Montoya J.

Increasing mtDNA levels as therapy for mitochondrial optic neuropathies. Drug Discov Today. Fauzi YR, Nakahata S, Chilmi S, Ichikawa T, Nueangphuet P, Yamaguchi R, Nakamura T, Shimoda K, Morishita K. Zhang ML, Zhao GL, Hou Y, Zhong SM, Xu LJ, Li F, Niu WR, Yuan F, Yang XL, Wang Z, et al. Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.

Kan E, Yakar K, Demirag MD, Gok M. Macular ganglion cell-inner plexiform layer thickness for detection of early retinal toxicity of hydroxychloroquine. Int Ophthalmol.

Reichel C, Berlin A, Radun V, Tarau IS, Hillenkamp J, Kleefeldt N, Sloan KR, Ach T. Transl Vis Sci Technol. Singh DK, Muhieddine L, Einstadter D, Ballou S. Incidence of blindness in a population of rheumatic patients treated with hydroxychloroquine.

Rheumatol Adv Pract. Amato R, Catalani E, Dal Monte M, Cammalleri M, Di Renzo I, Perrotta C, Cervia D, Casini G. Autophagy-mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy. Pharmacol Res. Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH.

Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K.

The NF1 tumor suppressor critically regulates TSC2 and mTOR. Fujita Y, Inagaki N. Metformin: clinical topics and new mechanisms of action. Exosomes derived from microRNAp-overexpressing bone marrow-derived mesenchymal stem cells confer neuroprotection to astrocytes following ischemic stroke via inhibition of LCN2.

Elsner, V. Therapeutic effectiveness of a single exercise session combined with WalkAide functional electrical stimulation in post-stroke patients: a crossover design study.

Feng, J. Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke. Expert Opin. Targets 21, — Ferreira, J.

Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Fu, B. Cell Longev. Furuhashi, M. New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.

GBD Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries and territories, a systematic analysis for the Global Burden of Disease Study Gelderblom, M.

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40, — George, P. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments.

Neuron 87, — Gong, X. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction.

Cell Physiol. Granger, D. Reperfusion injury and reactive oxygen species: the evolution of a concept. Guan, R. Mitophagy, a potential therapeutic target for stroke.

Guan, Y. Stem Cells Int. Guo, Q. ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress. EMBO J. Guo, Z. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases.

Tissue Eng. Guruswamy, R. Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions. Haupt, M. Lithium modulates miR levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation.

Cells Transl. CrossRef Full Text PubMed Abstract Google Scholar. He, H. Brain Res. He, J. Cell Dev. Hendouei, N. Alterations in oxidative stress markers and its correlation with clinical findings in schizophrenic patients consuming perphenazine, clozapine and risperidone.

Hong, Y. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats.

Hou, K. Bone mesenchymal stem cell-derived exosomal microRNAb-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway.

The progress of neuronal autophagy in cerebral ischemia stroke: mechanisms, roles and research methods. Hu, Z. Mechanism and regulation of autophagy and its role in neuronal diseases. Huang, B. Peptide modified mesenchymal stem cells as targeting delivery system transfected with miRb for the treatment of cerebral ischemia.

Huang, X. Exosomes derived from PEDF modified adipose-derived mesenchymal stem cells ameliorate cerebral ischemia-reperfusion injury by regulation of autophagy and apoptosis. Cell Res. Huang, Y. Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation.

Theranostics 8, — Aging Albany NY 12, — Iadecola, C. The immunology of stroke: from mechanisms to translation. Jayaraj, R. Neuroinflammation: friend and foe for ischemic stroke. Jiang, Q.

Hypoxia Inducible Factor-1alpha HIF-1alpha mediates NLRP3 inflammasome-dependent-pyroptotic and apoptotic cell death following ischemic stroke. Neuroscience , — Jiang, T. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke.

Jiang, Z. The role of the Golgi apparatus in oxidative stress: is this organelle less significant than mitochondria? Jorgensen, I. Pyroptotic cell death defends against intracellular pathogens. Kalani, A. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury.

Cell Biol. Kanazawa, M. Kang, J. Mitochondria: redox metabolism and dysfunction. Khoshnam, S. Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents. Stroke 19, — Kim, H. Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke.

Biomaterials Kim, K. Role of autophagy in endothelial damage and blood—brain barrier disruption in ischemic stroke. Koike, M. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Kong, D. IL Gene modification enhances the protective effects of mesenchymal stromal cells on intestinal ischemia reperfusion injury.

Kotur-Stevuljevic, J. Oxidative stress and paraoxonase 1 status in acute ischemic stroke patients. Atherosclerosis , — Kuang, Y.

Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR Vesicles 10, e The mesenchymal stem cell secretome: a new paradigm towards cell-free therapeutic mode in regenerative medicine.

Cytokine Growth Factor Rev. Lee, J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Lee, S. Enhancing the therapeutic potential of CCL2-Overexpressing mesenchymal stem cells in acute stroke. Leu, S. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats.

Li, D. Autologous transplantation of adipose-derived mesenchymal stem cells attenuates cerebral ischemia and reperfusion injury through suppressing apoptosis and inducible nitric oxide synthase. Li, W. Mesenchymal stem cells: a double-edged sword in regulating immune responses.

Cell Death Differ. Li, F. Li, X. Li, Y. Li, Z. Bone marrow-mesenchymal stem cells modulate microglial activation in the peri-infarct area in rats during the acute phase of stroke. Li, G. Cell Cycle 19, — Li, J. Mesenchymal stem cell therapy for ischemic stroke: a look into treatment mechanism and therapeutic potential.

Li, T. Effects of AMP-activated protein kinase in cerebral ischemia. Flow Metab. Cell Mol. Li, L. ROS and autophagy: interactions and molecular regulatory mechanisms.

Li, N. Interactions between mesenchymal stem cells and the immune system. Liddelow, S. Neurotoxic reactive astrocytes are induced by activated microglia.

Nature , — Liesz, A. DAMP signaling is a key pathway inducing immune modulation after brain injury. Lin, K. Xenogeneic and allogeneic mesenchymal stem cells effectively protect the lung against ischemia-reperfusion injury through downregulating the inflammatory, oxidative stress, and autophagic signaling pathways in rat.

Cell Transplant Liu, H. Cell Biochem. Liu, Y. Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia.

Autophagy 15, — Liu, J. Crosstalk between autophagy and ferroptosis and its putative role in ischemic stroke. Cell Neurosci. Chitosan hydrogel enhances the therapeutic efficacy of bone marrow—derived mesenchymal stem cells for myocardial infarction by alleviating vascular endothelial cell pyroptosis.

Liu, L. Transplantation of human umbilical cord blood mononuclear cells attenuated ischemic injury in MCAO rats via inhibition of NF-κB and NLRP3 inflammasome.

Liu, N. Expression of IL and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Liu, W. Electroacupuncture protects against ischemic stroke by reducing autophagosome formation and inhibiting autophagy through the mTORC1-ULK1 complex-Beclin1 pathway.

Lu, H. Neuroprotective effects of brain-derived neurotrophic factor and noggin-modified bone mesenchymal stem cells in focal cerebral ischemia in rats. Stroke Cerebrovasc. Lu, M. Mesenchymal stem cell-mediated mitochondrial transfer: a therapeutic approach for ischemic stroke. Stroke Res. Lu, Y.

Microthrombus-Targeting micelles for neurovascular remodeling and enhanced microcirculatory perfusion in acute ischemic stroke. Ma, Y. The biphasic function of microglia in ischemic stroke.

Manzanero, S. Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Mao, Q. Miljevic, C. Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.

Psychiatry Res. Mo, Y. Autophagy and inflammation in ischemic stroke. Nabavi, S. Novel therapeutic strategies for stroke: the role of autophagy.

Lab Sci. Nakka, V. Crosstalk between endoplasmic reticulum stress, oxidative stress, and autophagy: potential therapeutic targets for acute CNS injuries. Nazarinia, D. Neal, E. Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

Nogueira, R. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. Oh, S. Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model.

Otero-Ortega, L. Role of exosomes as a treatment and potential biomarker for stroke. Pan, Q. miRp priming enhances the effects of mesenchymal stromal cell-derived exosomes on ameliorating brain ischemic injury. Poh, L. Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke.

Brain Behav. Popa-Wagner, A. Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain?

Geroscience 41, — Pourmohammadi-Bejarpasi, Z. Qin, C. Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke 48, — Raffa, M. The reduction of superoxide dismutase activity is associated with the severity of neurological soft signs in patients with schizophrenia.

Psychiatry 39, 52— Rana, A. Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: opportunities, challenges and future directions for cerebral stroke management. Neuropharmacology , — Ravanan, P. Autophagy: the spotlight for cellular stress responses.

Saeed, S. Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Shi, J. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Song, H. Phytother Res. Spees, J. Su, P. The role of autophagy in modulation of neuroinflammation in microglia.

Sun, J. Sun, Y. Crosstalk between autophagy and cerebral ischemia. Tadokoro, K. Bone marrow stromal cell transplantation drives molecular switch from autophagy to the ubiquitin-proteasome system in ischemic stroke mice.

Tang, G. Mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia. Stem Cells 32, — Tang, J. Drug Des. Tobin, M.

Activated mesenchymal stem cells induce recovery following stroke via regulation of inflammation and oligodendrogenesis. Heart Assoc. Tseng, N. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: the role of Miro1.

Vizoso, F. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Wang, J. Treatment targets for M2 microglia polarization in ischemic stroke. Pharmacother , — Wang, P.

Autophagy in ischemic stroke. Wang, X. Wang, L. The shigella type III secretion effector IpaH4. Cell Infect.

Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 8, 77— Wang, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Wen, Y. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways.

Autophagy 4, — Weston, R. Inflammatory cell infiltration after endothelininduced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. Woodall, B. Mesenchymal Stem Cell-Mediated Autophagy Inhibition. Xia, C. Selective modulation of microglia polarization to M2 phenotype for stroke treatment.

Xin, H. MicroRNA cluster miR cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA b-Overexpressing multipotent mesenchymal stromal cells.

Cell Transplant. Xiong, X. Xu, L. Exosomes derived from CircAkap7-Modified adipose-derived mesenchymal stem cells protect against cerebral ischemic injury. Xu, P. Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke.

Cell Death Dis. Xue, L. Yan, B. Theranostics 10, — Yang, B. Stem Cells Dev. Procyanidins exhibits neuroprotective activities against cerebral ischemia reperfusion injury by inhibiting TLR4-NLRP3 inflammasome signal pathway.

Psychopharmacology Berl , — Yang, F. World J. Stem Cells 12, — Yang, Y. Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia.

Mediators Inflamm. Ye, A. Targeting pyroptosis to regulate ischemic stroke injury: molecular mechanisms and preclinical evidences. Ye, Y. The role of high mobility group box 1 in ischemic stroke.

Yuan, X. Zagrean, A. Multicellular crosstalk between exosomes and the neurovascular unit after cerebral ischemia.

therapeutic implications. Zeng, Q. Zhai, L. Nitrogen-doped carbon nanocages and human umbilical cord mesenchymal stem cells cooperatively inhibit neuroinflammation and protect against ischemic stroke.

Zhan, L. Neuroprotection of hypoxic postconditioning against global cerebral ischemia through influencing posttranslational regulations of heat shock protein 27 in adult rats. Brain Pathol. Zhang, C. Phytomedicine Zhang, D.

Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro. Zhang, L. Zhang, J. Zhao, R. Neuroscience , 99— Zhao, X. Zhao, Y.

Transplantation of lymphocytes co-cultured with human cord blood-derived multipotent stem cells attenuates inflammasome activity in ischemic stroke. Clin, Int. Aging 14, — Exosomes from MSCs overexpressing microRNAp attenuate cerebral ischemia through inhibiting microglial M1 polarization mediated inflammation.

Zheng, Z. Stem Cells 36, — Zitnanova, I. Oxidative stress markers and their dynamic changes in patients after acute ischemic stroke.

Zrzavy, T. Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts.

Keywords : mesenchymal stem cell, cerebral ischemic injury, oxidative stress, inflammation, autophagy dysfunction, extracellular vesicles.

Radicals can be oxidation and reduction depending on their redox potentials and the reacting substances. Although 8-hydroxypurines and formapyrimidines can originate in both presence and absence of oxygen, they better prefer to originate in an environment with oxygen.

These compounds are hemiorthoamids and they can turn into each other easily [ 50 ]. OH radical composes DNA product radicals as a result of the reaction with the atoms of guanine in positions numbered 4, 5 and 8.

OH product radicals of the fourth and fifth carbon atoms are dehydrated and the imidazole ring of the eighth carbon OH product radicals is exposed to the opening.

Other DNA base damage products have less mutagenic effects. For this reason, the most commonly measured 8-OHdG base damage product is a parameter that is widely used to determine the DNA damage [ 52 , 53 ].

For the first time, it was determined that 8-OHdG is an indicator of the DNA damage in by Kasai and Nishimura. Analysis of 8-OHdG, which is the major oxidation product of DNA, was reported in for the first time. There are two approaches for the analysis method of 8-OHdG.

The first of these, direct approach, is isolation of the DNA lesion by using physical and chemical methods and making DNA extraction and hydrolysation.

The second method, indirect approach, includes the saving of DNA structure and seeing the formation of lesion in site. In this approach, measurement is made by using antibodies that have low specific features or via the activity of specific DNA repair enzymes [ 54 , 55 ].

In addition to the studies of Swhweichel and Merker, who researched cell death mechanism morphologically for the first time, Clarke mentioned three basic cell morphology in cell death and described apoptosis as type I, autophagy as type II and cell death, which is not lysosomal, as type III programmed cell death [ 56 , 57 ].

It has been determined that, in this type of cell death, the morphological changes occurring in the cell take place as a result of cutting DNA and proteins by proteases called caspase.

The apoptotic bodies arising as a result of these fractures are resolved by lysosomes [ 57 ]. In autophagy, which is a mechanism in which intracellular macromolecules and organelles are directed to lysosomes in sachets and broken up in this mechanism, the short-lived proteins are broken up inside ubiquitin-proteasome system, intracellular organelles and long-lived proteins are benefited from as they are destroyed in autophagy system and decomposed into the building stones similar to amino acids to be used again inside the cell [ 58 , 59 ].

In the end, autophagy sachets form a compound with lysosome and make it possible for the material inside them to be broken up by the lysosomal enzymes [ 60 ]. Either apoptosis or autophagy, no matter what the death type is, it is known that these processes are regulated by molecular mechanisms.

In the same cell, as different death cell mechanisms can take action even simultaneously, these mechanisms can involve each other and they cannot be distinguished easily all the time.

It is difficult to describe whether the morphological changes, which come into light with the cell death mechanisms, are due to apoptosis or autophagy [ 61 ].

The reason for this can be that different cell death mechanisms have different main goals. The main goal of autophagic cell death is mainly cytoplasm, while the main goal of apoptosis is cell nucleus. Apoptosis can be sufficient for the disposal of cells with small cytoplasm.

However, in cells with large cytoplasm, more than one mechanism may have to take action together. In other words, while mechanisms dispose the nucleus, cytoplasm and organelles are cleaned by the autophagy event and the cell death can be accelerated.

In literature, there are studies supporting this view [ 62 , 63 ]. Caspases playing a role in apoptosis are classified in two ways: Caspases starting the apoptotic signals caspases 2, 8, 9, Lethal caspases that have a role in the breaking up of g-proteins caspases 3, 6 and 7.

Along with the caspase-dependent mechanisms that control the cell death, some cell deaths are reported to be caspase-free [ 64 ].

Caspase-dependent pathway triggers cell death by activating in two ways: extrinsic and intrinsic factors. In the extrinsic pathway, tumour necrosis factor- α TNF-α , which is on the surface of cell membrane, connects to TNF-like ligands such as FasL or TRAIL, and causes procaspase-8 or procaspase to be triggered and finally the apoptotic process starts [ 65 ].

In the intrinsic pathway, the failure of mitochondria results in cytochrome-C expression and then begins activations of caspases 9, 7 and 3. Another protein family having a role in the mitochondrial pathway is Bcl-2 family.

It is decided whether the cell will enter apoptotic phase as a result of the interaction between Bcl-2 family members and pro-apoptotic signal molecules. The members of the Bcl-2 family are divided into three groups:. Group that has pro-apoptotic activity including Bad, Bik, Bid, Bim, NOXA and Puma ç.

The extrinsic pathway, also called death receptor, is a mechanism which contains cell surface receptors that generate the start of apoptosis and the formation of the death-inducing signalling complex DISC that is a multi-protein complex [ 66 ].

With the connection of ligand, an adaptor protein called FADD, which brings caspase 8 to DISC, becomes a part of the activity [ 67 — 69 ]. In the activated caspase 8, either effector caspases such as caspase 3, directly activate the apoptosis pathway or intrinsic apoptosis pathway [ 70 ].

An apoptosis pathway can be activated when the endoplasmic reticulum is under stress [ 71 ]. As autophagy can block apoptosis and cell death occurs as a result of both of these events, it is believed that the regulation of these mechanisms is made in coordination.

Previously, it was considered that the same proteins control both of these processes. However, the latest data show that it is not true. p53 is a strong apoptosis inductive and it can also induce autophagy by increasing the expression of DRAM that is the direct p53 target gene [ 72 ].

In this way, it was understood that important signal pathways could increase or decrease both apoptosis and autophagy, simultaneously. In brief, central components proteins directly regulated both apoptosis and autophagy mechanisms [ 74 ]. Beclin-1 is described as a protein that can interact with Bcl-2, as well [ 74 ].

This case shows that an apoptosis regulator physically interacts with an autophagy regulator. Beclin-1 interacts with other major anti-apoptotic Bcl-2 family Bcl-xL proteins, either [ 75 ]. In the regulation of these mechanisms, depending on the presence of Bcl-2 in mitochondria and endoplasmic reticulum, in other words depending on its condition in the subcellular localization, there may be differences.

The inhibition of the autophagy with Bcl-2 function takes place only in the endoplasmic reticulum, and mitochondrial-directed Bcl-2, which is a strong inhibitor of many apoptotic stimuli, cannot inhibit autophagy [ 75 , 76 ].

Another mechanism that is able to control the autophagy via Bcl-2 was located in endoplasmic reticulum [ 77 ]. In this method, Bcl-2 blocks calcium passage in endoplasmic reticulum instead of interacting with Beclin This case causes mTOR inhibition to activate autophagy.

By this way, permission was given to Bcl-2 for autophagy inhibition instead of apoptosis inhibition in two completely different mechanisms [ 78 ]. Extrinsic death pathway, which is one of the best-described key components of apoptosis process, can control autophagy, as well. The connection of FADD adaptor protein to the ligand-dependent death receptor is a necessary step for the formation of DISC.

DISC accompanies death receptor signals with FADD, which acts as a platform in which caspase 8 dimerization and activation take place. FADD includes two protein areas, one death area and one death effector area, which interact with each other. The death area of the FADD can, unexpectedly, induce a new cell death mechanism, which includes really high levels of autophagy in normal epithelium cells.

Actually, as FADD death area does not have catalytic activity, it is possible that it induces autophagy by interacting with other proteins.

The interesting point is that autophagy response can be observed more easily when apoptosis stops and this case supports that the apoptosis and autophagy in normal epithelium cells are simultaneously induced by FADD death area [ 79 ].

These cases, mentioned above, show that the components of the apoptosis mechanism, which are regulated by intrinsic and extrinsic pathways, could control autophagy, as well. Contrary to this case, there are studies expressing that autophagy regulators control apoptosis.

These experiments, which analyse autophagic cell death originating from interferon and Atg-5, show that FADD can interact with Atg-5 [ 80 ]. The conducted study showed that this interaction ends with cell death only in a way that requires FADD and caspases, without the formation of autophagic vesicles.

From this study, the conclusion that Atg-5 can regulate extrinsic apoptosis pathway components is drawn. Another mechanism, which is about the ability of Atg-5 for regulating apoptosis, was described.

The key step in this mechanism is to provide the activation of intrinsic apoptosis pathway that can be blocked by Bcl-2 and to compose a protein form, which is translocated to mitochondria in order to start the cytochrome-C oscillation. To be able to realize this, Atg-5 must be cut by calpain.

The general importance of this mechanism is supported by the information that Atg-5 knock-down protects tumour cells against a kind of apoptosis stimulation. This case can still be complex and as the cutting of Atg-5 by calpain can cause a formation of protein, which is not able to activate autophagy, it is possible for calpain activity to increase or decrease autophagy [ 81 ].

There are some studies showing that calpain activity is necessary for autophagy, which is induced by the lack of rapamycin and amino acid [ 79 ]. Oxidative stress-mediated cell damages in the cell: Excessive ROS production can lead to damages in mitochondria, which can cause cell death or oxidative-damaged cell components are degraded by autophagy and promote cell survival.

Autophagy is a death mechanism characterized by the degradation of cellular components, and plays roles in the pathophysiology of many diseases , [ 82 , 83 ]. The damaged cellular components and contents are removed by lysosomal autophagy. In case of increasing the autophagic effect with oxidative stress or physiological stimulations, protein synthesis and energy output pathways, cell organelles and proteins are disrupted in the cells.

Also, under limited food intake, autophagy provides internal energy sources [ 82 , 83 ]. With this effect of lysosomal autophagy, cell can survive in case of oxidative stress. This survival system occurring in the cell is stimulated by stress factors such as hunger, hyperthermia and hypoxia [ 84 ].

mTOR mammalian target of rapamycin , which is a factor playing important role in autophagic activation, is a kinase signal pathway. This signal pathway is classically activated in case of hunger, hypoxia or stress condition [ 83 ].

In eukaryotic cells, the first step of the oxidative damage is antioxidant defence system and the second step is lysosomal autophagy [ 85 ]. In the second step, damaged cell components such as proteins, organelles or DNA are removed with lysosomal autophagy [ 82 ]. This defence system provides degradation of these components and cell surviving.

In the third defence step, there is type II cell death autophagy. Increased production of ROS stimulates the initiation of autophagy in association with stress signal pathways.

For this, cysteine protease Atg-4 inactivation is made with ROS accumulation in the cell. This inactivation results in Atg-4 phosphoethanolamine precursor accumulation, which is also necessary for the beginning of autophagosome [ 89 ].

In this way, under stress condition, oxidative damaged cell components are degraded by autophagy and continue its life by this way. There is a complex relation between cell death and stress adaptation [ 90 ]. The molecular relationship between cell death and autophagy has not been completely understood nowadays.

While autophagic cell death is the main cell death seen during the development, it has been reported in recent studies that apoptosis-induced cell death can be connected or related to autophagy [ 78 , 91 ].

The signal cross-talk between apoptosis and autophagy can be related to Bcl-2 gene family. Moreover, it has been shown that Bcl-2 family proteins inhibit the apoptosis and autophagy [ 75 , 92 ].

The association between the anti-apoptotic Bcl-2 protein and the autophagic Beclin-1 protein has an important role in the point of convergence of the apoptotic and autophagic cell death.

In the autophagic process, Bcl-2 protein has an important role in autophagosome formation via Beclin-1 network [ 75 ]. Also, anti-apoptotic Bcl-2 proteins inhibit the Beclindependent autophagic cell death [ 93 ]. The antioxidant effect of anti-apoptotic Bcl-2 proteins has been reported.

This anti-apoptotic protein decreases the production of reactive oxidants and inhibits the apoptotic cell death [ 94 ]. By this way, the overexpressed Bcl-2 and decreasing ROS level probably cause the repression of cytochrome-C from mitochondrion and the prevention of death cell [ 95 ].

As mentioned above, ROS creates a connection between cellular stress and the starting of autophagy, and autophagosome formation is started by stimulating Atgphosphoethanolamine precursor accumulation [ 89 ].

Endogenous and exogenous stress factors that cells are exposed to trigger the ROS production in the cell, which causes damages in cellular organelles. While autophagy is a type II cell death, it is also an alternative defence system that cell chooses to be able to survive in cells which are exposed to oxidative damage.

Autophagy can provide the removal of damaged organelles with lysosomal autophagy and ensures cell to survive. Investigations into the specific molecular targets of ROS in the autophagy pathway and the specific signalling mechanisms will be important for our understanding of biology and diseases.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Rizwan Ahmad. Open access peer-reviewed chapter Oxidative Stress and Autophagy Written By Adem Kara, Semin Gedikli, Emin Sengul, Volkan Gelen and Seckin Ozkanlar.

DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:. Choose citation style Select style Vancouver APA Harvard IEEE MLA Chicago Copy to clipboard Get citation. Choose citation style Select format Bibtex RIS Download citation.

IntechOpen Free Radicals and Diseases Edited by Rizwan Ahmad. From the Edited Volume Free Radicals and Diseases Edited by Rizwan Ahmad Book Details Order Print.

Chapter metrics overview 2, Chapter Downloads View Full Metrics. Impact of this chapter. Abstract Free radical production related with many stress factors including radiation, drugs, ageing and trauma plays a key role in cell death. Keywords oxidative stress free radicals autophagy cell death.

Apoptotic signals Caspases playing a role in apoptosis are classified in two ways: Caspases starting the apoptotic signals caspases 2, 8, 9, The members of the Bcl-2 family are divided into three groups: Anti-apoptotic group including Bcl-2, Bcl-xL and Mcl Group triggering apoptosis that includes Bax and Bak.

The molecular connections between apoptosis and autophagy As autophagy can block apoptosis and cell death occurs as a result of both of these events, it is believed that the regulation of these mechanisms is made in coordination.

Autophagy: type II cell death. References 1. Halliwell B. Free radicals and other reactive species in disease. Kara A, Akman S, Ozkanlar S, et al. Immune modulatory and antioxidant effects of melatonin in experimental periodontitis in rats. Free Radical Biology and Medicine. Kara A, Yücel A, Yücel N, Özcan H, Selli J and Ünal D.

Evaluation of the combined treatment with cisplatin and melatonin on neuroblastoma cell viability and antioxidant capacity. Journal of Experimental and Clinical Medicine. Babior BM. Phagocytes and oxidative stress. The American Journal of Medicine.

Chance B, Sies H and Boveris A. Hydroperoxide metabolism in mammalian organs. Physiological Reviews. Wagner BA, Venkataraman S and Buettner GR. The rate of oxygen utilization by cells. Filomeni G, Rotilio G and Ciriolo M. Disulfide relays and phosphorylative cascades: partners in redox-mediated signaling pathways.

Cell Death and Differentiation. Powers SK and Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Samoylenko A, Hossain JA, Mennerich D, Kellokumpu S, Hiltunen JK and Kietzmann T. Nutritional countermeasures targeting reactive oxygen species in cancer: From mechanisms to biomarkers and clinical evidence.

Antioxidants and Redox Signaling. Filomeni G, De Zio D and Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Hensley K, Robinson KA, Gabbita SP, Salsman S and Floyd RA.

Reactive oxygen species, cell signaling, and cell injury. Taverne YJ, Bogers AJ, Duncker DJ and Merkus D. Reactive oxygen species and the cardiovascular system. Oxidative Medicine and Cellular Longevity. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD and Sadoshima J.

NADPH oxidase 4 Nox4 is a major source of oxidative stress in the failing heart. Proceedings of the National Academy of Sciences. Dale DC, Boxer L and Liles WC. The phagocytes: neutrophils and monocytes. Pou S, Keaton L, Surichamorn W and Rosen GM.

Mechanism of superoxide generation by neuronal nitric-oxide synthase. The Journal of Biological Chemistry. Davis LM, Rho JM and Sullivan PG. Zuo L, Christofi FL, Wright VP, Bao S and Clanton TL.

Lipoxygenase-dependent superoxide release in skeletal muscle. Journal of Applied Physiology. Nanduri J, Vaddi DR, Khan SA, Wang N, Makerenko V and Prabhakar NR. Xanthine oxidase mediates hypoxia-inducible factor-2alpha degradation by intermittent hypoxia.

PLoS One. Chuang Y-YE, Chen Y, Chandramouli V, et al. Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Research. Hirota K, Matsui M, Murata M, et al.

Nucleoredoxin, glutaredoxin, and thioredoxin differentially regulate NF-kB, AP-1, and CREB activation in HEK cells. Biochemical and Biophysical Research Communications. Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB. Oxidative stress, redox, and the tumor microenvironment.

Semin Radiat Oncol. Kannan K and Jain SK. Oxidative stress and apoptosis. Suzuki YJ, Forman HJ and Sevanian A. Oxidants as stimulators of signal transduction. Pennisi E. Superoxides relay Ras protein's oncogenic message. Morel Y and Barouki R. Repression of gene expression by oxidative stress.

Biochemical Journal. Ushio-Fukai M, Alexander RW, Akers M and Griendling KK. p38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II role in vascular smooth muscle cell hypertrophy.

Journal of Biological Chemistry. Oxygen-dependent microbial killing by phagocytes. New England Journal of Medicine.

Jaeschke H. Mechanisms of oxidant stress-induced acute tissue injury. Experimental Biology and Medicine. Reactive oxygen intermediates, molecular damage, and aging: relation to melatonin.

Annals of the New York Academy of Sciences. Sies H. Biochemistry of oxidative stress. Angewandte Chemie International Edition in English. Kannan K, Holcombe RF, Jain SK, et al. Evidence for the induction of apoptosis by endosulfan in a human T-cell leukemic line.

Molecular and Cellular Biochemistry. Flohé L. Changing paradigms in thiology: from antioxidant defense toward redox regulation. Methods in Enzymology. Di Giacomo G, Rizza S, Montagna C and Filomeni G. Established principles and emerging concepts on the interplay between mitochondrial physiology and S- de nitrosylation: implications in cancer and neurodegeneration.

International Journal of Cell Biology. Stamler JS, Singel DJ and Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms.

Science-New York Then Washington. Casagrande S, Bonetto V, Fratelli M, et al. Glutathionylation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems. Haendeler J, Hoffmann J, Tischler V, Berk BC, Zeiher AM and Dimmeler S. Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine Nature Cell Biology.

Wang C, Li Z, Zhang Q, Zhao M and Liu W. Environmental Science and Technology. Doganlar O and Doganlar ZB. Effects of a mixture of volatile organic compounds on total DNA and gene expression of heat shock proteins in Drosophila melanogaster. Stem cell—based immunomodulation after stroke. Stroke 49, — Calio, M.

Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model. Free Radic Biol. Campbell, B. Ischaemic stroke. Primers Carbone, F. Pathophysiology and treatments of oxidative injury in ischemic stroke: focus on the phagocytic NADPH Oxidase 2.

Castets, P. Cecconi, F. The role of autophagy in mammalian development: cell makeover rather than cell death. Cell 15, — Cespedes, A. Energy-Sensing pathways in ischemia: the counterbalance between AMPK and mTORC. Chamorro, Á, Dirnagl, U.

Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. Chen, H. Chen, S. Targeting Myeloperoxidase MPO mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds.

Acta Pharmacol. Chen, K. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells ADMSC and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7, — Chen, X.

Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury. Cheng, Z. Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

Chong, Z. The rationale of targeting mammalian target of rapamycin for ischemic stroke. Cell Signal. Cunningham, C. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke.

Blood Flow Metab. Systemic conditioned medium treatment from interleukin-1 primed mesenchymal stem cells promotes recovery after stroke. Stem Cell Res. Darroudi, S. Biofactors 46, 55— Deans, R.

Mesenchymal stem cells: biology and potential clinical uses. Deng, Y. Exosomes derived from microRNAp-overexpressing bone marrow-derived mesenchymal stem cells confer neuroprotection to astrocytes following ischemic stroke via inhibition of LCN2.

Elsner, V. Therapeutic effectiveness of a single exercise session combined with WalkAide functional electrical stimulation in post-stroke patients: a crossover design study.

Feng, J. Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke. Expert Opin. Targets 21, — Ferreira, J.

Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Fu, B. Cell Longev. Furuhashi, M. New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.

GBD Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries and territories, a systematic analysis for the Global Burden of Disease Study Gelderblom, M.

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40, — George, P. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87, — Gong, X. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction.

Cell Physiol. Granger, D. Reperfusion injury and reactive oxygen species: the evolution of a concept. Guan, R. Mitophagy, a potential therapeutic target for stroke. Guan, Y. Stem Cells Int. Guo, Q. ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress. EMBO J.

Guo, Z. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. Tissue Eng. Guruswamy, R. Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions. Haupt, M. Lithium modulates miR levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation.

Cells Transl. CrossRef Full Text PubMed Abstract Google Scholar. He, H. Brain Res. He, J. Cell Dev. Hendouei, N. Alterations in oxidative stress markers and its correlation with clinical findings in schizophrenic patients consuming perphenazine, clozapine and risperidone.

Hong, Y. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. Hou, K. Bone mesenchymal stem cell-derived exosomal microRNAb-3p prevents hypoxic-ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway.

The progress of neuronal autophagy in cerebral ischemia stroke: mechanisms, roles and research methods. Hu, Z. Mechanism and regulation of autophagy and its role in neuronal diseases. Huang, B. Peptide modified mesenchymal stem cells as targeting delivery system transfected with miRb for the treatment of cerebral ischemia.

Huang, X. Exosomes derived from PEDF modified adipose-derived mesenchymal stem cells ameliorate cerebral ischemia-reperfusion injury by regulation of autophagy and apoptosis.

Cell Res. Huang, Y. Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation. Theranostics 8, — Aging Albany NY 12, — Iadecola, C. The immunology of stroke: from mechanisms to translation.

Jayaraj, R. Neuroinflammation: friend and foe for ischemic stroke. Jiang, Q. Hypoxia Inducible Factor-1alpha HIF-1alpha mediates NLRP3 inflammasome-dependent-pyroptotic and apoptotic cell death following ischemic stroke.

Neuroscience , — Jiang, T. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Jiang, Z. The role of the Golgi apparatus in oxidative stress: is this organelle less significant than mitochondria?

Jorgensen, I. Pyroptotic cell death defends against intracellular pathogens. Kalani, A. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Cell Biol. Kanazawa, M. Kang, J. Mitochondria: redox metabolism and dysfunction.

Khoshnam, S. Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents. Stroke 19, — Kim, H. Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. Biomaterials Kim, K.

Role of autophagy in endothelial damage and blood—brain barrier disruption in ischemic stroke. Koike, M. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury.

Kong, D. IL Gene modification enhances the protective effects of mesenchymal stromal cells on intestinal ischemia reperfusion injury. Kotur-Stevuljevic, J. Oxidative stress and paraoxonase 1 status in acute ischemic stroke patients.

Atherosclerosis , — Kuang, Y. Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR Vesicles 10, e The mesenchymal stem cell secretome: a new paradigm towards cell-free therapeutic mode in regenerative medicine.

Cytokine Growth Factor Rev. Lee, J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Lee, S. Enhancing the therapeutic potential of CCL2-Overexpressing mesenchymal stem cells in acute stroke. Leu, S. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats.

Li, D. Autologous transplantation of adipose-derived mesenchymal stem cells attenuates cerebral ischemia and reperfusion injury through suppressing apoptosis and inducible nitric oxide synthase. Li, W. Mesenchymal stem cells: a double-edged sword in regulating immune responses.

Cell Death Differ. Li, F. Li, X. Li, Y. Li, Z. Bone marrow-mesenchymal stem cells modulate microglial activation in the peri-infarct area in rats during the acute phase of stroke. Li, G. Cell Cycle 19, — Li, J. Mesenchymal stem cell therapy for ischemic stroke: a look into treatment mechanism and therapeutic potential.

Li, T. Effects of AMP-activated protein kinase in cerebral ischemia. Flow Metab. Cell Mol. Li, L. ROS and autophagy: interactions and molecular regulatory mechanisms.

Li, N. Interactions between mesenchymal stem cells and the immune system. Liddelow, S. Neurotoxic reactive astrocytes are induced by activated microglia.

Nature , — Liesz, A. DAMP signaling is a key pathway inducing immune modulation after brain injury. Lin, K. Xenogeneic and allogeneic mesenchymal stem cells effectively protect the lung against ischemia-reperfusion injury through downregulating the inflammatory, oxidative stress, and autophagic signaling pathways in rat.

Cell Transplant Liu, H. Cell Biochem. Liu, Y. Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia.

Autophagy 15, — Liu, J. Crosstalk between autophagy and ferroptosis and its putative role in ischemic stroke. Cell Neurosci. Chitosan hydrogel enhances the therapeutic efficacy of bone marrow—derived mesenchymal stem cells for myocardial infarction by alleviating vascular endothelial cell pyroptosis.

Liu, L. Transplantation of human umbilical cord blood mononuclear cells attenuated ischemic injury in MCAO rats via inhibition of NF-κB and NLRP3 inflammasome. Liu, N.

Expression of IL and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Liu, W. Electroacupuncture protects against ischemic stroke by reducing autophagosome formation and inhibiting autophagy through the mTORC1-ULK1 complex-Beclin1 pathway.

Lu, H. Neuroprotective effects of brain-derived neurotrophic factor and noggin-modified bone mesenchymal stem cells in focal cerebral ischemia in rats.

Stroke Cerebrovasc. Lu, M. Mesenchymal stem cell-mediated mitochondrial transfer: a therapeutic approach for ischemic stroke. Stroke Res. Lu, Y. Microthrombus-Targeting micelles for neurovascular remodeling and enhanced microcirculatory perfusion in acute ischemic stroke.

Ma, Y. The biphasic function of microglia in ischemic stroke. Manzanero, S. Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Mao, Q. Miljevic, C. Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.

Psychiatry Res. Mo, Y. Autophagy and inflammation in ischemic stroke. Nabavi, S. Novel therapeutic strategies for stroke: the role of autophagy. Lab Sci. Nakka, V.

Crosstalk between endoplasmic reticulum stress, oxidative stress, and autophagy: potential therapeutic targets for acute CNS injuries. Nazarinia, D. Neal, E. Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

Nogueira, R. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. Oh, S. Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model. Otero-Ortega, L. Role of exosomes as a treatment and potential biomarker for stroke.

Pan, Q. miRp priming enhances the effects of mesenchymal stromal cell-derived exosomes on ameliorating brain ischemic injury. Poh, L. Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke.

Brain Behav. Popa-Wagner, A. Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain?

Geroscience 41, — Pourmohammadi-Bejarpasi, Z. Qin, C. Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway.

Stroke 48, — Raffa, M. The reduction of superoxide dismutase activity is associated with the severity of neurological soft signs in patients with schizophrenia. Psychiatry 39, 52— Rana, A. Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: opportunities, challenges and future directions for cerebral stroke management.

Neuropharmacology , — Ravanan, P. Autophagy: the spotlight for cellular stress responses. Saeed, S. Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Shi, J. Pyroptosis: gasdermin-mediated programmed necrotic cell death.

Trends Biochem. Song, H. Phytother Res. Spees, J. Su, P. The role of autophagy in modulation of neuroinflammation in microglia. Sun, J. Sun, Y. Crosstalk between autophagy and cerebral ischemia.

Tadokoro, K. Bone marrow stromal cell transplantation drives molecular switch from autophagy to the ubiquitin-proteasome system in ischemic stroke mice. Tang, G.

Mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia.

Stem Cells 32, — Tang, J. Drug Des. Tobin, M. Activated mesenchymal stem cells induce recovery following stroke via regulation of inflammation and oligodendrogenesis. Heart Assoc. Tseng, N. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: the role of Miro1.

Vizoso, F. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Wang, J. Treatment targets for M2 microglia polarization in ischemic stroke. Pharmacother , — Wang, P. Autophagy in ischemic stroke. Wang, X. Wang, L. The shigella type III secretion effector IpaH4.

Cell Infect. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 8, 77— Wang, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Wen, Y. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways.

Autophagy 4, — Weston, R. Inflammatory cell infiltration after endothelininduced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. Woodall, B. Mesenchymal Stem Cell-Mediated Autophagy Inhibition. Xia, C. Selective modulation of microglia polarization to M2 phenotype for stroke treatment.

Xin, H. MicroRNA cluster miR cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA b-Overexpressing multipotent mesenchymal stromal cells.

Cell Transplant. Xiong, X. Xu, L. Exosomes derived from CircAkap7-Modified adipose-derived mesenchymal stem cells protect against cerebral ischemic injury. Xu, P. Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell Death Dis.

Xue, L. Yan, B. Theranostics 10, — Yang, B. Stem Cells Dev.