The Harms and Benefits of Inflammatory and Immune Responses in Vascular Disease
2006; Lippincott Williams & Wilkins; Volume: 37; Issue: 2 Linguagem: Inglês
10.1161/01.str.0000200561.69611.f8
ISSN1524-4628
AutoresÁngel Chamorro, John M. Hallenbeck,
Tópico(s)Systemic Lupus Erythematosus Research
ResumoHomeStrokeVol. 37, No. 2The Harms and Benefits of Inflammatory and Immune Responses in Vascular Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBThe Harms and Benefits of Inflammatory and Immune Responses in Vascular Disease Ángel Chamorro and John Hallenbeck Ángel ChamorroÁngel Chamorro From the Stroke Unit (A.C.), Institute of Clinical Neurosciences, Hospital Clínic; and the Stroke Branch (J.H.), National Institute of Neurological Disorders and Stroke/National Institutes of Health. and John HallenbeckJohn Hallenbeck From the Stroke Unit (A.C.), Institute of Clinical Neurosciences, Hospital Clínic; and the Stroke Branch (J.H.), National Institute of Neurological Disorders and Stroke/National Institutes of Health. Originally published12 Jan 2006https://doi.org/10.1161/01.STR.0000200561.69611.f8Stroke. 2006;37:291–293Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 12, 2006: Previous Version 1 Accumulating experimental evidence strongly supports a role for inflammatory, innate immune and adaptive immune mechanisms in many facets of vascular disease.1 This brief review will highlight recently published insights into inflammation and immune system involvement in stroke biomarker identification, atherosclerosis, abdominal aortic aneurysm (AAA) formation, thrombosis, ischemic tolerance, progression of ischemic brain injury, and peristroke infections.Inflammatory Biomarkers and StrokeInflammation plays a role in the genesis of brain ischemia and inflammatory processes and may facilitate serious and life-threatening complications in stroke patients.2 However, efforts to disentangle good from bad effects of inflammation in cerebrovascular disease reveal frequent discrepancies between preclinical and clinical data. A clinical goal for several decades has been the identification of reliable inflammatory biomarkers of impending stroke in asymptomatic subjects and clinical prognosis in stroke patients. So far, most markers have shown moderate utility at the bedside as the result of low sensitivity and specificity. The list of biomarkers includes high-sensitivity C-reactive protein (hsCRP), fibrinogen, serum amyloid A, matrix metalloproteinase (MMP)-9, P-selectin, sCD40L, myeloperoxidase, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-8. Novel markers evaluated in 2005 are PARK7,3 nucleoside diphosphate kinase A (NDKA),3 and adiponectin.4 PARK7 is a redox-sensitive molecular chaperone activated by oxidative stress; it increases within 30 minutes to 3 hours of stroke onset. Sensitivities are of 54% to 91%, for PARK7, and 70% to 90%, for NDKA, and specificities are 80% to 97%, for PARK7, and 90% to 97%, for NDKA. Adiponectin is an adipocytokine with anti-inflammatory and antiatherogenic properties that correlates inversely with infarction volume and neurological impairment in acute stroke patients.4Recent preclinical data showed that the administration of anti-TNF-α neutralizing mAb treatment in rats decreased upregulation of TNF-α in parallel with reduced infarct volume and cerebral edema after transient focal ischemia.5 However, TNF-α plasma levels did not predict the risk of edema-related malignant cerebral infarction in patients.6 Similarly, clinical stroke studies suggested that higher levels of VCAM-1 were predictors of bad outcome, but anti-VCAM-1 therapy showed no significant protection in stroked rats.7The population-based Rotterdam Scan Study8 illustrates that the study of biomarkers provides a deeper understanding of cerebrovascular disease; higher levels of hsCRP identified the presence and progression of white matter disease on MRI. Also, higher plasma levels of hsCRP, IL-6, or ICAM-1 were observed in Japanese9 and Austrian10 subjects with asymptomatic white matter infarctions. These studies reinforce the role of inflammation in small-vessel disease, a view also stressed in a recent case-control study in which a Gly174Cys polymorphism of the IL-6 gene correlated with lacunar stroke only.11 Future studies will assess additional biomarkers singly and in combination as predictors of stroke occurrence and prognosis.Immune System and AtherosclereosisFrom modern approaches to its molecular pathobiology, atherosclerosis emerges as perhaps the most common chronic inflammatory disease. Chronic exposure to low-density lipoprotein (LDL) modified by oxidation or enzymatic attack can activate endothelial cells and cells in the underlying intima to express adhesion molecules and inflammatory genes that promote monocyte accumulation and macrophage differentiation in developing atherosclerotic plaques.12 Pattern recognition receptors play a key role in this innate immune response that leads to local inflammation and both innate and adaptive immune responses. Major scavenger receptors, CD36 originally identified as a platelet integral membrane glycoprotein receptor for thrombospondin-1 and scavenger receptor A family members, bind and internalize modified LDL and activate macrophages.13 CD36 null and scavenger receptor A null gene modifications show robust suppression of atherosclerosis in apoE−/− and LDL receptor−/− mice.13 Toll-like receptors (TLR) discovered in 199714 as sharing homology with the toll receptor that is essential for dorsoventral patterning and antifungal immunity in Drosophila15 initiate and orchestrate inflammatory and immune responses in the plaque. TLR signal transduction in response to endogenous ligands released or formed under conditions of cellular stress (alarm or danger signals) or pathogen-associated molecular patterns can turn on immune and inflammatory responses.16 Of 11 known TLRs, genetic deficiency of TLR4 or TLR2 has been shown to reduce development of atherosclerosis in murine models.17 Also, the Asp299Gly TLR4 polymorphism, which attenuates TLR4 receptor signaling, is associated with a decreased risk of atherosclerosis in clinical studies.18 Novel approaches to atheroprotection involve several forms of immunomodulation. Based on observations indicating that native IgM antioxidized LDL antibodies reduce circulating levels of oxidized LDL, a series of oxidized LDL immunization studies in animal models of atherosclerosis were performed. Production of IgG antibodies to oxidized LDL and clear-cut reductions in plaque burden were noted in these studies.19 More recently, detailed molecular characterization of the complex oxidized LDL antigen has identified 2 epitopes that are atherogenic, malondialdehyde-ApoB-100 peptide sequences and oxidized phospholipids containing a phosphorylcholine head group. Immunization with these defined antigens reduces atherosclerosis in murine models, and future clinical studies are expected. Also, mucosal tolerization to mycobacterial heat shock protein 65, a molecular mimic of native heat shock protein 60, by nasal or oral administration generates regulatory T cells (Treg) that suppress local inflammatory and immune reactions and decrease development of atherosclerosis in preclinical models.19Immune System and AAAInterestingly, although stenotic atherosclerotic lesions are predominantly associated with Th1 cytokine profiles, recent evidence implicates Th2-predominant inflammation in AAA formation.20 In a murine allografted aorta aneurysm model, interferon-γ receptor–deficient (GRKO) hosts (with a consequent Th2 immune deviation) developed severe AAA formation associated with augmented elastolytic activity primarily attributable to expression of increased matrix metalloproteinase 12 (MMP-12). Allografts in GRKO recipients treated with anti–IL-4 antibody or allografts in GRKO hosts that were congenitally deficient in IL-4 did not develop AAA. This identifies IL-4, a Th2 cytokine, as an important stimulus for AAA formation.20Inflammation and ThrombosisInflammation and coagulation intermingle in many disease states; better understanding of this relationship might result in the development of safer and more efficacious drugs for acute treatment and secondary prevention of stroke. A major player in this network is tissue factor (TF), an extrinsic coagulation pathway activator in humans with cellular and soluble subtypes.21 In a recent study,22 soluble TF was expressed and released from human endothelial cells in response to TNF-α and IL-6, a finding confirmed in another study that showed thrombus formation was driven primarily by TF derived from blood vessel wall instead of leukocytes.23Thrombomodulin (TM) has shown novel anti-inflammatory properties in addition to its ability to activate Protein C. Abeyama and colleagues have identified an N-terminal lectin-like domain (D1) of TM with potent anti-inflammatory properties that include the binding and inhibition of high mobility group box 1 protein.24 The latter has powerful cytokine-like activity mediated by the receptor for advanced glycosylation end products, thus suggesting possible therapeutic potential of D1 of TM.CD40/CD40L is a membrane glycoprotein belonging to the TNF receptor superfamily. Its expression is increased in platelets and monocytes of patients with acute stroke, an effect that can facilitate the production of proinflammatory cytokines. In a model of focal ischemia/reperfusion, mice deficient in either CD40 or CD40L had less leukocyte and platelet recruitment, reduced brain injury, and less endothelial barrier dysfunction than wild-type animals.25 Further research on the therapeutic value of molecules targeting CD40/CD40L in patients with acute stroke would seem reasonable.Immune System and Ischemic ToleranceBased on the capacity of proinflammatory innate immune system mediators to induce cross-tolerance to ischemia, a novel unifying concept of ischemic tolerance that involves TLR function has been proposed.26 Preconditioning with lipopolysaccharide, a TLR4 ligand, and downstream cytokine effector molecules, IL-1 and TNF, has been shown to confer robust cytoprotection in subsequent severe brain ischemia. Activation of the TLR4 signal transduction cascade has been shown to upregulate multiple feedback inhibitors that include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines. Generation of feedback inhibition of TLR signal transduction by a preconditioning stress exposure that activates TLR receptors may be important in ischemic tolerance.Immune System and Stroke ProgressionThe literature on the cytoprotective mechanisms of immunomodulation by mucosal tolerization of locally expressed antigens has been recently extended.27 Nasal vaccination with myelin oligodendrocyte (MOG) glycoprotein to prime Treg with a brain-specific antigen targeted IL-10-secreting CD4+ Treg to ischemic brain in a transient middle cerebral artery occlusion model. The observed reduction in ischemic brain damage was associated with a local increase in IL-10, reduction in interferon-γ and reduced accumulation of CD11b+ cells (macrophages, neutrophils). Nasal MOG vaccination was ineffectual in IL-10−/− mice; adoptive transfer of CD4+ MOG-specific Treg from Wt mice reduced infarct volume in contrast to Treg from IL-10−/− donors. Thus, IL-10-secreting CD4+ Treg reduce injury after stroke.Infection and StrokeInfections may cause stroke and frequently complicate the clinical course of that disease; the mechanisms and best treatment response are being studied. Patients with stroke and preceding infection reveal a significantly increased proportion of platelet-leukocyte aggregates and higher P-selectin expression by flow cytometry assay compared with noninfected stroke patients.28 Blocking ICAM like P-selectin or the P-selectin glycoprotein ligand may provide clinical benefits. The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) Trial provides insights on the management of infection in acute stroke and highlights the relevance of appropriate antibiotic selection. Prophylactic levofloxacin (500 mg/100 mL/d for 3 days) was found not better than optimal care to prevent infections, and the drug lessened clinical recovery rates.29 Based on current knowledge, antibiotics that deserve clinical testing in acute stroke are minocycline,30 moxifloxacin,31 and ceftriaxone.32FootnotesCorrespondence to Ángel Chamorro, Stroke Unit, Institute of Clinical Neurosciences, Hospital Clinic, 170 Villarroel, 08036 Barcelona, Spain. E-mail [email protected] References 1 Hallenbeck JM, Hansson GK, Becker KJ. Immunology of ischemic vascular disease: plaque to attack. Trends Immunol. 2005; 26: 550–556.CrossrefMedlineGoogle Scholar2 Chamorro A. Role of inflammation in stroke and atherothrombosis. Cerebrovasc Dis. 2004; 17 (Suppl 3): 1–5.Google Scholar3 Allard L, Burkhard PR, Lescuyer P, Burgess JA, Walter N, Hochstrasser DF, Sanchez JC. PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke. Clin Chem. 2005; 51: 2043–2051.CrossrefMedlineGoogle Scholar4 Efstathiou SP, Tsioulos DI, Tsiakou AG, Gratsias YE, Pefanis AV, Mountokalakis TD. Plasma adiponectin levels and five-year survival after first-ever ischemic stroke. Stroke. 2005; 36: 1915–1919.LinkGoogle Scholar5 Hosomi N, Ban CR, Naya T, Takahashi T, Guo P, Song XY, Kohno M. Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2005; 25: 959–967.CrossrefMedlineGoogle Scholar6 Serena J, Blanco M, Castellanos M, Silva Y, Vivancos J, Moro MA, Leira R, Lizasoain I, Castillo J, Davalos A. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke. 2005; 36: 1921–1926.LinkGoogle Scholar7 Justicia C, Martin A, Rojas S, Gironella M, Cervera A, Panes J, Chamorro A, Planas AM. Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab. 2005. In press.Google Scholar8 van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation. 2005; 112: 900–905.LinkGoogle Scholar9 Hoshi T, Kitagawa K, Yamagami H, Furukado S, Hougaku H, Hori M. Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction. Stroke. 2005; 36: 768–772.LinkGoogle Scholar10 Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke. 2005; 36: 1410–1414.LinkGoogle Scholar11 Chamorro A, Revilla M, Obach V, Vargas M, Planas AM. The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis. 2005; 19: 91–95.CrossrefMedlineGoogle Scholar12 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.CrossrefMedlineGoogle Scholar13 Greaves DR, Gordon S. Thematic review series: the immune system and atherogenesis. Recent insights into the biology of macrophage scavenger receptors. J Lipid Res. 2005; 46: 11–20.CrossrefMedlineGoogle Scholar14 Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997; 388: 394–397.CrossrefMedlineGoogle Scholar15 Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996; 86: 973–983.CrossrefMedlineGoogle Scholar16 Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296: 301–305.CrossrefMedlineGoogle Scholar17 Tobias P, Curtiss LK. Thematic review series: The immune system and atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis. J Lipid Res. 2005; 46: 404–411.CrossrefMedlineGoogle Scholar18 Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002; 347: 185–192.CrossrefMedlineGoogle Scholar19 Nilsson J, Hansson GK, Shah PK. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler Thromb Vasc Biol. 2005; 25: 18–28.LinkGoogle Scholar20 Shimizu K, Shichiri M, Libby P, Lee RT, Mitchell RN. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. J Clin Invest. 2004; 114: 300–308.CrossrefMedlineGoogle Scholar21 Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med. 2003; 9: 458–462.CrossrefMedlineGoogle Scholar22 Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res. 2005; 96: 1233–1239.LinkGoogle Scholar23 Day SM, Reeve JL, Pedersen B, Farris DM, Myers DD, Im M, Wakefield TW, Mackman N, Fay WP. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood. 2005; 105: 192–198.CrossrefMedlineGoogle Scholar24 Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, Uchimura T, Ida N, Yamazaki Y, Yamada S, Yamamoto Y, Yamamoto H, Iino S, Taniguchi N, Maruyama I. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005; 115: 1267–1274.CrossrefMedlineGoogle Scholar25 Ishikawa M, Vowinkel T, Stokes KY, Arumugam TV, Yilmaz G, Nanda A, Granger DN. CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion. Circulation. 2005; 111: 1690–1696.LinkGoogle Scholar26 Kariko K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokine signaling–a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab. 2004; 24: 1288–1304.CrossrefMedlineGoogle Scholar27 Frenkel D, Huang Z, Maron R, Koldzic DN, Moskowitz MA, Weiner HL. Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. J Neurol Sci. 2005; 233: 125–132.CrossrefMedlineGoogle Scholar28 Zeller JA, Lenz A, Eschenfelder CC, Zunker P, Deuschl G. Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler Thromb Vasc Biol. 2005; 25: 1519–1523.LinkGoogle Scholar29 Chamorro A, Horcajada JP, Obach V, Vargas M, Revilla M, Torres F, Cervera A, Planas AM, Mensa J. The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial. Stroke. 2005; 36: 1495–1500.LinkGoogle Scholar30 Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004; 4: 7.CrossrefMedlineGoogle Scholar31 Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk HD, Dirnagl U, Meisel A. Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke. 2004; 35: 2–6.LinkGoogle Scholar32 Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005; 433: 73–77.CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Xu Y, Wen K, Liu A, Wang X, Xu H and Wen H (2023) Efficacy of curculigoside in protecting against ischemic brain injury through regulation of oxidative stress and NF-κB and PI3K/Akt expression, Journal of Ethnopharmacology, 10.1016/j.jep.2022.115804, 301, (115804), Online publication date: 1-Jan-2023. Li W, Shao C, Zhou H, Du H, Chen H, Wan H and He Y (2022) Multi-omics research strategies in ischemic stroke: A multidimensional perspective, Ageing Research Reviews, 10.1016/j.arr.2022.101730, 81, (101730), Online publication date: 1-Nov-2022. Wilkinson C, Katsanos A, Sander N, Kung T, Colbourne F, Shoamanesh A and Sirén A (2022) Colchicine pre-treatment and post-treatment does not worsen bleeding or functional outcome after collagenase-induced intracerebral hemorrhage, PLOS ONE, 10.1371/journal.pone.0276405, 17:10, (e0276405) Scott X, Chen S, Hadad R, Yavagal D, Peterson E, Starke R, Dietrich W, Keane R and de Rivero Vaccari J (2022) Cohort study on the differential expression of inflammatory and angiogenic factors in thrombi, cerebral and peripheral plasma following acute large vessel occlusion stroke, Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X221106956, 42:10, (1827-1839), Online publication date: 1-Oct-2022. Cardoso F, Salehpour F, Coimbra N, Gonzalez-Lima F and Gomes da Silva S (2022) Photobiomodulation for the treatment of neuroinflammation: A systematic review of controlled laboratory animal studies, Frontiers in Neuroscience, 10.3389/fnins.2022.1006031, 16 Zhao Y, Zhang S, Yi Y, Qu T, Gao S, Lin Y and Zhu H (2022) Neutrophil-to-lymphocyte ratio as a predictor for cardiovascular diseases: a cohort study in Tianjin, China, Journal of Human Hypertension, 10.1038/s41371-022-00724-7 Ballerini C, Njamnshi A, Juliano S, Kalaria R, Furlan R and Akinyemi R (2022) Non-Communicable Neurological Disorders and Neuroinflammation, Frontiers in Immunology, 10.3389/fimmu.2022.834424, 13 Shah D, Rajan R, Batra A, Anand I, Saraf A and Sethi P (2022) Evaluation of Neutrophil-to-Lymphocyte Ratio Among Ischemic Stroke Subtypes and Stroke Severity, Journal of Stroke Medicine, 10.1177/25166085221095183, 5:1, (40-47), Online publication date: 1-Jun-2022. Yan J, Li A, Chen X, Cao K, Song M, Guo S, Li Z, Huang S, Li Z, Xu D, Wang Y, Dai X, Feng D, Huo Y, He J and Xu Y (2022) Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells, Pharmacological Research, 10.1016/j.phrs.2022.106208, 179, (106208), Online publication date: 1-May-2022. Fang X, Ding S, Du X, Wang J and Li X (2022) Ferroptosis—A Novel Mechanism With Multifaceted Actions on Stroke, Frontiers in Neurology, 10.3389/fneur.2022.881809, 13 Majumder D, Debnath M, Sharma K, Shekhawat S, Prasad G, Maiti D and Ramakrishna S Olive Oil Consumption can Prevent Non-communicable Diseases and COVID-19: A Review, Current Pharmaceutical Biotechnology, 10.2174/1389201022666210412143553, 23:2, (261-275) Bazina Martinović A, Merkler A, Ćelić I, Starčević K, Šimić M, Karmelić I, Poljaković Z, Kalinić D and Sertić J (2022) Moderating effect of ppar-γ on the association of c-reactive protein and ischemic stroke in patients younger than 60, Gene, 10.1016/j.gene.2021.146029, 809, (146029), Online publication date: 1-Jan-2022. Jurcau A and Simion A (2021) Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies, International Journal of Molecular Sciences, 10.3390/ijms23010014, 23:1, (14) Kwon H and Kim H (2021) Recent aspects of ketogenic diet in neurological disorders, Acta Epileptologica, 10.1186/s42494-021-00053-1, 3:1, Online publication date: 1-Dec-2021. Sun Y, Lu J, Zheng D, Qian J, Zhang H, Xing D, Rong F, Cao Y, Liu C and You S (2020) Predictive value of monocyte to HDL cholesterol ratio for stroke-associated pneumonia in patients with acute ischemic stroke, Acta Neurologica Belgica, 10.1007/s13760-020-01418-y, 121:6, (1575-1581), Online publication date: 1-Dec-2021. Peng Z, Ji D, Qiao L, Chen Y and Huang H (2021) Autophagy Inhibition by ATG3 Knockdown Remits Oxygen–Glucose Deprivation/Reoxygenation-Induced Injury and Inflammation in Brain Microvascular Endothelial Cells, Neurochemical Research, 10.1007/s11064-021-03423-w, 46:12, (3200-3212), Online publication date: 1-Dec-2021. Dolgushin I, Zaripova Z and Karpova M (2021) The role of neutrophils in the pathogenesis of ischemic stroke, Bulletin of Siberian Medicine, 10.20538/1682-0363-2021-3-152-160, 20:3, (152-160) Xu S, Bian H, Shu S, Xia S, Gu Y, Zhang M, Xu Y and Cao X (2021) AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke, CNS Neuroscience & Therapeutics, 10.1111/cns.13699, 27:10, (1224-1237), Online publication date: 1-Oct-2021. Nalamolu K, Challa S, Fornal C, Grudzien N, Jorgenson L, Choudry M, Smith N, Palmer C, Pinson D, Klopfenstein J and Veeravalli K (2021) Attenuation of the Induction of TLRs 2 and 4 Mitigates Inflammation and Promotes Neurological Recovery After Focal Cerebral Ischemia, Translational Stroke Research, 10.1007/s12975-020-00884-z, 12:5, (923-936), Online publication date: 1-Oct-2021. Wang L, Chen P and Xiao W (2021) β-hydroxybutyrate as an Anti-Aging Metabolite, Nutrients, 10.3390/nu13103420, 13:10, (3420) Deng Q, Huang S, Li S, Zhai Q, Zhang Q, Wang Z, Chen W, Sun H, Lu M and Zhou J (2021) Inflammatory Factors as Potential Markers of Early Neurological Deterioration in Acute Ischemic Stroke Patients Receiving Endovascular Therapy – The AISRNA Study, Journal of Inflammation Research, 10.2147/JIR.S317147, Volume 14, (4399-4407) Chu M, Teng J, Guo L, Wang Y, Zhang L, Gao J and Liu L (2021) Mild hyperhomocysteinemia induces blood–brain barrier dysfunction but not neuroinflammation in the cerebral cortex and hippocampus of wild-type mice, Canadian Journal of Physiology and Pharmacology, 10.1139/cjpp-2020-0507, 99:9, (847-856), Online publication date: 1-Sep-2021. Huang X, Li F, Yang T, Li H, Liu T, Wang Y, Xu M, Yan L, Zhang Y, Wang Y, Fu L and Geng D (2021) Increased serum interleukin-34 levels as a novel diagnostic and prognostic biomarker in patients with acute ischemic stroke, Journal of Neuroimmunology, 10.1016/j.jneuroim.2021.577652, 358, (577652), Online publication date: 1-Sep-2021. Wu Y, Li J, Shou J, Zhang W and Chen C (2021) Diverse functions and mechanisms of regulatory T cell in ischemic stroke, Experimental Neurology, 10.1016/j.expneurol.2021.113782, 343, (113782), Online publication date: 1-Sep-2021. Su J, Luo M, Liang N, Gong S, Chen W, Huang W, Tian Y and Wang A (2021) Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases, Frontiers in Pharmacology, 10.3389/fphar.2021.745061, 12 Mahjoubin-Tehran M, Rezaei S, Jesmani A, Birang N, Morshedi K, Khanbabaei H, Khan H, Piranviseh A, Nejati M, Aschner M and Mirzaei H (2021) New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2021.111753, 140, (111753), Online publication date: 1-Aug-2021. Qi Z, Zhao Y, Su Y, Cao B, Yang J and Xing Q (2021) Serum Extracellular Vesicle–Derived miR-124-3p as a Diagnostic and Predictive Marker for Early-Stage Acute Ischemic Stroke, Frontiers in Molecular Biosciences, 10.3389/fmolb.2021.685088, 8 Shen L, Yang J and Tang Y (2021) Predictive Values of the SeLECT Score and IL-1β for Post-Stroke Epilepsy, Neuropsychiatric Disease and Treatment, 10.2147/NDT.S324271, Volume 17, (2465-2472) Rahman Z and Dandekar M (2021) Crosstalk between gut microbiome and immunology in the management of ischemic brain injury, Journal of Neuroimmunology, 10.1016/j.jneuroim.2021.577498, 353, (577498), Online publication date: 1-Apr-2021. Gao Q, Tian D, Han Z, Lin J, Chang Z, Zhang D, Ma D and Li X (2021) Network Pharmacology and Molecular Docking Analysis on Molecular Targets and Mechanisms of Buyang Huanwu Decoction in the Treatment of Ischemic Stroke, Evidence-Based Complementary and Alternative Medicine, 10.1155/2021/8815447, 2021, (1-15), Online publication date: 28-Feb-20
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