Human platelets display dysregulated sepsis-associated autophagy, induced by altered LC3 protein-protein interaction of the Vici-protein EPG5

References

• Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Critical Care Clinics. 2018;34(1):63–80.
   PubMed Web of Science ®Google Scholar
• Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590.
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348(2):138–150.
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 2006;6(11):813–822.
   PubMed Web of Science ®Google Scholar
• Dalager-Pedersen M, Sogaard M, Schonheyder HC, et al. Risk for myocardial infarction and stroke after community-acquired bacteremia: a 20-year population-based cohort study. Circulation. 2014;129(13):1387–1396.
   PubMed Web of Science ®Google Scholar
• Kaplan D, Casper TC, Elliott CG, et al. VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Chest. 2015;148(5):1224–1230.
   PubMed Web of Science ®Google Scholar
• Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004;351(25):2611–2618.
   PubMed Web of Science ®Google Scholar
• Bento CF, Renna M, Ghislat G, et al. Mammalian Autophagy: how Does It Work? Annu Rev Biochem. 2016;85(1):685–713.
   PubMedGoogle Scholar
• Shaid S, Brandts CH, Serve H, et al. Ubiquitination and selective autophagy. Cell Death Differ. 2013;20(1):21–30.
   PubMed Web of Science ®Google Scholar
• Zaffagnini G, Martens S. Mechanisms of Selective Autophagy. J Mol Biol. 2016;428(9):1714–1724.
   PubMed Web of Science ®Google Scholar
• Hurley JH, Young LN. Mechanisms of Autophagy Initiation. Annu Rev Biochem. 2017;86(1):225–244.
   PubMedGoogle Scholar
• Feng Y, He D, Yao Z, et al. The machinery of macroautophagy. Cell Res. 2014;24(1):24–41.
   PubMed Web of Science ®Google Scholar
• Suzuki H, Osawa T, Fujioka Y, et al. Structural biology of the core autophagy machinery. Curr Opin Struct Biol. 2017;43:10–17.
   PubMed Web of Science ®Google Scholar
• Wang Z, Miao G, Xue X, et al. The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes. Mol Cell. 2016;63(5):781–795.
   PubMed Web of Science ®Google Scholar
• Byrne S, Dionisi-Vici C, Smith L, et al. Vici syndrome: a review. Orphanet J Rare Dis. 2016;11(1):21.
   PubMedGoogle Scholar
• Zhao YG, Zhao H, Sun H, et al. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy. 2013;9(8):1258–1262.
   PubMed Web of Science ®Google Scholar
• Alzahrani A, Alghamdi AA, Waggass R. A Saudi Infant with Vici Syndrome: case Report and Literature Review. Open Access Maced J Med Sci. 2018;6(6):1081–1084.
   PubMedGoogle Scholar
• Lamb CA, Dooley HC, Tooze SA. Endocytosis and autophagy: shared machinery for degradation. Bioessays. 2013;35(1):34–45.
   PubMed Web of Science ®Google Scholar
• Ho J, Yu J, Wong SH, et al. Autophagy in sepsis: degradation into exhaustion? Autophagy. 2016;12(7):1073–1082.
   PubMed Web of Science ®Google Scholar
• Schmid D, Munz C. Innate and adaptive immunity through autophagy. Immunity. 2007;27(1):11–21.
   PubMed Web of Science ®Google Scholar
• Takahashi W, Watanabe E, Fujimura L, et al. Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis. Crit Care. 2013;17(4):R160.
   PubMed Web of Science ®Google Scholar
• Feng Y, Liu B, Zheng X, et al. The protective role of autophagy in sepsis. Microb Pathog. 2019;131:106–111.
   PubMed Web of Science ®Google Scholar
• Lin C-W, Lo S, Perng D-S, et al. Complete activation of autophagic process attenuates liver injury and improves survival in septic mice. Shock. 2014;41(3):241–249.
   PubMed Web of Science ®Google Scholar
• Chien W-S, Chen Y-H, Chiang P-C, et al. Suppression of autophagy in rat liver at late stage of polymicrobial sepsis. Shock. 2011;35(5):506–511.
   PubMed Web of Science ®Google Scholar
• Zhang L, Ai Y, Tsung A. Clinical application: restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis. Exp Ther Med. 2016;11(4):1159–1167.
   PubMed Web of Science ®Google Scholar
• Lo S, Yuan S-SF, Hsu C, et al. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice. Ann Surg. 2013;257(2):352–363.
   PubMed Web of Science ®Google Scholar
• Hsieh C-H, Pai P-Y, Hsueh H-W, et al. Complete induction of autophagy is essential for cardioprotection in sepsis. Ann Surg. 2011;253(6):1190–1200.
   PubMed Web of Science ®Google Scholar
• Rondina Mt, Carlisle M, Fraughton T, et al. Platelet-monocyte aggregate formation and mortality risk in older patients with severe sepsis and septic shock. J Gerontol A Biol Sci Med Sci. 2015;70(2):225–231.
   PubMed Web of Science ®Google Scholar
• Venkata C, Kashyap R, Farmer JC, et al. Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome. J Intensive Care. 2013;1(1):9.
   PubMedGoogle Scholar
• Yaguchi A, Lobo FL, Vincent J-L, et al. Platelet function in sepsis. J Thromb Haemost. 2004;2(12):2096–2102.
   PubMed Web of Science ®Google Scholar
• Hamzeh-Cognasse H, Damien P, Chabert A, et al. Platelets and Infections – Complex Interactions with Bacteria. Front Immunol. 2015;6:82.
   PubMed Web of Science ®Google Scholar
• Semple JW, Italiano JE Jr., Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–274.
   PubMed Web of Science ®Google Scholar
• Vieira-de-Abreu A, Campbell RA, Weyrich AS, et al. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol. 2012;34:5–30.
   PubMed Web of Science ®Google Scholar
• Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation. J Thromb Haemost. 2003;1(9):1897–1905.
   PubMed Web of Science ®Google Scholar
• Weyrich AS, Zimmerman GA. Platelets: signaling cells in the immune continuum. Trends Immunol. 2004;25(9):489–495.
   PubMed Web of Science ®Google Scholar
• Campbell RA, Franks Z, Bhatnagar A, et al. Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging. J Immunol. 2018;200(1):295–304.
   PubMed Web of Science ®Google Scholar
• Campbell RA, Schwertz H, Hottz ED, et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood. 2019;133(19):2013–2026.
   PubMed Web of Science ®Google Scholar
• Feng W, Chang C, Luo D, et al. Dissection of autophagy in human platelets. Autophagy. 2014;10(4):642–651.
   PubMed Web of Science ®Google Scholar
• Cao Y, Cai J, Zhang S, et al. Loss of autophagy leads to failure in megakaryopoiesis, megakaryocyte differentiation, and thrombopoiesis in mice. Exp Hematol. 2015;43(6):488–494.
   PubMed Web of Science ®Google Scholar
• You T, Wang Q, Zhu L. Role of autophagy in megakaryocyte differentiation and platelet formation. Int J Physiol Pathophysiol Pharmacol. 2016;8:28–34.
   PubMedGoogle Scholar
• Ouseph MM, Huang Y, Banerjee M, et al. Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. Blood. 2015;126(10):1224–1233.
   PubMed Web of Science ®Google Scholar
• Luo X-L, Jiang J-Y, Huang Z, et al. Autophagic regulation of platelet biology. J Cell Physiol. 2019;234(9):14483–14488.
   Web of Science ®Google Scholar
• Piano Mortari E, Folgiero V, Marcellini V, et al. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy. 2018;14(1):22–37.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222.
   PubMed Web of Science ®Google Scholar
• Li M, Khambu B, Zhang H, et al. Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity. J Biol Chem. 2013;288(50):35769–35780.
   PubMed Web of Science ®Google Scholar
• Cullup T, Kho AL, Dionisi-Vici C, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013;45(1):83–87.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Abdalla FC, Abeliovich H, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8:445–544.
   PubMed Web of Science ®Google Scholar
• Rondina MT, Schwertz H, Harris ES, et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost. 2011;9(4):748–758.
   PubMed Web of Science ®Google Scholar
• Schwertz H, Rowley JW, Schumann GG, et al. Endogenous LINE-1 (Long Interspersed Nuclear Element-1) Reverse Transcriptase Activity in Platelets Controls Translational Events Through RNA–DNA Hybrids. Arterioscler Thromb Vasc Biol. 2018;38(4):801–815.
   PubMed Web of Science ®Google Scholar
• Middleton EA, Rowley JW, Campbell RA, et al. Sepsis alters the transcriptional and translational landscape of human and murine platelets. Blood. 2019;134(12):911–923.
   PubMed Web of Science ®Google Scholar
• Cecchetti L, Tolley ND, Michetti N, et al. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood. 2011;118(7):1903–1911.
   PubMed Web of Science ®Google Scholar
• Denis MM, Tolley ND, Bunting M, et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell. 2005;122(3):379–391.
   PubMed Web of Science ®Google Scholar
• Rondina MT, Freitag M, Pluthero FG, et al. Non-genomic activities of retinoic acid receptor alpha control actin cytoskeletal events in human platelets. J Thromb Haemost. 2016;14(5):1082–1094.
   PubMed Web of Science ®Google Scholar
• Schwertz H, Tolley ND, Foulks JM, et al. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets. J Exp Med. 2006;203(11):2433–2440.
   PubMed Web of Science ®Google Scholar
• Manne BK, Bhatlekar S, Middleton EA, et al. Phospho-inositide-dependent kinase 1 regulates signal dependent translation in megakaryocytes and platelets. J Thromb Haemost. 2020;18(5):1183–1196.
   PubMed Web of Science ®Google Scholar
• Kawamoto T, Ii M, Kitazaki T, et al. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008;584(1):40–48.
   PubMed Web of Science ®Google Scholar
• Yang J, Liu H, Han S, et al. Melatonin pretreatment alleviates renal ischemia-reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling. FASEB J. 2020;34(9):12324–12337.
   PubMed Web of Science ®Google Scholar
• Zhou M, Xu W, Wang J, et al. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine. 2018;35:345–360.
   PubMed Web of Science ®Google Scholar
• Schattner M. Platelet TLR4 at the crossroads of thrombosis and the innate immune response. J Leukoc Biol. 2019;105(5):873–880.
   PubMed Web of Science ®Google Scholar
• Severin S, Ghevaert C, Mazharian A. The mitogen-activated protein kinase signaling pathways: role in megakaryocyte differentiation. J Thromb Haemost. 2010;8(1):17–26.
   PubMed Web of Science ®Google Scholar
• Wang Q, You T, Fan H, et al. Rapamycin and bafilomycin A1 alter autophagy and megakaryopoiesis. Platelets. 2017;28(1):82–89.
   PubMed Web of Science ®Google Scholar
• Liu Z-J, Italiano J Jr., Ferrer-Marin F, et al. Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes. Blood. 2011;117(15):4106–4117.
   PubMed Web of Science ®Google Scholar
• Sun R-J, Shan -N-N. Megakaryocytic dysfunction in immune thrombocytopenia is linked to autophagy. Cancer Cell Int. 2019;19(1):59.
   PubMedGoogle Scholar
• Guerra F, Bucci C. Multiple Roles of the Small GTPase Rab7. Cells. 2016;5(3):34.
   PubMed Web of Science ®Google Scholar
• Rowley JW, Oler AJ, Tolley ND, et al. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood. 2011;118(14):e101–11.
   PubMed Web of Science ®Google Scholar
• Rowley JW, Schwertz H, Weyrich AS. Platelet mRNA: the meaning behind the message. Curr Opin Hematol. 2012;19(5):385–391.
   PubMed Web of Science ®Google Scholar
• Rowley JW, Chappaz S, Corduan A, et al. Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. Blood. 2016;127(14):1743–1751.
   PubMed Web of Science ®Google Scholar
• Lindemann S, McIntyre TM, Prescott SM, et al. Platelet Signal-Dependent Protein Synthesis. In: Fitzgerald DJ, Quinn M, editors. Platelet Function: assessment, Diagnosis, and Treatment. Totowa: The Humana Press Inc; 2005. p. 151–176.
   Google Scholar
• Schwertz H, Koster S, Kahr WHA, et al. Anucleate platelets generate progeny. Blood. 2010;115(18):3801–3809.
   PubMed Web of Science ®Google Scholar
• Schwertz H, Rondina MT. Platelets and their Microparticles go hand in hand. Thromb Res. 2018;168:164–165.
   PubMed Web of Science ®Google Scholar
• Schwertz H, Rowley JW, Tolley ND, et al. Assessing protein synthesis by platelets. Methods Mol Biol. 2012;788:141–153.
   PubMedGoogle Scholar
• Schwertz H, Rowley JW, Zimmerman GA, et al. Retinoic acid receptor-α regulates synthetic events in human platelets. J Thromb Haemost. 2017;15(12):2408–2418.
   PubMed Web of Science ®Google Scholar
• Kraemer BF, Campbell RA, Schwertz H, et al. Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation. PLoS Pathog. 2011;7(11):e1002355.
   PubMed Web of Science ®Google Scholar
• Rondina M, Garraud O, Schwertz H. Platelets and bacterial infections. In: P LJ G, Kleiman NS, and Page CP, editors. Platelets in Thrombotic and Non- thrombotic Disorders - Pathophysiology, Pharmacology and Therapeutics: an Update. Cham (Switzerland): Springer; 2017. p. 1071–1084.
   Google Scholar
• Kraemer BF, Campbell RA, Schwertz H, et al. Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets. Blood. 2012;120(25):5014–5020.
   PubMed Web of Science ®Google Scholar
• Rondina MT, Garraud O. Emerging evidence for platelets as immune and inflammatory effector cells. Front Immunol. 2014;5:653.
   PubMed Web of Science ®Google Scholar
• Paul M, Hemshekhar M, Kemparaju K, et al. Aggregation is impaired in starved platelets due to enhanced autophagy and cellular energy depletion. Platelets. 2019;30(4):487–497.
   PubMed Web of Science ®Google Scholar
• Balasubramaniam S, Riley LG, Vasudevan A, et al. EPG5-Related Vici Syndrome: a Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders. JIMD Rep. 2018;42:19–29.
   PubMedGoogle Scholar
• Byrne S, Jansen L, U-King-Im J-M, et al. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain. 2016;139(3):765–781.
   PubMed Web of Science ®Google Scholar
• Hedberg-Oldfors C, Darin N, Oldfors A. Muscle pathology in Vici syndrome–A case study with a novel mutation in EPG5 and a summary of the literature. Neuromuscul Disord. 2017;27(8):771–776.
   PubMed Web of Science ®Google Scholar
• Hori I, Otomo T, Nakashima M, et al. Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Sci Rep. 2017;7(1):3552.
   PubMed Web of Science ®Google Scholar
• Lee J-H, Yu WH, Kumar A, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146–1158.
   PubMed Web of Science ®Google Scholar
• Tong J, Yan X, Yu L. The late stage of autophagy: cellular events and molecular regulation. Protein Cell. 2010;1(10):907–915.
   PubMed Web of Science ®Google Scholar
• Noda T, Fujita N, Yoshimori T. The late stages of autophagy: how does the end begin? Cell Death Differ. 2009;16(7):984–990.
   PubMed Web of Science ®Google Scholar
• Laursen MA, Larsen JB, Larsen KM, et al. Platelet function in patients with septic shock. Thromb Res. 2020;185:33–42.
   PubMed Web of Science ®Google Scholar
• Tunjungputri RN, van de Heijden W, Urbanus RT, et al. Higher platelet reactivity and platelet-monocyte complex formation in Gram-positive sepsis compared to Gram-negative sepsis. Platelets. 2017;28(6):595–601.
   PubMed Web of Science ®Google Scholar
• New J, Thomas SM. Autophagy-dependent secretion: mechanism, factors secreted, and disease implications. Autophagy. 2019;15(10):1682–1693.
   PubMed Web of Science ®Google Scholar
• Banerjee M, Huang Y, Ouseph MM, et al. Autophagy in Platelets. Methods Mol Biol. 2019;1880:511–528.
   PubMedGoogle Scholar
• Button RW, Roberts SL, Willis TL, et al. Accumulation of autophagosomes confers cytotoxicity. J Biol Chem. 2017;292(33):13599–13614.
   PubMed Web of Science ®Google Scholar
• Macintosh RL, Ryan KM. Autophagy in tumour cell death. Semin Cancer Biol. 2013;23(5):344–351.
   PubMed Web of Science ®Google Scholar
• Claushuis TAM, van Vught LA, Scicluna BP, et al. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood. 2016;127(24):3062–3072.
   PubMed Web of Science ®Google Scholar
• Assinger A, Schrottmaier WC, Salzmann M, et al. Platelets in Sepsis: an Update on Experimental Models and Clinical Data. Front Immunol. 2019;10:1687.
   PubMed Web of Science ®Google Scholar
• Kuchitsu Y, Fukuda M. Revisiting Rab7 Functions in Mammalian Autophagy: rab7 Knockout Studies. Cells. 2018;7(11):215.
   Web of Science ®Google Scholar
• Gutierrez MG, Munafo DB, Beron W, et al. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117:2687–2697.
   PubMed Web of Science ®Google Scholar
• Munford RS. Severe sepsis and septic shock: the role of gram-negative bacteremia. Annu Rev Pathol. 2006;1:467–496.
   PubMed Web of Science ®Google Scholar
• D’Atri LP, Rodriguez CS, Miguel CP, et al. Activation of toll-like receptors 2 and 4 on CD34(+) cells increases human megakaryo/thrombopoiesis induced by thrombopoietin. J Thromb Haemost. 2019;17:2196–2210.
   PubMed Web of Science ®Google Scholar
• Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
   PubMed Web of Science ®Google Scholar
• Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.
   PubMed Web of Science ®Google Scholar
• Xu Y, Jagannath C, Liu XD, et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007;27:135–144.
   PubMed Web of Science ®Google Scholar
• Dionisi Vici C, Sabetta G, Gambarara M, et al. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet. 1988;29:1–8.
   PubMed Web of Science ®Google Scholar
• Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.
   PubMed Web of Science ®Google Scholar
• Jones CA, London NR, Chen H, et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med. 2008;14:448–453.
   PubMed Web of Science ®Google Scholar
• Grubetamayer KS, Yserentant K, Herten DP. Photons in - numbers out: perspectives in quantitative fluorescence microscopy for in situ protein counting. Methods Appl Fluoresc. 2019;7:012003.
   PubMed Web of Science ®Google Scholar
• Vangindertael J, Camacho R, Sempels W, et al. An introduction to optical super-resolution microscopy for the adventurous biologist. Methods Appl Fluoresc. 2018;6:022003.
   PubMed Web of Science ®Google Scholar
• Wegel E, Gohler A, Lagerholm BC, et al. Imaging cellular structures in super-resolution with SIM, STED and Localisation Microscopy: a practical comparison. Sci Rep. 2016;6:27290.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Yoshimori T. How to interpret LC3 immunoblotting. Autophagy. 2007;3:542–545.
   PubMed Web of Science ®Google Scholar
• Rubinsztein DC, Cuervo AM, Ravikumar B, et al. In search of an “autophagomometer”. Autophagy. 2009;5:585–589.
   PubMed Web of Science ®Google Scholar
• Kahr WH, Hinckley J, Li L, et al. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nat Genet. 2011;43:738–740.
   PubMed Web of Science ®Google Scholar
• Soderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006;3:995–1000.
   PubMed Web of Science ®Google Scholar
• Ono Y, Maejima Y, Saito M, et al. TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice. Sci Rep. 2020;10:694.
   PubMed Web of Science ®Google Scholar
• Takashima K, Matsunaga N, Yoshimatsu M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157:1250–1262.
   PubMed Web of Science ®Google Scholar