TBI-related deaths (2019) Centers for Disease Control and Prevention, https://www.cdc.gov/traumaticbraininjury/data/index.html. Accessed 15 April 2020,

GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators (2019) Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the global burden of Disease Study 2016. Lancet Neurol 18(1):56–87. https://doi.org/10.1016/S1474-4422(18)30415-0

Article  Google Scholar 

Lee HF, Chen CH, Chang CF (2020) A preclinical controlled cortical impact model for traumatic hemorrhage contusion and neuroinflammation. J Vis Exp 16010.3791/61393

Omer M, Posti JP, Gissler M, Merikukka M, Bärnighausen T, Wilson ML (2022) Birth order and pediatric traumatic brain injury. Sci Rep 12(1):14451. https://doi.org/10.1038/s41598-022-18742-3

Article  CAS  PubMed  PubMed Central  Google Scholar 

Narouiepour A, Ebrahimzadeh-Bideskan A, Rajabzadeh G, Gorji A, Negah SS (2022) Neural stem cell therapy in conjunction with curcumin loaded in niosomal nanoparticles enhanced recovery from traumatic brain injury. Sci Rep 12(1):3572. https://doi.org/10.1038/s41598-022-07367-1

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hegdekar N, Lipinski MM, Sarkar C (2021) N-Acetyl-L-leucine improves functional recovery and attenuates cortical cell death and neuroinflammation after traumatic brain injury in mice. Sci Rep 11(1):9249. https://doi.org/10.1038/s41598-021-88693-8

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nikolian VC, Dekker SE, Bambakidis T, Higgins GA, Dennahy IS, Georgoff PE, Williams AM, Andjelkovic AV, Alam HB (2018) Improvement of blood-brain Barrier Integrity in Traumatic Brain Injury and hemorrhagic shock following treatment with Valproic Acid and Fresh Frozen plasma. Crit Care Med 46(1):e59–e66. https://doi.org/10.1097/CCM.0000000000002800

Article  PubMed  Google Scholar 

Jahanbazi Jahan-Abad A, Sahab Negah S, Hosseini Ravandi H, Ghasemi S, Borhani-Haghighi M, Stummer W, Gorji A, Khaleghi Ghadiri M (2018) Human neural Stem/Progenitor cells derived from epileptic human brain in a self-assembling peptide Nanoscaffold Improve Traumatic Brain Injury in rats. Mol Neurobiol 55(12):9122–9138. https://doi.org/10.1007/s12035-018-1050-8

Article  CAS  PubMed  Google Scholar 

Luo ML, Pan L, Wang L, Wang HY, Li S, Long ZY, Zeng L, Liu Y (2019) Transplantation of NSCs promotes the recovery of cognitive functions by regulating neurotransmitters in rats with traumatic brain Injury. Neurochem Res 44(12):2765–2775. https://doi.org/10.1007/s11064-019-02897-z

Article  CAS  PubMed  Google Scholar 

Zhang Y, Zhang Y, Chopp M, Zhang ZG, Mahmood A, Xiong Y (2020) Mesenchymal stem cell-derived Exosomes improve functional recovery in rats after traumatic Brain Injury: a dose-response and therapeutic window study. Neurorehabil Neural Repair 34(7):616–626. https://doi.org/10.1177/1545968320926164

Article  PubMed  PubMed Central  Google Scholar 

Lin SJ, Cao LX, Cheng SB, Dai QF, Lin JH, Pu L, Chen WH, Zhang YJ, Chen SL, Zhang YM (2018) Effect of acupuncture on the TLR2/4-NF-κB signalling pathway in a rat model of traumatic brain injury. Acupunct Med 36(4):247–253. https://doi.org/10.1136/acupmed-2017-011472

Article  PubMed  PubMed Central  Google Scholar 

Begemann M, Leon M, van der Horn HJ, van der Naalt J, Sommer I (2020) Drugs with anti-inflammatory effects to improve outcome of traumatic brain injury: a meta-analysis. Sci Rep 10(1):16179. https://doi.org/10.1038/s41598-020-73227-5

Article  CAS  PubMed  PubMed Central  Google Scholar 

Oliveira SR, Dionísio PA, Brito H, Franco L, Rodrigues CAB, Guedes RC, Afonso CAM, Amaral JD, Rodrigues CMP (2018) Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation. Cell Death Discov 4:10. https://doi.org/10.1038/s41420-018-0067-0

Article  CAS  PubMed  Google Scholar 

He S, Wang X (2018) RIP kinases as modulators of inflammation and immunity. Nat Immunol 19(9):912–922. https://doi.org/10.1038/s41590-018-0188-x

Article  CAS  PubMed  Google Scholar 

Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, Qi D, Lin C, Tong R, Wang Y (2019) RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (review). Int J Mol Med 44(3):771–786. https://doi.org/10.3892/ijmm.2019.4244

Article  CAS  PubMed  PubMed Central  Google Scholar 

Khan N, Lawlor KE, Murphy JM, Vince JE (2014) More to life than death: molecular determinants of necroptotic and non-necroptotic RIP3 kinase signaling. Curr Opin Immunol 26:76–89. https://doi.org/10.1016/j.coi.2013.10.017

Article  CAS  PubMed  Google Scholar 

Jayakumar A, Bothwell ALM (2019) RIPK3-Induced inflammation by I-MDSCs promotes intestinal tumors. Cancer Res 79(7):1587–1599. https://doi.org/10.1158/0008-5472.CAN-18-2153

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu ZM, Chen QX, Chen ZB, Tian DF, Li MC, Wang JM, Wang L, Liu BH, Zhang SQ, Li F, Ye H, Zhou L (2018) RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: dependent on AMPK pathway. Biochem Biophys Res Commun 499(2):112–119. https://doi.org/10.1016/j.bbrc.2018.02.150

Article  CAS  PubMed  Google Scholar 

Zhang Y, Li M, Li X, Zhang H, Wang L, Wu X, Zhang H, Luo Y (2020) Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell Death Dis 11(7):565. https://doi.org/10.1038/s41419-020-02770-w

Article  CAS  PubMed  PubMed Central  Google Scholar 

Guo C, Fu R, Zhou M, Wang S, Huang Y, Hu H, Zhao J, Gaskin F, Yang N, Fu SM (2019) Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation. J Autoimmun 103:102286. https://doi.org/10.1016/j.jaut.2019.05.014

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ma F, Zhu Y, Chang L, Gong J, Luo Y, Dai J, Lu H (2022) Hydrogen sulfide protects against ischemic heart failure by inhibiting RIP1/RIP3/MLKL-mediated necroptosis. Physiol Res 71(6):771–781. https://doi.org/10.33549/physiolres.934905

Article  CAS  PubMed  PubMed Central  Google Scholar 

Duan C, Xu X, Lu X, Wang L, Lu Z (2022) RIP3 knockdown inhibits necroptosis of human intestinal epithelial cells via TLR4/MyD88/NF-κB signaling and ameliorates murine colitis. BMC Gastroenterol 22(1):137. https://doi.org/10.1186/s12876-022-02208-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dionísio PA, Oliveira SR, Gaspar MM, Gama MJ, Castro-Caldas M, Amaral JD, Rodrigues CMP (2019) Ablation of RIP3 protects from dopaminergic neurodegeneration in experimental Parkinson’s disease. Cell Death Dis 10(11):840. https://doi.org/10.1038/s41419-019-2078-z

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang Y, Song M, Zhou P, Wang J, Zheng J, Xu H (2021) TNFAIP3-upregulated RIP3 exacerbates acute pancreatitis via activating NLRP3 inflammasome. Int Immunopharmacol 100:108067. https://doi.org/10.1016/j.intimp.2021.108067

Article  CAS  PubMed  Google Scholar 

Chen D, Gregory AD, Li X, Wei J, Burton CL, Gibson G, Scott SJ, St Croix CM, Zhang Y, Shapiro SD (2021) RIP3-dependent necroptosis contributes to the pathogenesis of chronic obstructive pulmonary disease. JCI Insight 6(12):e144689. https://doi.org/10.1172/jci.insight.144689

Article  PubMed  PubMed Central  Google Scholar 

Wei S, Zhou H, Wang Q, Zhou S, Li C, Liu R, Qiu J, Shi C, Lu L (2019) RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1-TLR4-NF-κB pathway in macrophages. FASEB J 33(10):11180–11193. https://doi.org/10.1096/fj.201900752R

Article  CAS  PubMed  Google Scholar 

Ma D, Wang X, Liu X, Li Z, Liu J, Cao J, Wang G, Guo Y, Zhao S (2022) Macrophage infiltration initiates RIP3/MLKL-Dependent necroptosis in Paclitaxel-Induced Neuropathic Pain. Mediators Inflamm 2022:1567210. https://doi.org/10.1155/2022/1567210

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu S, Joshi K, Denning MF, Zhang J (2021) RIPK3 signaling and its role in the pathogenesis of cancers. Cell Mol Life Sci 78(23):7199–7217. https://doi.org/10.1007/s00018-021-03947-y

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang H, Wu X, Li X, Li M, Li F, Wang L, Zhang X, Zhang Y, Luo Y, Wang H, Jiang Y, Zhang H (2020) Crucial roles of the RIP homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent cell death and lymphoproliferative disease. Cell Rep 31(7):107650. https://doi.org/10.1016/j.celrep.2020.107650

Article  CAS  PubMed  Google Scholar 

Weber K, Roelandt R, Bruggeman I, Estornes Y, Vandenabeele P (2018) Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. Commun Biol 1:6. https://doi.org/10.1038/s42003-017-0007-1

Article  PubMed  PubMed Central  Google Scholar 

Kasof GM, Prosser JC, Liu D, Lorenzi MV, Gomes BC (2000) The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. FEBS Lett 473(3):285–291. https://doi.org/10.1016/s0014-5793(00)01473-3

Article  CAS  PubMed  Google Scholar 

Hanna-Addams S, Liu S, Liu H, Chen S, Wang Z, CK1α (2020) CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis. Proc Natl Acad Sci U S A 117(4):1962–1970. https://doi.org/10.1073/pnas.1917112117