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Although the morphological appearance of necrosis has been described by pathologists already in the early nineteenth century long before the discovery of programmed cell death (PCD) or apoptosis, we only start to understand some of the molecular mechanisms involved in necrosis. The insight that necrosis is also regulated gave rise to the intriguing and clinically neglected possibility to interfere with necrosis in pathophysiological settings. The form of regulated necrosis that is best characterized has been named necroptosis and is initiated by the combined action of RIPK1, RIPK3, and MLKL. Importantly, direct tissue damage by necroptosis has been reported for a series of devastating disorders. It is unclear today to which extent it will be possible to therapeutically interfere with necroptosis using, e.g., RIPK1/3 and MLKL inhibitors due to its rapid progression and thus narrow therapeutic window. Despite this, inhibition of RIPK1 kinase activity has been successfully shown in experimental disease models of ischemia–reperfusion injury (IRI), myocardial infarction, brain trauma, acute pancreatitis, inflammatory bowel disease, ophthalmologic diseases, and systemic inflammatory diseases following TNF administration. In addition, necroptosis was demonstrated to be of importance in tumorigenesis, atherosclerosis, ophthalmologic diseases, sepsis, and solid organ transplantation. One of the bottlenecks to target necroptosis will be the anticipation of the onset of necroptosis or the inhibition of the molecular constellation that sensitizes for necroptosis. To explore this concept of prevention of necroptosis in a clinically relevant setting, a prophylactic interference with necroptosis in, e.g., solid organ transplantation, which is invariably associated with IRI, could be considered. The development of second-generation RIPK1/3 inhibitors or the identification of novel MLKL inhibitors will undoubtedly help in paving the roads towards clinical trials for the prevention of delayed graft function, and attenuation of allograft rejection-mediated injury will emerge.

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Citation

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Chicago
Linkermann, Andreas, Tom Vanden Berghe, Nozomi Takahashi, Ulrich Kunzendorf, Stefan Krautwald, and Peter Vandenabeele. 2014. “The Potential Role of Necroptosis in Diseases.” In Necrotic Cell Death, ed. Han-Ming Shen and Peter Vandenabeele, 1–21. New York, NY, USA: Humana Press - Springer.
APA
Linkermann, A., Vanden Berghe, T., Takahashi, N., Kunzendorf, U., Krautwald, S., & Vandenabeele, P. (2014). The potential role of necroptosis in diseases. In H.-M. Shen & P. Vandenabeele (Eds.), Necrotic cell death (pp. 1–21). New York, NY, USA: Humana Press - Springer.
Vancouver
1.
Linkermann A, Vanden Berghe T, Takahashi N, Kunzendorf U, Krautwald S, Vandenabeele P. The potential role of necroptosis in diseases. In: Shen H-M, Vandenabeele P, editors. Necrotic cell death. New York, NY, USA: Humana Press - Springer; 2014. p. 1–21.
MLA
Linkermann, Andreas, Tom Vanden Berghe, Nozomi Takahashi, et al. “The Potential Role of Necroptosis in Diseases.” Necrotic Cell Death. Ed. Han-Ming Shen & Peter Vandenabeele. New York, NY, USA: Humana Press - Springer, 2014. 1–21. Print.
@incollection{5889114,
  abstract     = {Although the morphological appearance of necrosis has been described by pathologists already in the early nineteenth century long before the discovery of programmed cell death (PCD) or apoptosis, we only start to understand some of the molecular mechanisms involved in necrosis. The insight that necrosis is also regulated gave rise to the intriguing and clinically neglected possibility to interfere with necrosis in pathophysiological settings. The form of regulated necrosis that is best characterized has been named necroptosis and is initiated by the combined action of RIPK1, RIPK3, and MLKL. Importantly, direct tissue damage by necroptosis has been reported for a series of devastating disorders. It is unclear today to which extent it will be possible to therapeutically interfere with necroptosis using, e.g., RIPK1/3 and MLKL inhibitors due to its rapid progression and thus narrow therapeutic window. Despite this, inhibition of RIPK1 kinase activity has been successfully shown in experimental disease models of ischemia--reperfusion injury (IRI), myocardial infarction, brain trauma, acute pancreatitis, inflammatory bowel disease, ophthalmologic diseases, and systemic inflammatory diseases following TNF administration. In addition, necroptosis was demonstrated to be of importance in tumorigenesis, atherosclerosis, ophthalmologic diseases, sepsis, and solid organ transplantation. One of the bottlenecks to target necroptosis will be the anticipation of the onset of necroptosis or the inhibition of the molecular constellation that sensitizes for necroptosis. To explore this concept of prevention of necroptosis in a clinically relevant setting, a prophylactic interference with necroptosis in, e.g., solid organ transplantation, which is invariably associated with IRI, could be considered. The development of second-generation RIPK1/3 inhibitors or the identification of novel MLKL inhibitors will undoubtedly help in paving the roads towards clinical trials for the prevention of delayed graft function, and attenuation of allograft rejection-mediated injury will emerge.},
  author       = {Linkermann,  Andreas and Vanden Berghe, Tom and Takahashi, Nozomi and Kunzendorf,  Ulrich and Krautwald, Stefan and Vandenabeele, Peter},
  booktitle    = {Necrotic cell death},
  editor       = {Shen, Han-Ming and Vandenabeele, Peter},
  isbn         = {9781461482208},
  language     = {eng},
  pages        = {1--21},
  publisher    = {Humana Press - Springer},
  series       = {Cell Death in Biology and Diseases},
  title        = {The potential role of necroptosis in diseases},
  url          = {http://dx.doi.org/10.1007/978-1-4614-8220-8\_1},
  year         = {2014},
}

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