生物谷报道：细胞死亡至少可以分为细胞凋亡和细胞坏死这两种主要形式。坏死，作为细胞死亡的一种新途径，在7月份的《自然—化学生物学》上有相关的研究进展介绍。坏死是人体病变中的一种普遍特征，不像细胞凋亡现象被认为是细胞对外来伤害的一种被动反应。Junying Yuan及其同事发现了一种导致细胞坏死的细胞代谢新途径，他们称之为necroptosis。该研究小组发现，当没有足够的血液达到大脑时，也就是发生缺血性脑伤害时，细胞坏死将会发生。
虽然过去数十年，研究工作者发现了细胞凋亡的重要机制，但是在实验中，人们也能发现一些奇怪的现象，如非凋亡的程序性死亡。经典的理论认为，细胞凋亡是程序化的，而细胞坏死则是突发性的，被动的。本周Nature Chemical Biology, 上刊登了华人袁钧英教授及其同事的新的发现，通过体外以及小鼠的脑缺血的体内模型均观察到一种非凋亡的程序性死亡的新现象。
近来，有关带有坏死特征的非凋亡性细胞死亡的研究报道变得越来越多。但是，研究者们并没有合适的工具来进行有关这些现象的潜在机制研究。要解决这些问题，Yuan及其同事找到了一种化学因子Nec-1，它具有抑制这种非凋亡性程序性细胞死亡的专一性。他们发现，Nec-1阻止了所有的这类细胞死亡，表明了导致细胞坏死的necroptosis的这一细胞代谢途径确实是存在的。他们进一步发现，在小鼠模型中Nec-1减少了缺血性脑伤害的程度。对于遭受击打后的脑伤害病人，Nec-1应该是一种很有前景的治疗方向。此外，Nec-1还为以后的研究者提供了一种非常重要的化学研究工具来进行相关研究。
对于此项研究，各界细胞生物学家给予了极高的评价。Rockefeller University教授Shai Shaham,告诉记者：“以往已发现很多类似的现象，但是一直没有合适的工具来研究这种机制，也不知道哪些蛋白质参与这一过程”。以前发现经典的Fas/TNFR的细胞凋亡信号通路能激活caspases家族很多蛋白质，从而诱导细胞凋亡的发生，但是，如果阻止了caspase活性，但是细胞出现了坏死，而不是凋亡。Georgetown University医学中心Alan Faden说，“这些现象说明了细胞凋亡中确实存在坏死样的类型”。但是人们却不知道是什么物质在其中起作用，袁钧英对记者说，我们回答了这样一个问题：我们发现了什么物质抑制了这些细胞的死亡。
袁钧英及其同事筛选了大约15000种化合物，发现了这种小分子能抑制这种特殊形式的细胞死亡。命名为necrostatin-1或Nec-1，能抑制TNF诱导的细胞坏死。这也是第一次提供另一种细胞程序性死亡的有力证据。Faden告诉记者，“看样子这是一条新的途径，这是极其优秀的发现”。
袁钧英认为，这种非凋亡性程序性死亡在中风病人身上会有发生，新的Nec-1有望抑制这种现象的发生，从而为将来研究相关的药物，甚至临床应用提供有力的证据。不过Shaham认为这条新的途径并非与经典的途径毫无关系，而认为它们可能同相互作用，共同导致细胞损伤。他认为袁钧英教授这篇文章提供了一条重要的线索是促进人们寻找如何阻止这种程序性死亡的发生的方法。生物谷专家认为，袁钧英教授这项发现不仅使人们重新认识了细胞凋亡的过程，也使人们意识到细胞的死亡过程可能是非常复杂的行为。即独立于细胞凋亡和坏死之外还会存在第三种类型。这也为预防和治疗损伤类疾病提供新的治疗依据。
Reference:
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 29 May 2005. http://www.nature.com/nchembio/
A.G. Yakolev, A.I. Faden, "Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies," Neurorx, 1:5-16, January 2004. [PubMed Abstract]
Junying Yuan http://cellbio.med.harvard.edu/faculty/yuan/
Shai Shaham http://www.rockefeller.edu/labheads/shaham/shaham-lab.php
H. Matsumura et al., "Necrotic death pathway in Fas receptor signaling," J Chem Biol, 151:1247-56, December 11, 2000. [PubMed Abstract]
Alan I. Faden http://www.neuro.georgetown.edu/faden.htm
E.H. Lo et al., "Mechanisms, challenges and opportunities in stroke," Nat Rev Neurosci. 4:399-415, May 2003. [PubMed Abstract]
附：
袁钧英教授简介
Department of Cell Biology
Harvard Medical School
240 Longwood Avenue
Boston, MA 02115
Junying Yuan received her Ph.D. in Neuroscience from Harvard University in 1989 and her undergraduate degree from Fudan University, Shanghai, China, in 1982. Dr. Yuan carried out her postdoctoral research at the Massachusetts Institute of Technology. She was first appointed as Assistant Professor at Harvard Medical School in 1992, when she became a Principal Investigator of the Cardiovascular Research Center at Massachusetts General Hospital. She joined the Department of Cell Biology in 1996 and was appointed a Professor of Cell Biology at Harvard Medical School in 2000.
袁钧英教授在线虫发育，细胞凋亡研究中均有一系列重大发现。尤其是发现了caspase家族的众多成员，是国际公认的细胞凋亡领域研究权威，近年来在锌指蛋白，细胞凋亡新蛋白研究中屡有突破性进展。文章虽不多，但多以Cell, Nature上居多，质量十分高。
生物谷内以往对袁钧英教授的相关介绍及报道：
袁钧英博士简介
袁钧英的文章欣赏
有关人员对袁钧英教授此文的评论：
评论1
The paper by Degterev et al. is a tour de force characterization of necroptosis, a non-apoptotic form of programmed cell death that involves necrosis and autophagy. Existence of this caspase-independent pathway was hypothesized from observations that several different cultured cell types undergo a common necrotic death upon stimulation of death domain receptor proteins in the presence of caspase inhibitors. To investigate a necroptosis pathway, the authors performed a chemical screen of 15,000 small molecules for necroptosis inhibition. Of these, a heterocyclic compound, Necrostatin-1 (Nec-1), was shown to be a very potent and specific inhibitor of necroptosis.
Application of Nec-1 did not block apoptosis, autophagy, or oxidative stress-induced necrosis, and also did not disrupt normal cellular physiology. Significantly, necroptosis was shown to be a delayed component of ischemia-associated neuronal cell death induced by cerebral artery occlusion in mice. Administration of Nec-1 attenuated the extent of ischemia-induced neuronal death and did not disrupt general brain physiology. Furthermore, Nec-1 exhibited an extended time window of protection and was able to exert its effects 6 hours after the onset of injury. The simultaneous addition of Nec-1 and the zVAD.fmk caspase inhibitor yielded an additive protective effect, suggesting a potentially effective therapeutic combination.
Overall, necroptosis has a delayed latency compared to apoptosis, and the authors hypothesize that it may act as a redundant mechanism to provide cells with an ability to die when they find themselves in an environment non-permissive to apoptosis. Future studies to determine the site of Nec-1 action and characterize the components of necroptosis pathway promise to provide important insight not only into a conserved and important mechanism for cell death, but also to develop effective treatments for a variety of human pathologies.
评论2
Two general mechanisms of cell death have been described: programmed cell death and necrosis. Programmed cell death, or apoptosis, is a directed program that proceeds through specific signal transduction pathways common to different cell types. In particular, apoptosis initiates a sequential activation of multiple caspases. In contrast, the alternative to programmed cell death, necrosis, is thought to be a nondirected cellular response to overwhelming stress. Therapeutic strategies to prevent cell death in pathological conditions have targeted apoptosis rather than necrosis, because of the perception that necrosis is unregulated and relatively nonspecific. However, recent reports have implicated specific signal transduction pathways, such as stimulation of death domain receptors (DRs) by their ligands, in necrotic cell death. In a paper that is stunning in its elegance and simplicity, Degterev et al. build on these observations by identifying a new type of programmed cell death that resembles necrosis but is distinct from both apoptosis and necrosis. They call it necroptosis.
The authors had followed the growing number of studies suggesting that under certain situations, DR-induced cell death, which normally proceeds via an apoptotic pathway, is not prevented by caspase inhibitors and resembles necrosis. Because this caspase-independent DR-induced cell death led to similar necrotic morphological features in a wide variety of cell types, Degterev and collaborators suspected the involvement of a non-apoptotic programmed signal transduction pathway shared by multiple cell types. They chose an ingenious way to find out whether such a pathway actually exists. Cells treated simultaneously with the DR agonist TNFα and a pan-caspase inhibitor, a combination the authors used to devise an operational definition of necroptosis, were used to screen a library of chemical compounds for inhibitors of the death of these cells. The screen resulted in the selection of a molecule dubbed necrostatin-1 (Nec-1).
The authors then used Nec-1 to answer a number of questions about this new pathway that they called necroptosis. First, they asked whether this pathway was indeed distinct from apoptosis. When cells are exposed to FasL (Fas ligand), they exhibit classic symptoms of apoptosis. Stimulation of cells with FasL in the presence of a pan-caspase inhibitor, in contrast, leads to morphological symptoms of necrosis. The authors showed that Nec-1 did not inhibit apoptotic morphology (cytoplasm condensation, chromatin marginalization, nuclear fragmentation, and plasma membrane blebbing) displayed by FasL-treated cells. However, Nec-1 did inhibit the appearance of necrotic morphology (nuclear condensation, organelle swelling, and early loss of plasma membrane integrity) displayed by cells exposed to FasL in the presence of the caspase inhibitor zVAD.fmk. Of special interest was the fact that the onset of apoptosis in response to FasL was faster than the onset of necroptosis in response to FasL in conjunction with zVAD.fmk. The authors suggest that apoptosis usually conceals or forestalls necroptosis because of its faster kinetics.
The authors then asked whether necroptotic cell death utilized factors involved in known cell death signaling pathways. They compared the activity of Nec-1 with that of small-molecule inhibitors of such factors as calpains, calcium homeostasis perturbation, PARP, and nitric oxide synthase. None of the tested compounds inhibited necroptosis in all cell types, as Nec-1 does, establishing the uniqueness of the necroptotic pathway. Furthermore, necroptosis was not inhibited by antioxidants, nor did Nec-1 block the classic necrosis caused by the cell stressor menadione, showing the independence of necroptosis from oxidative stress.
Neuronal cell death caused by ischemic brain injury is known to display some non-apoptotic features, and the participation of DRs in ischemic cell death has been postulated. The authors thought that perhaps ischemia produces conditions that are more conducive to necroptosis than to apoptosis. So they administered Nec-1 intracerebroventricularly to mice that had undergone middle cerebral artery occlusion (MCAO), a model for inducing ischemic damage in mice. Strikingly, Nec-1 reduced the infarct volume without blocking caspase 3 activation, showing that at least a portion of the cell death resulting from MCAO is necroptotic.
A growing body of evidence supports the idea that apoptosis is at least one means by which neurons die in Alzheimer disease (AD). However, a number of studies have described non-apoptotic features of AD neurodegeneration. Furthermore, DRs have been implicated both in neuritic degeneration in AD brain and in neuronal death induced by β-amyloid (e.g., Morishima et al., 2001). It is possible that necroptosis also plays a role in AD neurodegeneration. It will be interesting to assess the effect of Nec-1 on neuropathology in mouse transgenic models of AD, or on neurodegeneration in in vitro models of AD neurodegeneration. If necroptosis is shown to be a component of AD pathology, a new world of therapeutic strategies, aimed at necroptotic pathways, would be opened up for this devastating disease.
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