Molecular Mechanism Of Necroptosis Research Articles

Necroptosis in bacterial infections.

Necroptosis, a recently discovered form of cell-programmed death that is distinct from apoptosis, has been confirmed to play a significant role in the pathogenesis of bacterial infections in various animal models. Necroptosis is advantageous to the host, but in some cases, it can be detrimental. To understand the impact of necroptosis on the pathogenesis of bacterial infections, we described the roles and molecular mechanisms of necroptosis caused by different bacterial infections in this review.

The potential role of necroptosis in clinical diseases (Review).

As an important type of programmed cell death in addition to apoptosis, necroptosis occurs in a variety of pathophysiological processes, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors. It can be triggered by a variety of factors, such as tumor necrosis factor receptor and Toll-like receptor families, intracellular DNA and RNA sensors, and interferon, and is mainly mediated by receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein. A better understanding of the mechanism of necroptosis may be useful in the development of novel drugs for necroptosis-related diseases. In this review, the focus is on the molecular mechanisms of necroptosis, exploring the role of necroptosis in different pathologies, discussing their potential as a novel therapeutic target for disease therapy, and providing suggestions for further study in this area.

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives.

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.

Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury.

While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.

Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases.

Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL), being also generally dependent on RIP1 kinase activity. Necroptosis can be recruited during pathological conditions, usually following the activation of death receptors under specific cellular contexts. In this regard, necroptosis has been implicated in the pathogenesis of multiple disorders, including acute and chronic neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, and multiple sclerosis. Here, we summarize the molecular mechanisms regulating the induction of necroptosis and downstream effectors of this form of cell death, besides exploring non-necroptotic roles for necroptosis-related proteins that may impact on alternative cell death pathways and inflammatory mechanisms in disease. Finally, we outline the recent evidence implicating necroptosis in neurodegenerative conditions and the emerging therapeutic perspectives targeting necroptosis in these diseases.

The molecular mechanism of necroptosis

Programmed necrosis called necroptosis, is different from traditional necrosis and apoptosis, it has attracted considerable attention over the last few years. Necroptosis can be initiated through many factors such as tumor necrosis factor receptor (TNFR) or pattern recognition receptor (PRR), and receptor-interacting protein (RIP) 1 and 3 are two key proteins during the process. A lot of molecules have been characterized as modulators and effectors of necroptosis, including poly(ADP-ribose) polymerase (PARP-1), reactive oxygen species (ROS), Ca(2+), which can destruct mitochondria or other organelles and induce cell dead through caspase-independent pathway. Then, damage-associated molecular pattern (DAMP) molecules were released from necroptosis cells, recognized and internalized by phagocytes. Here, we briefly discuss the initiation and execution of necroptosis and the clearance of death cells.

Calpain: a molecule to induce AIF-mediated necroptosis in RGC-5 following elevated hydrostatic pressure.

BackgroundRIP3 (Receptor-interacting protein 3) pathway was mainly described as the molecular mechanism of necroptosis (programmed necrosis). But recently, non-RIP3 pathways were found to mediate necroptosis. We deliberate to investigate the effect of calpain, a molecule to induce necroptosis as reported (Cell Death Differ 19:245–256, 2012), in RGC-5 following elevated hydrostatic pressure.ResultsFirst, we identified the existence of necroptosis of RGC-5 after insult by using necrostatin-1 (Nec-1, necroptosis inhibitor) detected by flow cytometry. Immunofluorescence staining and western blot were used to detect the expression of calpain. Western blot analysis was carried out to describe the truncated AIF (tAIF) expression with or without pretreatment of ALLN (calpain activity inhibitor). Following elevated hydrostatic pressure, necroptotic cells pretreated with or without ALLN was stained by Annexin V/PI, The activity of calpain was also examined to confirm the inhibition effect of ALLN. The results showed that after cell injury there was an upregulation of calpain expression. Upon adding ALLN, the calpain activity was inhibited, and tAIF production was reduced upon injury along with the decreased number of necroptosis cells.ConclusionOur study found that calpain may induce necroptosis via tAIF-modulation in RGC-5 following elevated hydrostatic pressure.

Chemical regulation of signaling pathways to programmed necrosis

Necroptosis is an active and well-orchestrated necrosis, distinctive from apoptosis in microscopic structure, and biochemical and molecular features. Unlike apoptosis-undergoing cells, which are removed by macrophage or neighboring cells, necrotic cell death releases danger signals and provokes inflammation, and further a severe damage to neighbor tissue. A regulated necrosis, termed as necroptosis or programmed necrosis, is emerging as a new paradigm of cell death that can be activated when apoptotic machinery is genetically or pathogenically defective. It plays biological significances in pathogenesis of a variety of inflammatory diseases as well as in a beneficial innate immune defense mechanism. This review highlights the identification of hits against necroptosis, and comprehensive approaches to discovery of small molecules that regulate necroptotic cell death. Also, the signaling molecular mechanism of necroptosis and future clinical uses of necroptosis inhibitor will be described in brief.

The role of necroptosis, an alternative form of cell death, in cancer therapy

Programmed cell death plays an important role in animal development, tissue homeostasis and eliminating harmful or virally infected cells. Necroptosis, a novel form of programmed cell death, is caspase independent but RIPK and RIPK3 dependent. Moreover, it is suggested that necroptosis can be specifically inhibited by small molecular inhibitors such as necrostatin-1. Its signaling pathways have something in common with apoptosis, although the molecular mechanisms of necroptosis need to be further elucidated. Previous evidences suggest that necroptosis has significant effects in regulating various physiological processes and disease, such as ischemic brain injury, immune system disorders and cancer. In this review, the molecular mechanism of necroptosis is described and how it could be manipulated in the treatment of cancer is summarized.

The molecular mechanism of necroptosis

Background Necroptosis is a programned cell death and has been a focus of many research fields.Objective To provide some useful information for related researches,this review summarized the receptors,signaling pathway and the relationship among necroptosis-related molecules.Content Necroptosis is mediated by death receptor ligation when apoptotic pathway is inhibited.The complex Ⅱ,which is formed by increasing aggregation of,unbiqutinated receptor-interact protein 1 (RIP1)and the interaction between RIP1 and RIP3 are the key elements for necroptosis signaling pathway activation.Necrostatin-1 blocks death receptor-induced necroptosis as an allosteric RIP kinase inhibitor.Necroptosis requires energy.While metabolism increases,reactive oxygen species(ROS) deriveing from mitochondriacan acts as the downstream transduction signal involving in tumor necrosis factor(TNF) mediated necroptosis.Trend Necroptosis contributes to the occurrence and development of multiple diseases such as inflammation and trauma and are of profound significance for directing clinical therapy. Key words: Necroptosis; Receptor-interact protein 1 ; Receptor-interact protein 3 ; Reactive oxygen species

Molecular mechanisms of necroptosis: an ordered cellular explosion

For a long time, apoptosis was considered the sole form of programmed cell death during development, homeostasis and disease, whereas necrosis was regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, 'necroptosis', by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. Necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.