300 research outputs found
Autophagy in cancer and chemotherapy
No full textCancer cells often exhibit mutations in critical molecules of the apoptotic machinery, resulting in resistance to common anticancer therapies. In the absence of apoptosis, autophagic cell death can be an alternative form of cell death by excessive self-digestion. Therefore, autophagic cell death can be considered as a backup cell death mechanism when apoptotic cell death mechanisms fail. However, many tumors also exhibit deficiencies in autophagy that may result in both genomic instability and further anticancer drug resistance. This chapter summarizes our current understanding regarding the regulation of autophagy in tumors and discusses potential new anticancer drug treatment strategies
Apoptosis regulation by autophagy gene 5
No full textAutophagy is a cellular process, in which cellular proteins and cytoplasmic organelles are degraded. It reflects the response of a cell to stress or starvation with the primary goal of cell survival. On the other hand, if the autophagic activity is too high, cell death happens, suggesting that this process requires a tight control. Autophagic cell death has often been observed under conditions, in which apoptosis is blocked. Recent studies suggest that autophagy may promote apoptosis and that Bcl-2 cannot block only apoptosis, but also autophagy and autophagic cell death. Here, we discuss recent findings regarding the interrelations between autophagy and apoptosis. In particular, we would like to draw the attention of the readers to Atg5, which exhibits, like Bcl-2, a dual function by modulating both autophagy and apoptosis
Extracellular DNA traps in allergic, infectzious, and autoimmune diseases
No full textExtracellular DNA traps are part of the innate immune response and are seen with many infectious, allergic, and autoimmune diseases. They can be generated by several different leukocytes, including neutrophils, eosinophils, and monocytes, as well as mast cells. Here, we review the composition of these extracellular DNA-containing structures as well as potential mechanisms for their production and function. In general, extracellular DNA traps have been described as binding to and killing pathogens, particularly bacteria, fungi, but also parasites. On the other hand, it is possible that DNA traps contribute to immunopathology in chronic inflammatory diseases, such as bronchial asthma. In addition, it has been demonstrated that they can initiate and/or potentiate autoimmune diseases. Extracellular DNA traps represent a frequently observed phenomenon in inflammatory diseases, and they appear to participate in the cross-talk between different immune cells. These new insights into the pathogenesis of inflammatory diseases may open new avenues for targeted therapies
Autophagy in cells of the blood
No full textAutophagy is a conserved proteolytic mechanism that degrades cytoplasmic material including cell organelles. The importance of autophagy for cell homeostasis and survival has long been appreciated. Recent data suggest that autophagy is also involved in non-metabolic functions that particularly concern blood cells. Here, we review these findings, which point to an important role of autophagy in several cellular functions related to host defense
Actin polymerization and its glutathionylation are required for NET formation
No full textNeutrophils are the most abundant cells in blood and their antimicrobial defense capabilities are defined, at least partially, by their formation of neutrophil extracellular traps (NETs). For the past decade, efforts have been made to elucidate the molecular mechanisms of NET formation. In this study, we demonstrate that disruption of the cellular cytoskeleton in neutrophils using pharmacological inhibitors or in knockout mice having defects in genes regulating the actin network prevents the DNA release and degranulation required for NET formation. For instance, Wiskott–Aldrich syndrome protein (WASP)deficient mouse (Was-/-) neutrophils, unable to polymerize actin, were consequently unable to release DNA or to degranulate. Furthermore, activation of mouse and human neutrophils exhibiting a genetic defect of the NADPH oxidase also failed to cause actin polymerization and subsequent NET formation. Finally, activated glutaredoxin 1 (Grx1) – deficient mouse (Grx1-/-) neutrophils accumulated high levels of glutathionylated actin that prevented actin polymerization, DNA release and degranulation. Taken together, we conclude that a functional actin network is achieved by a balance between ROS-mediated polymerization and glutathionylation and Grx1-mediated de-glutathionylation that is required for NET formation. Thus, these findings enlighten us about the molecular mechanisms involved in NET formation and provide new strategies for increasing the anti-microbial activity of neutrophils in patients with defects in the innate immune syste
Eosinophil extracellular DNA traps: molecular mechanisms and potential roles in disease
No full textEosinophil extracellular traps (EETs) are part of the innate immune response and are seen in multiple infectious, allergic, and autoimmune eosinophilic diseases. EETs are composed of a meshwork of DNA fibers and eosinophil granule proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). Interestingly, the DNA within the EETs appears to have its origin in the mitochondria of eosinophils, which had released most their mitochondrial DNA, but were still viable, exhibiting no evidence of a reduced life span. Multiple eosinophil activation mechanisms are represented, whereby toll-like, cytokine, chemokine, and adhesion receptors can all initiate transmembrane signal transduction processes leading to the formation of EETs. One of the key signaling events required for DNA release is the activation of the NADPH oxidase. Here, we review recent progress made in the understanding the molecular mechanisms involved in DNA and granule protein release, discuss the presence of EETs in disease, speculate on their potential role(s) in pathogenesis, and compare available data on other DNA-releasing cells, particularly neutrophils
Necroptosis and neutrophil-associated disorders.
No full textNecroptosis is a form of regulated necrosis and is dependent on a signaling pathway involving receptor interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Necroptosis is considered to have important functions in inflammation and, based on studies with animal disease models, is believed likely to be involved in the pathogenesis of many human inflammatory diseases. In neutrophils, necroptosis has recently been reported to be triggered by tumor necrosis factor (TNF) stimulation, ligation of adhesion receptors, exposure to monosodium urate (MSU) crystals, or phagocytosis of Staphylococcus aureus (S. aureus). Because neutrophils are involved in many kinds of tissue inflammation and disease, neutrophil necroptosis probably plays a vital role in such processes. Dissecting the signaling pathway of neutrophil necroptotic death may help to identify novel drug targets for inflammatory or autoimmune diseases. In this review, we discuss different mechanisms which regulate neutrophil necroptosis and are thus potentially important in neutrophil-associated disorders
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