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Physiological Reviews Apr 2018Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate... (Review)
Review
Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.
Topics: Animals; Apoptosis; Cell Death; Humans; Microglia; Neurons; Phagocytosis; Signal Transduction
PubMed: 29488822
DOI: 10.1152/physrev.00011.2017 -
The American Journal of Pathology Jan 1995The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis,... (Review)
Review
The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from ónkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.
Topics: Animals; Apoptosis; Cell Death; Humans; Necrosis
PubMed: 7856735
DOI: No ID Found -
Burns & Trauma 2023Globally, ischemic stroke causes millions of deaths per year. The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and... (Review)
Review
Globally, ischemic stroke causes millions of deaths per year. The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region. In the infarct region, cell injuries follow either the regulated pathway involving precise signaling cascades, such as apoptosis and autophagy, or the nonregulated pathway, which is uncontrolled by any molecularly defined effector mechanisms such as necrosis. However, numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic; this type of necrosis is referred to as regulated necrosis. Depending on the signaling pathway, various elements of regulated necrosis contribute to the development of ischemic stroke, such as necroptosis, pyroptosis, ferroptosis, pathanatos, mitochondrial permeability transition pore-mediated necrosis and oncosis. In this review, we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis. We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemia-induced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.
PubMed: 38026442
DOI: 10.1093/burnst/tkad016 -
Journal of Nuclear Medicine : Official... Oct 2008Cells can die by several pathways, such as accidental death, apoptosis, autophagy, pyroptosis, and oncosis. These are important in normal physiology and many disease... (Review)
Review
Cells can die by several pathways, such as accidental death, apoptosis, autophagy, pyroptosis, and oncosis. These are important in normal physiology and many disease states, such as cancer and cardiovascular disease. Specific biochemical changes occur in cells undergoing apoptosis that provide potential targets for molecular imaging agents. Several of these molecular steps have been evaluated to date, including phosphatidylserine exposure at the extracellular face of the plasma membrane, detected by proteins such as annexin V; caspase activation in the intracellular compartment, detected by labeled enzyme substrates or inhibitors; and mitochondrial membrane potential collapse, detected by reduced levels of phosphonium cations that normally accumulate in healthy mitochondria. Phase I clinical trials have been performed with 1 of these agents, annexin V. Future work will likely include development of new agents that detect targets not exploited by current agents, translational research on the significance of imaging the different forms of cell death, and further improvements in the techniques for labeling existing agents to improve sensitivity and reduce nonspecific background.
Topics: Animals; Annexins; Apoptosis; Caspases; Cell Membrane; Diagnostic Imaging; Enzyme Activation; Humans; Membrane Potentials; Models, Biological; Nuclear Medicine; Radioisotopes
PubMed: 18794267
DOI: 10.2967/jnumed.108.052803 -
Microbiology and Molecular Biology... Nov 2020Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate... (Review)
Review
Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate within host cells and to induce long-lasting infections. organisms barely induce neutrophil activation and survive within these leukocytes by resisting microbicidal mechanisms. Very few -infected neutrophils are found in the target organs, except for the bone marrow, early in infection. Still, induces a mild reactive oxygen species formation and, through its lipopolysaccharide, promotes the premature death of neutrophils, which release chemokines and express "eat me" signals. This effect drives the phagocytosis of infected neutrophils by mononuclear cells that become thoroughly susceptible to replication and vehicles for bacterial dispersion. The premature death of the infected neutrophils proceeds without NETosis, necrosis/oncosis, or classical apoptosis morphology. In the absence of neutrophils, the Th1 response exacerbates and promotes bacterial removal, indicating that -infected neutrophils dampen adaptive immunity. This modulatory effect opens a window for bacterial dispersion in host tissues before adaptive immunity becomes fully activated. However, the hyperactivation of immunity is not without a price, since neutropenic -infected animals develop cachexia in the early phases of the disease. The delay in the immunological response seems a requirement for the development of long-lasting brucellosis. This property may be shared with other pathogenic alphaproteobacteria closely related to We propose a model in which -infected polymorphonuclear neutrophils (PMNs) function as "Trojan horse" vehicles for bacterial dispersal and as modulators of the Th1 adaptive immunity in infection.
Topics: Animals; Apoptosis; Brucella; Brucellosis; Host-Pathogen Interactions; Humans; Immunity, Innate; Lipopolysaccharides; Neutrophils; Phagocytosis; Th1 Cells; Virulence
PubMed: 33055283
DOI: 10.1128/MMBR.00048-20 -
Immunological Reviews Sep 2011Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that... (Review)
Review
Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that have been commandeered by microbial pathogens become detrimental to the host. When macrophages and dendritic cells are compromised in this way, they can be lysed by pyroptosis, a cell death mechanism that is distinct from apoptosis and oncosis/necrosis. Pyroptosis is triggered by Caspase-1 after its activation by various inflammasomes and results in lysis of the affected cell. Both pyroptosis and apoptosis are programmed cell death mechanisms but are dependent on different caspases, unlike oncosis. Similar to oncosis and unlike apoptosis, pyroptosis results in cellular lysis and release of the cytosolic contents to the extracellular space. This event is predicted to be inherently inflammatory and coincides with interleukin-1β (IL-1β) and IL-18 secretion. We discuss the role of distinct inflammasomes, including NLRC4, NLRP3, and AIM2, as well as the role of the ASC focus in Caspase-1 signaling. We further review the importance of pyroptosis in vivo as a potent mechanism to clear intracellular pathogens.
Topics: Animals; CARD Signaling Adaptor Proteins; Calcium-Binding Proteins; Carrier Proteins; Caspase 1; Cell Death; DNA-Binding Proteins; Dendritic Cells; Humans; Infection Control; Infections; Inflammasomes; Interleukin-18; Interleukin-1beta; Macrophages; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear Proteins; Signal Transduction
PubMed: 21884178
DOI: 10.1111/j.1600-065X.2011.01044.x -
Chemical Science Jun 2018Oncosis is a non-apoptotic form of programmed cell death (PCD), which differs from apoptosis in both morphological changes and inner pathways, and might hold the key to...
Oncosis is a non-apoptotic form of programmed cell death (PCD), which differs from apoptosis in both morphological changes and inner pathways, and might hold the key to defeating a major obstacle in cancer therapy - drug-resistance, which is often a result of the intrinsic apoptosis resistance of tumours. However, despite the fact that the term "oncosis" was coined and used much earlier than apoptosis, little effort has been made to discover new drugs which can initiate this form of cell death, in comparison to drugs inducing apoptosis or any other type of PCD. So herein, we present the synthesis of a series of mitochondria-targeting cyclometalated Ir(iii) complexes, which activated the oncosis-specific protein porimin and calpain in cisplatin-resistant cell line A549R, and determined their cytotoxicity against a wide range of drug-resistant cancer types. To the best of our knowledge, these complexes are the very first metallo-components to induce oncosis in drug-resistant cancer cells.
PubMed: 29997872
DOI: 10.1039/c8sc01142g -
International Journal of Molecular... Jul 2023Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT)...
Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from , which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.
Topics: Animals; Humans; Mice; Adenosine Triphosphate; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Lung Neoplasms; Mitochondria; Reactive Oxygen Species
PubMed: 37569328
DOI: 10.3390/ijms241511953 -
Molecules (Basel, Switzerland) Nov 2022The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that... (Review)
Review
The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that quercetin's powerful antioxidant effects may relate to its ability to treat disease. Glutamate excitotoxicity occurs when a neuron is overstimulated by the neurotransmitter glutamate and causes dysregulation of intracellular calcium concentrations. Quercetin has been shown to be preventative against many forms of neuronal cell death resulting from glutamate excitotoxicity, such as oncosis, intrinsic apoptosis, mitochondrial permeability transition, ferroptosis, phagoptosis, lysosomal cell death, parthanatos, and death by reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. The clinical importance for the attenuation of glutamate excitotoxicity arises from the need to deter the continuous formation of tissue infarction caused by various neurological diseases, such as ischemic stroke, seizures, neurodegenerative diseases, and trauma. This review aims to summarize what is known concerning glutamate physiology and glutamate excitotoxic pathophysiology and provide further insight into quercetin's potential to hinder neuronal death caused by cell death pathways activated by glutamate excitotoxicity. Quercetin's bioavailability may limit its use clinically, however. Thus, future research into ways to increase its bioavailability are warranted.
Topics: Humans; Glutamic Acid; Quercetin; Antioxidants; Reactive Oxygen Species; Neurodegenerative Diseases
PubMed: 36364448
DOI: 10.3390/molecules27217620 -
Oxidative Medicine and Cellular... 2018Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose) deprivation, which occurs because of insufficient blood supply. This results... (Review)
Review
Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose) deprivation, which occurs because of insufficient blood supply. This results in necrotic cell death in the core region of solid tumors. Necrotic cells release their cellular cytoplasmic contents into the extracellular space, such as high mobility group box 1 (HMGB1), which is a nonhistone nuclear protein, but acts as a proinflammatory and tumor-promoting cytokine when released by necrotic cells. These released molecules recruit immune and inflammatory cells, which exert tumor-promoting activity by inducing angiogenesis, proliferation, and invasion. Development of a necrotic core in cancer patients is also associated with poor prognosis. Conventionally, necrosis has been thought of as an unregulated process, unlike programmed cell death processes like apoptosis and autophagy. Recently, necrosis has been recognized as a programmed cell death, encompassing processes such as oncosis, necroptosis, and others. Metabolic stress-induced necrosis and its regulatory mechanisms have been poorly investigated until recently. Snail and Dlx-2, EMT-inducing transcription factors, are responsible for metabolic stress-induced necrosis in tumors. Snail and Dlx-2 contribute to tumor progression by promoting necrosis and inducing EMT and oncogenic metabolism. Oncogenic metabolism has been shown to play a role(s) in initiating necrosis. Here, we discuss the molecular mechanisms underlying metabolic stress-induced programmed necrosis that promote tumor progression and aggressiveness.
Topics: Apoptosis; Autophagy; Cell Death; Disease Progression; Humans; Necrosis; Neoplasms
PubMed: 29636841
DOI: 10.1155/2018/3537471