Cell deaths and their associated mechanisms

In the last few years many new cell death modalities have been described. To classify different types of cell death, the term 'regulated cell death' was introduced to discriminate it from 'accidental cell death'. Regulated cell death involves the activation of genetically encoded molecular machinery that couples the presence of some signal to cell death. These forms of cell death, like apoptosis, necroptosis and pyroptosis have important physiological roles in development, tissue repair, and immunity. Accidental cell death occurs in response to physical or chemical insults and occurs independently of molecular signalling pathways. Ferroptosis, an emerging and recently (re)discovered type of regulated cell death occurs through Fe(II)-dependent lipid peroxidation when the reduction capacity of a cell is insufficient. Ferroptosis is coined after the requirement for free ferrous iron. Here, we will consider the extent to which ferroptosis is similar to other regulated cell deaths and explore emerging ideas about the physiological role of ferroptosis.

Different types of cell death in diabetic endothelial dysfunction

Chapter 20 - Cell Death Pathways: Apoptosis and Regulated Necrosis

APOPTOSIS: PHYSIOLOGICAL CELL DEATH Apoptosis, as a biological phenomenon, is readily identifiable by several characteristic features. It characteristically affects scattered single cells, not groups of contiguous cells as in necrosis, with the dying cell undergoing a relatively ordered form of cell death. This physiological cell death is characterized by cell shrinkage, cellular crenation, cytoplasmic and chromatin condensation, and internucleosomal DNA fragmentation (1). Changes in membrane glycosylation and lipid profiles, and alteration in expression of surface receptors have been observed. The apoptotic cells are rapidly phagocytosed and degraded by neighbouring cells or resident macrophages without an inflammatory response. This mechanism prevents the release of the phlogistic contents of cells and avoids the possibility of neighbouring host cell injury. The process differs significantly from cell death by necrosis or lysis where cells release their contents into the surrounding tissues and perpetuate the local inflammatory response. A glossary of terms pertinent to this review is included as an appendix. APOPTOSIS: MORPHOLOGICAL EVENTS During apoptosis, the dying cell undergoes a series of profound structural changes. The earliest event observed by electron microscopy is condensation of chromatin to form sharply circumscribed, uniformly dense, cresentic masses that abut the nuclear envelope (2). Nucleolar changes include the dispersal of peripheral nucleolar chromatin to form aggregates in the centre of the nucleus. Simultaneously with the nuclear changes, apoptotic cells detach from neighbouring cells, and specialized surface structures such as microvilli appear. Cell volume decreases, cell density increases, cytoplasmic organelles compact, and convolution of the cell and nuclear outline becomes evident (1) (Fig. 1). Cytoplasmic changes include cytoskeletal filament aggregation, clumping of ribosomal particles, and rearrangement of rough endoplasmic reticulum to form a series of concentric whorls (3). Cytoplasmic and nuclear condensation is followed by the production of numerous membrane protuberances at the plasma membrane that subsequently separate with sealing of the plasmalemma to form membrane-bound apoptotic bodies of varying sizes with condensed cytoplasm and crowded, intact cytoplasmic organelles. The production of apoptotic bodies is a late occurrence in the apoptotic process and is observed extensively in vitro, but less commonly in vivo. This observation emphasises the rapidity of the apoptotic process whereby apoptotic cells are rapidly phagocytosed in vivo prior to apoptotic body formation (4). Phagocytosis is mediated by adjacent epithelial cells, mononuclear phagocytes, or tumor cells. Once phagocytosed, apoptotic bodies are degraded by lysosomal enzymes derived from the ingesting cell. Rapid phagocytosis of apoptotic cells in vivo before their secondary degeneration helps explain the absence of inflammation associated with apoptosis. Apoptotic bodies that escape phagocytosis lose their integrity after an hour or so, resulting in swelling, loss of density, membrane rupture, and organelle disruption and dispersal referred to as secondary necrosis (Fig. 1).Fig. 1: Morphological aspects of cell death by oncosis and apoptosis. Necrosis can occur after both forms of cell death. A normal cell is shown at the top. 1a, Swelling. 1b, Blebbing, vacuolization, and increased permeability. 2a, Shrinkage and pyknosis. 2b, Budding and karyohexis. 2c, Apoptotic bodies. 3, Necrotic changes (shrinkage, coagulation, and karyolysis) occurring after rupture of a cell surface bleb in oncosis, or secondarily due to failure of apoptotic bodies to be phagocytosed in apoptosis. Adapted from Majno and Joris, 1995.APOPTOSIS: BIOCHEMICAL EVENTS Cytoskeletal and membrane alterations Cell shrinkage and apoptotic body formation require significant changes in both the cytoskeleton and plasma membrane lipid bilayer. Cytoskeletal changes include tissue transglutaminase activation, microtubule disruption, α-fodrin (non-erythroid spectrin) and actin cleavage, and a requirement for actin polymerization. These changes facilitate membrane budding and play a role in the maintenance of plasma membrane integrity in apoptotic cells (5). Membrane changes include redistribution of phosphatidylserine from its normal location on the inner leaf of the plasma membrane lipid bilayer to the outer leaf, exposure of surface sugar residues from loss of membrane sialic acid, and loss of expression of surface markers such as FcγRIII (CD16), complement regulatory molecules (CD45 and CD59), and adhesion molecules (CD11/CD18). These membrane changes are believed to play a role in the recognition and eventual phagocytosis of apoptotic cells (6). Cell shrinkage Condensation of the cytoplasmic space resulting in cell shrinkage appears to be a universal characteristic of apoptosis (7). This change is thought to be consequent to net movement of water out of the cell due to vesicles budding from the endoplasmic reticulum and Golgi apparatus fusing with the plasma membrane with release of their contents into the extracellular space. A role for active ion efflux has been implicated in cell shrinkage with active efflux of Na+ and K+ ions through the Na+,K+ ATPase pump and Ca2+-dependent channel (8,9). Apoptotic DNA degradation Apoptotic cells display dramatic changes in the nucleus, including chromatin condensation and margination. A further nuclear-associated event during apoptosis is the degradation of DNA into 180- to 200-bp oligonucleosomal fragments. These fragments form a ladder-type pattern when subjected to agarose gel electrophoresis, a feature that is now one of the biochemical hallmarks of apoptosis (10). However, it should be noted that apoptotic internucleosomal DNA fragmentation is not universal, although higher molecular weight fragments (50–300 Kbp) have been reported in certain cell types immediately proceeding or in the absence of oligonucleosomal fragmentation (11). A number of putative endonucleases have been proposed, including, DNase I, DNase II, NUC-18, as well as other novel endonucleases including the caspase-activated deoxyribonuclease (12). The fact that mRNA of these endonucleases is expressed in only a limited number of human tissues suggests that other enzymes may participate in the degradation of DNA during apoptosis. Regulators of apoptosis It is well established that cell proliferation and differentiation are highly regulated processes; however, it is now emerging that regulation of cell death is just as complex and equally important in the maintenance of tissue homeostasis (13). Apoptotic cell death is regulated by genetic factors, and the intrinsic death program can be modulated by exogenous "survival" factors. Despite Kerr's seminal work (14) revealing that most physiological forms of cell death share a common set of morphological features, and the assumption that a predictable developmental and morphological event implies genetic regulation, evidence for the genetic regulation of cell death was not revealed until the 1980s following studies on developmental mutants of the nematode Caenorhabditis elegans by Ellis and Horvitz (15). Genetic studies of the nematode identified two genes, ced-3 and ced-4, which were required for normal developmental cell death, and a third, ced-9, which appeared to act as a negative regulator of cell death (Fig. 2). The discovery of mammalian homologues of these genes initiated an intense search for new genes involved in the regulation or execution of cell death pathways. Many new cell death regulators have been identified, and a number of regulators have been shown to be previously identified oncogenes or supressor genes (e.g., bcl-2, myc, ras, and p53). Thus, the genetic regulation of apoptosis is controlled by the activation of genes whose actions are to kill the cell and the corresponding deactivation of genes whose actions are to maintain cell homeostasis (Table 1).Table 1: Positive and negative genetic regulators of apoptosisFig. 2: Homology between cell death pathways in C. elegans and mammals. The ced 9/bcl-2 family consists of pro-apoptotic (egl-1 and bax) and anti-apoptotic (ced-9 and bcl-2) protein members. The ced-9/bcl-2 family integrates positive and negative apoptotic signals and arbitrates whether apoptosis should occur; activation of ced-4/apaf-1 commits a cell to apoptosis and the ced3/caspase family mediates the proteolytic destruction of the cell. Adapted from Adams and Cory, 1998.However, the genetic regulation of a death program can be modulated by exogenous stimuli from the cells immediate environment. The concept that certain mammalian cells are under social controls with extrinsic cellular events regulating endogenous apoptotic programmes was first expounded by Raff (16): individual cells are programmed to commit suicide unless they receive signals for survival. In the presence of a limited supply of extracellular growth factors, cell numbers are maintained relatively constant as a result of competition for growth factors, thereby maintaining a balance between division and cell death. A review of the important positive and negative genetic and environmental regulators of apoptosis follows. Positive genetic regulators c-Myc gene family The myc family of protooncogenes (Myc, Mad, Max, and Mxi-1) encode short-lived nuclear proteins with DNA-binding properties, which can heterodimerize to from transcriptional activators or repressors (17). c-myc is a `Janus gene' involved in both cell proliferation and apoptosis (18). This apparent contradiction is reconciled through an understanding of the different responses exacted by survival signals from this gene. In the presence of a survival signal such as anti-apoptotic cytokines [e.g., insulin-like growth-factor-1 (19)] or overexpression of a negative regulator of apoptosis [e.g., bcl-2, (20)], Myc drives proliferation, and in its absence, the default program induced by Myc results in apoptosis. It is now generally believed that oncoprotein-induced apoptosis may reflect the fact that the pathways mediating growth and apoptosis are coupled processes: the dual signal model (21,22). In this model, activation of cell proliferation necessarily primes the apoptotic program that, unless countermanded by appropriate survival signals, automatically removes the affected cell. Survival signals are normally provided by neighbouring cells, and this ensures that somatic cells remain mutually interdependent for survival and so limits the possible proliferative autonomy of any individual cell. This has direct implications for malignant progression, as generally two or more mutations are required to initiate and promote cellular transformation. Thus, the combination of deregulated Myc and survival signals promotes cell proliferation in the absence of apoptosis and provides a rationale for oncogene cooperation in tumorogenesis (Fig. 3) (23).Fig. 3: Model of the relationship between oncogenes and death signals. In this model, oncoproteins do not trigger apoptosis directly, but they act as a sensitizer to apoptotic triggers (death receptor activation/hypoxia, etc.). In the absence of survival signals, myc sensitises the cell to an apoptotic trigger; however, the combination of deregulated Myc and survival signals act to promote cell proliferation. P53 may sensitize cells in part through upregulation of Fas, although other mechanisms likely exist. Adapted from Evan and Littlewood, 1998.p53 tumor supressor gene The p53 protein is a transcription transactivator that plays a central role in mediating the cellular response to DNA damage, helping to maintain genomic stability (24). Inactivation or loss of p53 are the most common aberrations in human cancers and they indicate that inactivation of tumor supressor genes is as equally important as activation of oncogenes like c-myc in tumorogenesis. Following sublethal DNA damage, p53 directs a G1 cell cycle arrest, allowing DNA repair to occur prior to further replication (reviewed in Ref. 25). In the event of excessive DNA damage, p53 initiates execution of the apoptotic program (26). Although the mechanism whereby p53 induces apoptosis is controversial, several studies have suggested that p53 regulates apoptosis by transcriptional suppression of anti-apoptotic proteins such as bcl-2 and induction of proapoptotic proteins such as bax, insulin-like growth factor binding protein 3 (IGF-BP3), and upregulation of the Fas receptor (Fig. 3). However, apoptosis can proceed by p53-independent pathways (e.g., glucocorticoid-mediated apoptosis of thymocytes), and is not required for developmental cell death (27,28). In sepsis, both p53-dependent and -independent pathways of apoptotic cell death have been reported (29). Overall, these findings suggest that the main role of p53 may be as a sensor of DNA damage and the mediation of the appropriate cellular response, cell cycle arrest, or apoptosis. Death receptor and death factor expression Death receptors belong to the tumor necrosis factor receptor (TNFR) gene superfamily, which is defined by similar cysteine-rich extracellular domains (30). A number of mammalian death receptors belonging to the TNFR family have been identified, including Fas, TNFR1, DR-3 (death receptor-3), DR-4, DR-5, and cytopathic avian leukosis-sarcoma virus receptor 1 (CAR1). In addition, this subfamily of TNFR contains a homologous cytoplasmic 80-amino acid domain termed the `death domain' (DD). DDs enable death receptors to engage the cell's apoptotic machinery (31). Aggregation of these receptors by a trimeric ligand induces apoptosis by recruiting adaptor proteins. The adaptor proteins also contain a DD that interacts with the DD of the receptor. The ligands that activate the death receptors are structurally related molecules belonging to the TNF gene superfamily (30). Fas ligand binds to Fas; TNF and lymphotoxin á bind to TNFR1; Apo3 ligand (Apo3L, also called TWEAK) binds DR-3;, and TRAIL (also called Apo2 ligand) binds to DR-4 and DR-5. The ligand for CAR1 is unknown. Following ligand-receptor binding, further protein-protein interactions are involved in the signalling of the death pathway. Homotypic domain interactions between proteins is a common theme in apoptosis. The recent identification of death factor-receptor pairs that regulate apoptosis brings a new level of complexity to the understanding of apoptotic cell death. It indicates that an external killer can control apoptosis in certain instances, and that it may trigger the death pathway through an autocrine, paracrine, or systemic fashion. Furthermore, alterations in death factor-receptor signalling may have important pathogenic roles in mediating inappropriate cell death in human diseases. Caspase [interleukin-1β-converting enzyme (ICE)-like protease] family Two genes were found to be essential in mediating developmental cell death in C. elegans: ced-3 and ced-4. The cloning and characterization of the ced-3 death-promoting gene revealed significant homology to the mammalian ICE, and provided the first indication that proteases may play a central role in apoptosis (Fig. 2) (32). Alnemri et al. (33) proposed a "caspase" nomenclature (for cysteine proteases that cleave after aspartate residues) for human members of this family (Table 2). Further support for a central role of caspases as effectors of apoptosis came from the fact that overexpression of caspases induced apoptosis (34), and the ability of selective caspase inhibitors such as viral cowpox-encoded protein CrmA prevented apoptosis (35). In sepsis, caspase inhibitors have been shown to improve survival by preventing lymphocyte apoptosis, leading to enhanced immunity (36). However, caspase-1-null mice display an apparently normal phenotype (37), suggesting that there may be functional redundancy in the caspase system, allowing a fail-safe mechanism through which the apoptotic process can be completed. However, evidence is now emerging that suggests that although caspase inhibitors may prevent certain characteristic biochemical and morphological features of apoptosis, cells that have sustained a cytotoxic insult and have been treated with caspase inhibitors have lost their replicative or clonogenic potential and all are destined to die, albeit by a slower mechanism not readily identifiable as classical apoptosis (38).Table 2: The human caspase familyNegative genetic regulators Bcl-2 gene family The intrinsic susceptibility of a cell to undergo apoptosis is determined by members of the protooncogene bcl-2 gene family, the mammalian homologue of ced-9 (Fig. 2). The prototypic regulator of cell death is bcl-2. Bcl-2 sets the basic apoptotic resistance threshold of cells (39), and overexpression of bcl-2 has been shown to prolong cellular survival by blocking apoptosis induced by a broad range of signals, including ultraviolet irradiation, cytokines, growth factor deprivation, and heat shock (reviewed in Ref. 40). In addition, overexpression of the bcl-2 gene has been shown to improve survival in sepsis, with a decrease bcl-2 expression found in peripheral monocytes in patients not surviving a septic insult (41,42). Bcl-2 belongs to a growing family of apoptosis regulatory gene products. Several homologues of the bcl-2 gene family have been recognised, including apoptotic antagonists (bcl-2, bcl-w, bcl-xL, bf1-1, brag-1, mcl-1, and A1) and apoptotic agonists [bax (bcl-2-associated protein x), bak, bik, bad, bcl-xs, bid, and hrk] (43). Many members of the bcl-2 protein family are capable of directly interacting with each other through a network of homo- and heterodimers. A dynamic equilibrium is established, with the ratio of death antagonists to agonists determining a cell's life or death response to an apoptotic stimulus (44). Just how bcl-2 blocks cell death is incompletely understood. Bcl-2 appears to have a number of functions in modulating the cellular response to an apoptotic stimulus, including acting as an ion channel, a mitochondrial membrane stabilizer, and as an adaptor or docking protein (Fig. 4) (43,45).Fig. 4: A model of the putative mechanisms of action of the bcl-2 family in regulating apoptosis. Anti-apoptotic bcl-2 family members such as bcl-xL appear to function at multiple levels to block apoptosis. bcl-xL may form discrete ion channels and regulate transmembrane ion fluxes; bcl-xL appears to act as an adaptor or docking protein by pulling other apoptotic regulating proteins out of the cytosol, functioning to either inactivate them to allow them to interact with other sequestered proteins; bcl-xL may act as a mitochondrial membrane stabilzer by inhibiting the opening of the permeability transition (PT) pore and preventing loss of the mitochondrial membrane potential (Δψm). A death signal may, for example, result in heterodimerizing of pro-apoptotic bcl-2 family members such as bax with bcl-xL and block its anti-apoptotic function. Bax may act to either block or alter bcl-xL's ion channel function, to prevent its adaptor function, to open the PT pore, or all three. In addition, bax appears to have intrinsic ion channel activity and may fulfil its pro-apoptotic role by promoting the loss of (Δψm).Ras gene family Ras gene family members (Ha, Ki, and N-ras) encode an almost identical 21-kD membrane-associated GTP-binding protein that has been associated with both proliferation and apoptosis (46). Ras proteins are key transducers of mitogenic signals, a fact attested by the high frequency of mutations in human (46). Ras proteins their potential through activation of the promoting cells to through G1 of the cell cycle the In to cellular overexpression of has been shown to apoptosis The protooncogene is a protein thought to play a role during cell cycle The forms of the family of and have been reported to of their through suppression of apoptosis between on to on the oncogene and a of the a of activity by and can growth cell from apoptosis induced by growth factor has been shown to be involved in activation In to intrinsic genetic factors, extracellular also regulate the susceptibility of cells to undergo apoptosis. Many factors, previously referred to as growth (e.g., insulin-like growth factor and growth are capable of apoptosis and maintaining cell in the absence of proliferation. are now referred to as control of regulation has support the number of and that all cells the of the a default apoptotic program and undergo apoptosis unless they are by the presence of survival This suggests that cell types be to the tissues their survival and of the survival factor Thus, of survival may be a common pathway to apoptosis. example, cells and cells have been shown to be on survival such as factor factor and (reviewed in Ref. The requirement of cells for survival signals may be in appropriate and of cells during and after an response. Following a systemic cytokines such as and are both and at found in have been shown to and apoptosis in and in the inflammatory response have also been shown to and suggesting that both and mechanisms may cell survival. Following of a local decrease in cytokines be to apoptosis in the cell with a to the regulatory controls evident in apoptosis, it is not that a complex and range of signalling molecules are following of an apoptotic response. molecular have been implicated in the apoptotic signalling including and The of morphological and biochemical events observed between different and cell types in the of apoptosis has to that these signals may a central or of the apoptotic process The of a common pathway may explain how negative regulators of apoptosis such as bcl-2 can apoptosis following by a broad of Several have the as the central of the apoptotic process acting to the of apoptosis. the apoptotic process can be into several but the induction in which the apoptotic process is and common are the central execution or in which the and anti-apoptotic signals are and the is in which the characteristic morphological and biochemical features of apoptosis The division of apoptosis, a complex process with multiple regulatory into although highly allow to in a important signalling events in the apoptotic and common signals in apoptosis Death receptor signalling for apoptosis In the number of there has been an in understanding of the death and regulator proteins involved in the release of apoptotic initiated following of the death receptor by its This has provided with at the complexity and of the death signal pathway. is now is that there multiple signalling pathways to cell death. or on the death signal the cell and the balance between apoptotic and survival signals. in the of growth regulation, multiple signalling pathways allow for multiple and regulation of apoptosis. and apoptotic pathways are the most and the binding of to Fas induces of the Fas receptor and activation of its cytoplasmic death recruiting a set of proteins into a signalling complex apoptotic pathways have been proposed (Fig. The characterized pathway the adaptor protein death domain which interacts with Fas its death domain and its death activation of the domain of caspase Caspase caspases such as caspase the mammalian functional homologue of the cell to Fas apoptotic pathways. 1 is by 3 with to form a complex that caspase Following of the apoptotic a series of signalling are which include activation of protein These enzymes can result in a of signalling including activation of and changes, including activation of protein and activation of transcription The of signalling in apoptosis is both cell and on the activation of the cell. of has been shown during apoptosis of peripheral suggesting that of proteins regulates apoptosis in these cells. In activation of in and prevents apoptosis and has been observed during The of on apoptosis is a number of factors, including the cell involved the activation and functioning of and the of inactivation of has been shown to be involved in A event in apoptosis in cell is the of resulting in a sustained in ions appear to play a central role in mediating apoptosis in certain cell with of extracellular or inhibiting apoptosis in these cells has been shown to have multiple potential of action in the apoptotic including activation of enzymes such as tissue and chromatin and gene However, in the of alteration in cellular levels not appear to be essential for the induction of apoptosis, the possibility that alterations in in certain cells occur as a of apoptosis. Furthermore, apoptotic cell death following is not of has been shown to apoptosis in certain cells such as in potential a has been observed cell following the induction of apoptosis by a range of stimuli and has been proposed as a apoptotic However, the requirement for production is not as production is not evident during induction of apoptosis in all cell indicate that the of the cell may be during apoptosis without of through a mechanism In addition, proapoptotic stimuli can apoptosis in the absence, or absence, of which implies that are not the of apoptosis important in the mediating in apoptosis have been production

Gliomas are primary tumors that originate in the central nervous system. The conventional treatment options for gliomas typically encompass surgical resection and temozolomide (TMZ) chemotherapy. However, despite aggressive interventions, the median survival for glioma patients is merely about 14.6 months. Consequently, there is an urgent necessity to explore innovative therapeutic strategies for treating glioma. The foundational study of regulated cell death (RCD) can be traced back to Karl Vogt's seminal observations of cellular demise in toads, which were documented in 1842. In the past decade, the Nomenclature Committee on Cell Death (NCCD) has systematically classified and delineated various forms and mechanisms of cell death, synthesizing morphological, biochemical, and functional characteristics. Cell death primarily manifests in two forms: accidental cell death (ACD), which is caused by external factors such as physical, chemical, or mechanical disruptions; and RCD, a gene-directed intrinsic process that coordinates an orderly cellular demise in response to both physiological and pathological cues. Advancements in our understanding of RCD have shed light on the manipulation of cell death modulation - either through induction or suppression - as a potentially groundbreaking approach in oncology, holding significant promise. However, obstacles persist at the interface of research and clinical application, with significant impediments encountered in translating to therapeutic modalities. It is increasingly apparent that an integrative examination of the molecular underpinnings of cell death is imperative for advancing the field, particularly within the framework of inter-pathway functional synergy. In this review, we provide an overview of various forms of RCD, including autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis and immunogenic cell death. We summarize the latest advancements in understanding the molecular mechanisms that regulate RCD in glioma and explore the interconnections between different cell death processes. By comprehending these connections and developing targeted strategies, we have the potential to enhance glioma therapy through manipulation of RCD.

In the dentate gyrus of adult female meadow voles, a high dose of estradiol benzoate (EB) increases (within 4 h) then decreases (within 48) the number of dividing progenitor cells (Ormerod BK, Galea LAM. 2001. Reproductive status regulates cell proliferation within the dentate gyrus of the adult female meadow vole: A possible regulatory role for estradiol. Neurosci 2:169-179). We investigated whether time-dependent EB exposure differentially influences the number of new granule cells produced in the adult female rat dentate gyrus and whether EB-stimulated adrenal activity mediates the decrease in cell proliferation. Ovariectomized rats received either an EB (10 microg in 0.1 mL) or vehicle (0.1 mL) injection either 4 or 48 h (Experiment 1) before a BrdU injection (200 mg/kg) and were perfused 24 h later to assess the number of new cells. Relative to vehicle, the number of new cells increased following a 4 h exposure (p < or = 0.04) but decreased following a 48 h exposure (p < or = 0.006) to EB. In Experiment 2, the number of new cells within the dentate gyrus of ovariectomized and adrenalectomized females did not significantly differ between groups exposed to EB versus vehicle for 48 h prior to BrdU administration, suggesting the decreased number of new cells observed within the dentate gyrus of adrenal-intact adult female rats is mediated by EB-stimulated adrenal activity. We conclude that estradiol dynamically regulates cell proliferation within the dentate gyrus of adult female rats in the time-dependent manner observed previously in voles and suppresses cell proliferation by influencing adrenal steroids. Investigating how estradiol dynamically regulates neurogenesis could provide insight into the mechanisms by which the proliferation of progenitor cells is controlled within the adult rodent hippocampus.

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Regulated cell death (RCD) encompasses the activation of cellular pathways that initiate and execute a self-dismissal process. RCD occur over a range of stressors doses that overcome pro-survival cellular pathways, while higher doses cause excessive damage leading to passive accidental cell death (ACD). Hydrogen peroxide (HP) has been proposed as a potential tool to control harmful cyanobacterial blooms, given its capacity to remove cyanobacterial cells and oxidize cyanotoxins. HP is a source of hydroxyl radicals and is expected to induce RCD only within a limited range of concentrations. This property makes this compound very useful to better understand stress-driven RCD. In this work, we analyzed cell death in microcystin-producing Microcystis aeruginosa by means of a stochastic dose response model using a wide range of HP concentrations (0, 0.29, 1.76, 3.67, 7.35, 14.70, and 29.5 mM). We used flow cytometry and unsupervised classification to study cell viability and characterize transitional cell death phenotypes after exposing cells to HP for 48 and 72 h. Non-linear regression was used to fit experimental data to a logistic cumulative distribution function (cdf) and calculate the half maximal effective concentration (EC50). The EC50 of M. aeruginosa exposed to HP were 3.77 ± 0.26 mM and 4.26 ± 0.22 mM at 48 and 72 h, respectively. The derivative of cdf (probability density function; pdf) provided theoretical and practical demonstration that EC50 is the minimal dose required to cause RCD in 50% of cells, therefore maximizing the probability of RCD occurrence. 1.76 mM HP lead to an antioxidant stress response characterized by increased reactive oxygen species (ROS) levels and HP decomposition activity. The exposure of 3.67 mM HP induced a dose-related transition in cell death phenotype, and produced several morphological changes (a less dense stroma, distortion of the cell membrane, partial disintegration of thylakoids, extensive cytoplasmic vacuolation and highly condensed chromatin). The EC50 and the stochastic cdf and pdf together with the multidimensional transitional phenotypic analysis of single cells contribute to further characterize cell death pathways in cyanobacteria.

Emerging role of necroptosis, pyroptosis, and ferroptosis in breast cancer: New dawn for overcoming therapy resistance

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

Cell death mechanisms are broadly classified into accidental cell death (ACD) and regulated cell death (RCD). ACD such as necrosis, is an uncontrolled, accidental process, while RCD is tightly regulated by specific signaling pathways and molecular mechanisms. Tumor cells are characterized by their ability to evade cell death and sustain uncontrolled proliferation. The failure of programmed cell death is a key contributor to tumor initiation, progression, and resistance to cancer therapies. Traditionally, research has focused primarily on apoptosis as the dominant form of RCD in cancer. However, emerging evidence highlights the importance of other non-apoptotic forms of RCD, such as pyroptosis, ferroptosis, necroptosis, and parthanatos, in tumorigenesis and treatment response. These pathways are gaining attention for their potential roles in overcoming therapy resistance. In this review, we will discuss the recent advances in the study of non-apoptotic cell death pathways in malignant tumors and explore their therapeutic implications, offering insights into new targets for cancer treatment strategies.

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

Ischaemic damage to the brain is the main cause of brain injury after cardiac arrest. The current treatment focuses on early reperfusion, but reperfusion tends to cause reperfusion injury, which is a significant problem. Cell death is an irreversible and normal end to cell life, playing key roles in maintaining the homeostasis and development of multicellular organisms. To date, cell death can be classified into two categories: accidental cell death (ACD) and regulated cell death (RCD). Cell death plays an indispensable role in cerebral ischaemia injury. An increasing number of scholars are exploring the mechanisms and sites of cell death during targeted inhibition of cerebral ischaemia to treat cerebral ischaemia injury. In addition to the established cell death pathways, namely, the apoptosis, pyroptosis and necroptosis pathways, ferroptosis and cuproptosis pathways have been discovered. This article reviews the cell death pathways involved in ischaemic brain injury, discusses the roles played by these death modalities, and suggests therapeutic directions for future targeting of cell death sites.

Cell Death in the Liver—All Roads Lead to JNK

BACKGROUND: Millions of cells in multicellular organisms regenerate every day to replace aged and died cells. Effective cell clearance (efferocytosis) is critical for tissue homeostasis, as the human body recycles its cellular components. We summarize what is known about the mechanisms of efferocytosis and how it impacts the physiology of the organism, effects on inflammation and the adaptive immune response, as well as the consequences of defects in this critical homeostatic mechanism in this review.CONTENT: Cell death is the process by which the human body replaces aged or damaged cells with new ones. It can be triggered by genetically encoded machinery or regulated cell death, or by specific pharmacologic or genetic interventions, resulting in accidental cell death. Dying cells release signals that entice phagocytes to engulf them in a process known as efferocytosis. Efferocytosis is a multistep process involving the release of “find me” and “eat me” signals and destruction of death cells by phagocytes. Different types of cell death including apoptosis and necroptosis can express pro- or anti-inflammatory signals via macrophage activity modulation.SUMMARY: Failed or ineffective efferocytosis can result in disruption of tissue homeostasis, which can contribute to the development of chronic inflammatory diseases such as atherosclerosis, obesity, diabetes, and heart failure. Therefore, any therapeutic strategy that enhances efferocytosis will have a beneficial effect on the treatment of these metabolic disorders.KEYWORDS: apoptosis, necroptosis, phagocytosis, efferocytosis, macrophage.