Relationship between autophagy and apoptotic cell death in human neuroblastoma cells treated with paraquat: could autophagy be a "brake" in paraquat-induced apoptotic death?

Paraquat (PQ) (1, 1'-dimethyl-4, 4'-bipyridinium dichloride), a widely used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). In neurons from patients with PD display characteristics of autophagy, a degradative mechanism involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. Low concentrations of paraquat have been recently found to induce autophagy in human neuroblastoma cells, and ultimately the neurons succumb to apoptotic death. Whereas caspase inhibition retarded cell death, autophagy inhibition accelerated the apoptotic cell death induced by paraquat. These findings suggest a relationship between autophagy and apoptotic cell death in human neuroblastoma cells treated with paraquat and open a new line of investigation to advance our knowledge regarding the origin of PD.     

Salmonella-induced cell death: apoptosis, necrosis or programmed cell death?

Over the past several years, it has become apparent that enteropathogens activate cell death programs. For Salmonella and Shigella species, the induction of cell death is required for pathogenesis, and the mechanisms by which these bacteria induce cell death is an area of intense investigation. Although initial studies suggested that Salmonella induce cell death through an apoptotic pathway, recent studies demonstrate that cell death occurs through a unique caspase 1-dependent mechanism.     

"Natural cause of death or not?" How do nursing home physicians act when in doubt of natural cause of death?

The objective of the study was to explore if nursing home physicians act by law, when they doubt the natural cause of death. In May 1999, a questionnaire was sent to 153 nursing home physicians in the region of Utrecht and Nijmegen. They were asked if they consult the coroner when they have doubts about the natural cause of death. Eighty-six percent (104) returned the questionnaire. Thirty-two percent of the nursing home physicians always consult the coroner and 52% does so most of the time. Only 12% does not consult the coroner most of the time and 2% never does. The main reasons for not consulting the coroner were that nursing home physicians judge a death after a fall as an incident that fits in the descending lifeline of patients and that some nursing home physicians had bad experiences consulting the coroner. We conclude that this policy may lead to underregistration of unnatural deaths. Changing the definition or changing the law may reduce this problem. Education and information can also contribute to change in physician's attitudes.     

α-Synuclein and neuronal cell death

Mutations in the DJ-1 gene have been linked to autosomal recessive familial Parkinson's disease. To understand the function of DJ-1, we determined the DJ-1 expression in both zebrafish and post mortem human brains. We found that DJ-1 was expressed early during zebrafish development and throughout adulthood. Knock down (KD) of DJ-1 by injection of morpholino did not cause dramatic morphologic alterations during development, and no loss of dopaminergic neurons was observed in embryos lacking DJ-1. However, DJ-1 KD embryos were more susceptible to programmed cell death. While a slight reduction in staining for islet-1 positive neurons was observed in both DJ-1 KD and H₂O₂ treated embryos, the number of apoptotic cells was significantly increased in both KD and H₂O₂ treated embryos. Interestingly, DJ-1 expression was increased in brains of zebrafish under conditions of oxidative stress, indicating that DJ-1 is a part of stress-responsive machinery. Since oxidative stress is one of the major contributors to the development of Alzheimer's disease (AD), we also examined DJ-1 expression in AD brains. Using DJ-1 specific antibodies, we failed to detect a robust staining of DJ-1 in brain tissues from control subjects. However, DJ-1 immunoreactivity was detected in hippocampal pyramidal neurons and astrocytes of AD brains. Therefore, our results strongly suggest that DJ-1 expression is not necessary during zebrafish development but can be induced in zebrafish exposed to oxidative stress and is present in human AD brains.     

Apoptosis or programmed cell death?

Although there are different ways in which cells may die, it is now thought that in a developmental context cells are induced to positively commit suicide whilst in a homeostatic context the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.     

Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

Unicellular organisms, such as the protozoan parasite Leishmania, can be stimulated to show some morphological and biochemical features characteristic of mammalian apoptosis. This study demonstrates that under a variety of stress conditions such as serum deprivation, heat shock and nitric oxide, cell death can be induced leading to genomic DNA fragmentation into oligonucleosomes. DNA fragmentation was observed, without induction, in the infectious stages of the parasite, and correlated with the presence of internucleosomal nuclease activity, visualisation of 45 to 59 kDa nucleases and detection of TUNEL-positive nuclei. DNA fragmentation was not dependent on active effector downstream caspases nor on the lysosomal cathepsin L-like enzymes CPA and CPB. These data are consistent with the presence of a caspase-independent cell death mechanism in Leishmania, induced by stress and differentiation that differs significantly from metazoa.     

Cloning and identifying of a novel protein binding with death domain of the death receptor 4

DR4 (Death Receptor 4) belongs to the tumor necrosis factor (TNF) receptor gene family, which is defined by similar, cysteine-rich extracellular domain and a homologous cytoplasmic sequence termed as "death domain". DR4 can transmit apoptosis signal initiated by Apo2L/TRAIL (TNF-related apoptosis inducing ligand). It can activate caspases within seconds of ligand binding and cause an apoptotic demise of the cell within hours. Despite several investigations, the mechanisms of apoptosis initiation by Apo2L/TRAIL remain unclear.     

Brain death: a durable consensus?

Is it even conceivable that this global consensus [on the whole-brain definition of death] could, in time, be regarded as a very temporary and makeshift expedient, a momentary substitute for a resolution of some profoundly difficult issues which for a time, perhaps a brief time, fit with both the technical capacities and the legal needs of those who endorsed it? And that in the long run it could linger as a footnote, or perhaps a chapter heading, in the long history of man's conceptions of life and death? This suggestion is so far from conventional wisdom today that one who espouses it risks being regarded as a crank. Nevertheless, I believe that the argument in its favor, while not conclusive, is much stronger than the argument against it (and in favor of the prevailing consensus). I will state the argument briefly, with particular reference to the landmark report in 1982 in Washington of the President's Commission for the Study of Ethical Problems in Medicine, and will situate the argument in the context of trends in contemporary bioethics. I do not expect to win over, in this one pass, those who have been convinced of the validity of the conventional view. I do hope, however, to re-open the issue; in particular, to provide reasons to regard the issue as far from settled.     

Can the famous really postpone death?

David P. Phillips has reported evidence that famous people are often able to postpone their deaths until after a birthday. A reexamination of Phillips' data shows some aspects of his analysis to be questionable, including the lumping together of deaths that occur during the birthmonth, which does not distinguish deaths that occurred before the birthday from those that occurred afterward. A reanalysis of his data shows that there were actually a relatively large number of deaths in the month preceding and the months following the birthday. One explanation is that the anxiety associated with this milestone and the excesses associated with its celebration are sometimes fatal. Another explanation is that Phillips' results were a fluke created by a selective use of data.     

Daxx: death or survival protein?

The death domain-associated protein (Daxx) was originally cloned as a CD95 (FAS)-interacting protein and modulator of FAS-induced cell death. Daxx accumulates in both the nucleus and the cytoplasm; in the nucleus, Daxx is found associated with the promyelocytic leukaemia (PML) nuclear body and with alpha-thalassemia/mental retardation syndrome protein (ATRX)-positive heterochromatic regions. In the cytoplasm, Daxx has been reported to interact with various proteins involved in cell death regulation. Despite a significant number of studies attempting to determine Daxx function in apoptotic and non-apoptotic cell death, its precise role in this process is only partially understood. Here, we critically review the current understanding of Daxx function and shed new light on this interesting field.     

Does autophagy contribute to cell death?

Autophagy (specifically macroautophagy) is an evolutionarily conserved catabolic process where the cytoplasmic contents of a cell are sequestered within double membrane vacuoles, called autophagosomes, and subsequently delivered to the lysosome for degradation. Autophagy can function as a survival mechanism in starving cells. At the same time, extensive autophagy is commonly observed in dying cells, leading to its classification as an alternative form of programmed cell death. The functional contribution of autophagy to cell death has been a subject of great controversy. However, several recent loss-of-function studies of autophagy (atg) genes have begun to address the roles of autophagy in both cell death and survival. Here, we review the emerging evidence in favor of and against autophagic cell death, discuss the possible roles that autophagic degradation might play in dying cells, and identify salient issues for future investigation.     

The end of autophagic cell death?

In the mammalian system, cell death is often preceded or accompanied by autophagic vacuolization, a finding that initially led to the widespread belief that so-called "autophagic cell death" would be mediated by autophagy. Thanks to the availability of genetic tools to disable the autophagic machinery, it has become clear over recent years that autophagy usually constitutes a futile attempt of dying cells to adapt to lethal stress rather than a mechanism to execute a cell death program. Recently, we systematically addressed the question as to whether established or prospective anticancer agents may induce "autophagic cell death". Although a considerable portion among the 1,400 compounds that we evaluated induced autophagic puncta and actually increased autophagic flux, not a single one turned out to kill tumor cells through the induction of autophagy. Thus, knockdown of essential autophagy genes (such as ATG5 and ATG7) failed to prevent and rather accelerated chemotherapy-induced cell death, in spite of the fact that this manipulation efficiently inhibits autophagosome formation. Herein, we review these finding and--polemically--raise doubts as to the very existence of "autophagic cell death".     

Freezing or death feigning? Beetles selected for long death feigning showed different tactics against different predators

Prey evolve antipredator strategies against multiple enemies in nature. We examined how a prey species adopts different predation avoidance tactics against pursuit or sit‐and‐wait predators. As prey, we used three strains of Tribolium beetles artificially selected for short (short strain) or long (long strain) duration of death feigning, and a stock culture (base population). Death feigning is known to be effective for evading a jumping spider in the case of the long strains, while the present study showed that the long‐strain beetles used freezing against a sit‐and‐wait type predator, Amphibolus venator, in this study. The short‐ strain beetles were more easily oriented toward predators. The time to predation was also shorter in the short strains compared to the long strains. The results showed that, as prey, the short strains displayed the same behavior, escaping, against both types of predators. Traditionally, death feigning has been thought to be the last resort in a series of antipredator avoidance behaviors. However, our results showed that freezing and death feigning were not parts of a series of behaviors, but independent strategies against different predators, at least for long‐strain beetles. We also examined the relationship between a predator''s starvation level and its predatory behavior. In addition, the orientation behavior toward and predation rate on the prey were observed to determine how often the predatory insect attacked the beetles.