Paraptosis (from the Greek παρά para, "related to" and apoptosis) is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.
The first reported use of the term "paraptosis" was by Sabina Sperandio et al. in 2000. The group used human insulin-like growth factor 1 receptor (IGF-1R) to stimulate cell death in 293T cells and mouse embryonic fibroblasts, observing distinct differences from other forms of cell death. They coined the term "paraptosis", derived from the Greek preposition para, meaning beside or related to, and apoptosis.
While Sperandio was the first to publish the term paraptosis, this was not the first time cell death with the properties of paraptosis was observed. Terms such as "cytoplasmic" and "type 3 cell death" had previously been used to describe these forms of cell death. These forms are very similar to paraptosis morphologically, and it is possible that some instances of cell death originally described as one of these forms are occurrences of paraptosis.
Paraptosis is a form of type III programmed cell death with a unique combination of certain apoptotic and necrotic characteristics. Paraptosis does not demonstrate nuclear fragmentation, formation of apoptotic bodies, or definitive demonstration of chromatin condensation - all seen in apoptosis. Instead, paraptosis displays a somewhat primitive cell death path, comparable to necrosis, including characteristic cytoplasmic vacuole formation and late mitochondrial swelling and clumping. The number and size of vacuoles increases over time. Eventually, the vacuole sizes reach a point of no return and the cell cannot recover.
Similar to apoptosis, staining techniques can be used to identify paraptotic cells by highlighting the translocation of phosphatidylserine from the plasma membrane cytoplasmic (inner) leaflet to the cell surface or outer leaflet.
Almost immediately, major structural rearrangements such as rounded cells, cytoplasmic reorganization, and vacuolation of cells undergoing paraptosis can be seen through light microscopy. There is physical enlargement of the mitochondria and endoplasmic reticulum. This swollen appearance can be attributed to intracellular ion imbalance and eventual osmotic lysis. Once ruptured, particles and substances are released, including: (1) high mobility group B-1 (HMGB1) (2) heat shock proteins and (3) various other proteases. These substances are "danger signals" and result in inflammation.
While certain templates of programmed cell death have been known to rely on de novo protein synthesis, paraptotic cell death induced by IGFIR-IC in 293T cells is deterred by actinomycin D and cycloheximide, thus demonstrating a dependence on transcription and translation.
Induction of paraptosis has been determined to be mediated through two positive signal transduction pathways, MAPK and JNK, by using IGF-IR at the receptor level. As such, paraptosis can be prevented by inhibiting specific protein kinases of these pathways.
Paraptosis-like phenotype has also been described in human colorectal cancer cells following overactivation of the non-receptor tyrosine kinase c-Src suggesting potential involvement of Src-signalling in paraptosis.
Cell death induced by IGFIR-IC in 293T cells demonstrated cell death without associated caspase activity. This is in comparison to apoptosis, in which the proapoptotic protein Bax induced caspase activation and cell death. Additionally, research found that caspase inhibitors (zVAD.fmk, p53, BAF), x-chromosome-linked inhibitor (xiap), and Bcl-xL( from the Bcl-2 family) did not prevent cell death in 293T cells when induced by IGFIR-IC. Therefore, paraptosis was concluded to differ from apoptosis (cell death type 1) in being unaffected by inhibitors of apoptosis.
The most defining difference observed (as of April 2014) between paraptosis and autophagic cell death (cell death type 2) is paraptosis' lack of the characteristic autophagic vacuoles seen in autophagic cell death. As expected, autophagic cell death inhibitors (for instance, 3-methyladenine) are ineffective at inhibiting paraptosis.
|Membrane Blebbing||No||Yes||Yes, late|
|Programmed cell death||Yes||Yes||No|
|Actinomycin D, cycloheximide||Yes||Sometimes||No|
|Caspase inhibitors (zVAD.fmk, p53, BAF)||No||Yes||No|
In cells undergoing paraptosis:
PEBP, or Raf kinase inhibitor protein (RKIP) is diminished in paraptotic cells, thus resultant down regulation of PEBP and/or other kinase inhibitors seem to indicate participation in the MAPK and JNK pathways, as diminished PEBP would allow for the levels of MAPK and JNK to accumulate enough to be sufficient to induce cell death.
Paratotic cells demonstrated a 3.4 fold increased in prohibitin. Increased levels of prohibitin in conjugation with a paratotic stimulus can result in cell death that is unable to be inhibited by caspase inhibitors.
Many anti-cancer substances have been shown to cause paraptosis in a large range of human cancer cells. This includes several compounds derived from natural sources as well as metal complexes. The use of naturally derived compounds to treat cancer can provide a way to avoid many of the harmful side effects of traditional chemotherapy. Paraptosis is also an area of interest for Cancer Research as a way to treat apoptosis resistant cancers.
Paclitaxel, commonly distributed under the trade name Taxol, is a cancer drug used for the treatment of breast and ovarian cancers. At high concentrations (70 μM), one study showed it to induce a paraptosis-like cell death, and could be an important mechanism for treating apoptosis-resistant cancers.
Researchers have reported finding that γ-Tocotrienol, a form of vitamin E derived from palm oil, induced paraptosis-like cell death in colon cancer cells. Along with inducing paraptosis, γ-tocotrienol also suppressed the Wnt signaling pathway, which plays a role in tumor development. The combination of these two features could provide a novel mechanism for treating colon cancer.
Steamed American ginseng extract has been reported to "potently kill colorectal cancer cells". Specifically, derivatives of protopanaxadiol Rg3 and Rh2, are the key ginsenosides found in the extract. In colorectal cancer cell lines, HCT116, cytosolic vacuolization has been induced by Rh2. Furthermore, Rh2-induced vacuolization was inhibited by a MEK1/2 specific inhibitor U0126, cycloheximide, thus confirming two characteristic properties of paraptosis, signaling via MAP kinase and required protein translation. Rh2 also induces increase ROS levels, which activate the NF-κB signaling pathway, while blocking ROS with NAC or catalase prevents the activation of NF-κB signaling and further enhances cell death induced by Rh2. This suggests an antioxidant-enhanced anticancer effect of Rh2.
Honokiol, a compound derived from Magnolia officinalis, can induce paraptosis in human leukemia cells. In the NB4 cell line, paraptosis was the primary method of cell death. In K562 cells, apoptosis was the primary mechanism, with paraptosis occasionally found. Researchers stated that this suggests that leukemia cell death can be induced by multiple pathways.
In one experiment a phosphine copper(I) complex caused paraptosis in colon cancer cells by inducing endoplasmic reticulum stress. Another copper complex, the A0 thioxotriazole copper (II) complex, also caused paraptosis in HT1080 fibrosarcoma cells via endoplasmic reticulum stress and cytoplasmic vacuolization. Along with cytotoxic effects such as an increase in oxidized glutathione and prevention of proteasome activity, A0 prevented the activity of caspase-3, which may inhibit apoptosis and cause the cells to die via paraptosis.
The activity of the mammalian tumor suppressor p53 depends on levels of an isoform of p53, p44. In an experiment with transgenic mice that had an over-expression of p44, hyper-activation of IGF-1R occurred, which in turn led to accelerated aging and death. The mice also experienced neuronal death in areas of the brain related to memory formation and retrieval. This IGF-1R induced neurodegeneration was caused by both paraptosis and autophagic cell death. IGF-1R is an important area of research for neurodegenerative diseases, as defects in IGF-1R siginaling, including increased levels of IGF-1R, have been found in the brains of Alzheimer's patients.
Paraptosis-like programmed cell death has been observed in both plants and protists. Apoptotic death similar to that found in animals does not occur in plants, due to the cell wall of plant cells preventing phagocytosis. In an experiment with tobacco, bleomycin was used to introduce double strand breaks in the cells' DNA. This then caused cells to undergo programmed cell death with considerable vacuolization and an absence of DNA fragmentation and caspase inhibition, similar to paraptosis. A study with the algae Dunaliella viridis demonstrated the ability of protists to undergo programmed cell death via several types, including paraptosis and apoptosis, depending on different environmental stimuli. A combination of these factors have led to speculation that paraptosis may be an ancestral form of programmed cell death, conserved across different forms of life.
Algor mortis (Latin: algor—coldness; mortis—of death), the second stage of death, is the change in body temperature post mortem, until the ambient temperature is matched. This is generally a steady decline, although if the ambient temperature is above the body temperature (such as in a hot desert), the change in temperature will be positive, as the (relatively) cooler body acclimates to the warmer environment. External factors can have a significant influence.
The term was first used by Dowler in 1849. The first published measurements of the intervals of temperature after death were done by Dr John Davey in 1839.Dead on arrival
Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.
In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.Death hoax
A death hoax is a deliberate or confused report of someone's death that turns out to be incorrect and murder rumors. In some cases it might be because the person has intentionally faked death.Death messenger
Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.Death pose
Dinosaur and bird fossils are frequently found in a characteristic posture consisting of head thrown back, tail extended, and mouth wide open. The cause of this posture—sometimes called a "death pose"—has been a matter of scientific debate. Traditional explanations ranged from strong ligaments in the animal's neck desiccating and contracting to draw the body into the pose, to water currents randomly arranging the remains in the position.Faux and Padian suggested in 2007 that the live animal was suffering opisthotonus during its death throes, and that the pose is not the result of any post-mortem process at all. They also reject the idea of water as responsible for randomly arranging the bodies in a "death pose", as different parts of the body and the limbs can be in different directions, which they found unlikely to be the result of moving water. They also found that the claim that drying out of ligaments would make the position does not seem believable either.
Alicia Cutler and colleagues from Brigham Young University in Provo, Utah, think it is related to water. In 2012, paleontologists Achim G. Reisdorf and Michael Wuttke published a study regarding death poses. According to the conclusions of this study, the so-called "opisthotonic posture" is not the result of a cerebral illness creating muscle spasms, and also not of a rapid burial. Rather, peri-mortem submersion resulted in buoyancy that enabled the Ligamentum elasticum to pull the head and tail back.Death rattle
Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.Dignified death
Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.Dysthanasia
In medicine, dysthanasia means "bad death" and is considered a common fault of modern medicine.Dysthanasia occurs when a person who is dying has their biological life extended through technological means without regard to the person's quality of life. Technologies such as an implantable cardioverter defibrillator, artificial ventilation, ventricular assist devices, and extracorporeal membrane oxygenation can extend the dying process.
Dysthanasia is a term generally used when a person is seen to be kept alive artificially in a condition where, otherwise, they cannot survive; sometimes for some sort of ulterior motive. The term was used frequently in the investigation into the death of Formula One driver Ayrton Senna in 1994.Fan death
Fan death is a well-known superstition in Korean culture, where it is thought that running an electric fan in a closed room with unopened or no windows will prove fatal. Despite no concrete evidence to support the concept, belief in fan death persists to this day in Korea, and also to a lesser extent in Japan.Funeral director
A funeral director, also known as an undertaker (British English) or mortician (American English), is a professional involved in the business of funeral rites. These tasks often entail the embalming and burial or cremation of the dead, as well as the arrangements for the funeral ceremony (although not the directing and conducting of the funeral itself unless clergy are not present). Funeral directors may at times be asked to perform tasks such as dressing (in garments usually suitable for daily wear), casketing (placing the human body in the coffin), and cossetting (applying any sort of cosmetic or substance to the best viewable areas of the corpse for the purpose of enhancing its appearance). A funeral director may work at a funeral home or be an independent employee.Lazarus sign
The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus raised from the dead in the Gospel of John.Megadeath
Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.Necronym
A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.
For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.Necrophobia
Necrophobia is a specific phobia which is the irrational fear of dead things (e.g., corpses) as well as things associated with death (e.g., coffins, tombstones, funerals, cemeteries). With all types of emotions, obsession with death becomes evident in both fascination and objectification. In a cultural sense, necrophobia may also be used to mean a fear of the dead by a cultural group, e.g., a belief that the spirits of the dead will return to haunt the living.Symptoms include: shortness of breath, rapid breathing, irregular heartbeat, sweating, dry mouth and shaking, feeling sick and uneasy, psychological instability, and an altogether feeling of dread and trepidation. The sufferer may feel this phobia all the time. The sufferer may also experience this sensation when something triggers the fear, like a close encounter with a dead animal or the funeral of a loved one or friend. The fear may have developed when a person witnessed a death, or was forced to attend a funeral as a child. Some people experience this after viewing frightening media.The fear can manifest itself as a serious condition. Treatment options include medication and therapy.The word necrophobia is derived from the Greek nekros (νεκρός) for "corpse" and the Greek phobos (φόβος) for "fear".Obituary
An obituary (obit for short) is a news article that reports the recent death of a person, typically along with an account of the person's life and information about the upcoming funeral. In large cities and larger newspapers, obituaries are written only for people considered significant. In local newspapers, an obituary may be published for any local resident upon death. A necrology is a register or list of records of the deaths of people related to a particular organization, group or field, which may only contain the sparsest details, or small obituaries. Historical necrologies can be important sources of information.
Two types of paid advertisements are related to obituaries. One, known as a death notice, omits most biographical details and may be a legally required public notice under some circumstances. The other type, a paid memorial advertisement, is usually written by family members or friends, perhaps with assistance from a funeral home. Both types of paid advertisements are usually run as classified advertisements.Pallor mortis
Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.Post-mortem interval
Post-mortem interval (PMI) is the time that has elapsed since a person has died. If the time in question is not known, a number of medical/scientific techniques are used to determine it. This also can refer to the stage of decomposition of the body.Rigor mortis
Rigor mortis (Latin: rigor "stiffness", mortis "of death"), or postmortem rigidity, is the third stage of death. It is one of the recognizable signs of death, characterized by stiffening of the limbs of the corpse caused by chemical changes in the muscles postmortem. In humans, rigor mortis can occur as soon as four hours after death.Skeletonization
Skeletonization refers to the final stage of decomposition, during which the last vestiges of the soft tissues of a corpse or carcass have decayed or dried to the point that the skeleton is exposed. By the end of the skeletonization process, all soft tissue will have been eliminated, leaving only disarticulated bones. In a temperate climate, it usually requires three weeks to several years for a body to completely decompose into a skeleton, depending on factors such as temperature, humidity, presence of insects, and submergence in a substrate such as water. In tropical climates, skeletonization can occur in weeks, while in tundra areas, skeletonization may take years or may never occur, if subzero temperatures persist. Natural embalming processes in peat bogs or salt deserts can delay the process indefinitely, sometimes resulting in natural mummification.The rate of skeletonization and the present condition of a corpse or carcass can be used to determine the time of death.After skeletonization, if scavenging animals do not destroy or remove the bones, acids in many fertile soils take about 20 years to completely dissolve the skeleton of mid- to large-size mammals, such as humans, leaving no trace of the organism. In neutral-pH soil or sand, the skeleton can persist for hundreds of years before it finally disintegrates. Alternately, especially in very fine, dry, salty, anoxic, or mildly alkaline soils, bones may undergo fossilization, converting into minerals that may persist indefinitely.