Elias Tzakas MBBS MRCOG

• Mitera Hospital, Athens, Greece

The organ dose calculation allows for effects of external shielding and shielding provided by other tissues erectile dysfunction doctors in sri lanka viagra super active 50 mg order online. This factor reflexology erectile dysfunction treatment discount viagra super active, which accounts for differences in the biological effectiveness of different particles impotence help 50 mg viagra super active order fast delivery, is used to convert an absorbed dose into a dose equivalent erectile dysfunction drugs injection buy 25 mg viagra super active amex. Quality factor values as high as 100 may be deemed appropriate as additional research continues erectile dysfunction treatment with diabetes generic viagra super active 50 mg with amex. Rad (United States)/gray (international) the absorbed dose, rad, is the amount of energy absorbed from radiation per mass of material (1 rad ¼ 100 ergs gÀ 1). Chemical and biological changes in tissue exposed to ionizing radiation depend upon the energy absorbed in the tissue from the radiation rather than upon the amount of ionization that the radiation produces in air. To describe the energy absorbed in a medium from any type of ionizing radiation, the quantity of radiation should be described in units of rads. The rad, which was originally an acronym for radiation absorbed dose, is a unit of absorbed dose and represents the absorption of 10À 2 Joules of energy per kilogram (or 100 ergs gÀ 1) of absorbing material: 1 rad ¼ 10À2 J kgÀ1 ¼ 100 ergs gÀ1 the absorbed dose D in rads delivered to a small mass m in kilograms is D rad ¼ E=m Ä 10À2 J kgÀ1 where E, the absorbed energy in joules, is "the difference between the sum of the energies of all directly and indirectly ionizing particles which have entered the volume and the sum of the energies of all those which left it minus the energy equivalent of any increase in rest mass that took place in nuclear or elementary particle reactions within the volume. Radiation weighting factor (Wr) Factor, established by consensus and used in radiation protection, to weight the absorbed dose averaged over an organ to obtain the equivalent dose on a common scale for types of ionizing radiation. Radioisotope Radioactive species of an element with the same atomic number and identical chemical properties. Radionuclide Radioactive species of an atom characterized by the constituents of its nucleus (atomic number). Radiosensitivity Relative susceptibility of cells, tissues, organs, and organisms to the injurious action of radiation. Radiosensitivity and its antonym, radioresistance, are used in a comparative sense rather than an absolute sense. For equal absorbed doses, various types of ionizing radiation often differ in the efficiency with which they illicit a particular chemical or biological response. It is computed by comparing results obtained with the radiation in question to the results obtained with a reference radiation. Risk coefficient Increase in the incidence of disease or mortality per person exposed per unit equivalent dose. The relative risk coefficient is the fractional increase in the baseline incidence or mortality rate for a unit dose. Risk estimate Number of cases (or deaths) projected to occur in a specified exposed population per unit of collective dose for a specified exposure regime and expression period, for example, number of cases per person (in gray). The Roentgen is a measure of the quantity of ionization induced in air from radiation exposure. When an individual is exposed to mixed sources of radiation, the total biologically effective dose is calculated by multiplying the physical dose (expressed in units called gray) of each kind of radiation by a corresponding factor (the Q-factor) specified for the type of radiation and its energy, after which these amounts are summed. Solar flare Sudden release of energy across the electromagnetic spectrum from a relatively small region of the Sun. Flares are often characterized by brightening in an optical wavelength (Ha, a red wavelength) or soft X-rays (1­8 Å). Flares are classified on a logarithmic scale using B, C, M, and X designations for very small, small, moderate, and large X-ray flares. Stochastic effects Random events leading to effects whose probability of occurrence in an exposed population of cells or individuals (rather than severity in an affected cell or individual) is a direct function of dose. Some somatic effects, especially carcinogenesis, are regarded as being stochastic. Target theory (hit theory) Explains some biological effects of radiation on the basis that ionization, which occurs in a discrete volume (the target) within a cell, directly causes a lesion that later results in a physiological response to the damage at that location. One, two, or more hits (ionizing events within the target) may be necessary to elicit this response. Threshold dose Dose level below which there is no effect of radiation on the biological response. It is often difficult to distinguish between a threshold and a linear quadratic dose response, where the response changes only slightly at low doses. A threshold model postulates that radiation does not cause the effect at any level below the threshold. Radiation thresholds are generally thought to be limited to acute (short-term) effects that are called deterministic, because they require depletion of certain cells in the body to below a critical number in a given organ or tissue. These effects include radiation sickness (nausea and vomiting), infection and bleeding, and loss of hair. Transport calculation Calculation of particle distributions and energy behind a specific shield. Transportation calculation is derived from the basic nuclear cross sections for interaction and fragmentation in shielding. Ionizing radiation may be in the form of either electromagnetic waves or particles; however, it must have sufficient energy to cause ionization in the target molecule. This article will first describe the physical interaction between the different forms of ionizing radiation and cellular and subcellular components, as well as the factors that are likely to produce an elevated risk of neoplasia. Next, the biological and molecular effects of radiation within living systems will be examined, followed by a presentation of the epidemiological evidence for radiation as a carcinogen in animals and humans. Some risk models for carcinogenesis following an exposure to ionizing radiation, as well as some strategies for protection against radiation-induced biological damage, are included. Important new avenues of research and some of the controversial issues surrounding radiation carcinogenesis are brought forth. Finally, the significance of ionizing radiation-induced carcinogenesis to the understanding and management of the broader issue of the etiology of human cancer will be addressed. The electromagnetic spectrum is a continuum of all electromagnetic waves according to frequency and wavelength. Electromagnetic energy at a particular wavelength l (measured in meters) has an associated frequency f (measured in cycles per seconds, i. Thus, the electromagnetic spectrum may be expressed in terms of any of these three quantities. Thus, high-frequency electromagnetic waves have a short wavelength and high energy, whereas low-frequency waves have a long wavelength and low energy. Therefore, a shorter wavelength corresponds to more energetic radiation and an increased potential for biological harm. The electromagnetic spectrum is divided into different types of radiation based on wavelength ranges and encompasses a wide range of terrestrial applications. The scale at the bottom indicates representative objects that are equivalent to the wavelength scale and their respective energy. In contrast to this, charged particles, such as high-energy electrons, protons, a-particles (a helium atom nucleus moving at a very high speed), b-particles (a high-speed electron or positron), and fast heavy ions, are termed direct ionizing radiation because while they traverse the cell, they ionize numerous molecules by direct collisions with their electrons. Nonionizing radiation is present in a wide range of occupational settings and can pose a considerable health risk. In the context of biological systems, ionizing radiation must be understood in terms of the radioactivity of the source, the energy of the radiation, the level of background radiation, and the level of radiation energy absorbed. The latter, from an occupational exposure point of view, is the most important parameter. By definition, the common unit of measure for energy present in ionizing radiation is the electron volt (eV). Other parameters, apart from the energy level of a particular type of radiation, are important to the understanding of the biological effects of ionizing radiation (Table 1). One gray is equivalent to 1 J of radiation energy absorbed per kilogram of tissue (1 J kgÀ 1 ¼ 6. However, the types of radiation are diverse in how they deposit energy; therefore, the absorbed dose is a poor descriptor of biological effects (Durante and Cucinotta, 2008). A dose of energetic particles normally causes more damage than an equivalent dose of energetic photons (X- or g-rays). The nucleus emits a-, b-particles, or electromagnetic rays during the process Curie (Ci), 1 Ci ¼ 3. The figure emphasizes the biological impacts as a function of charged particle tracks. Our understanding of biological knowledge decreases with increasing atomic number. The dose equivalent or biologically dose equivalent, H ¼ D Â Q, represents the absorbed dose adjusted for the biological effectiveness of a particular type of radiation. Thus, the dose equivalent is intended to encompass all aspects of a certain radiation exposure influencing a biological effect. Finally, another important factor needs to be introduced to understand the influence of dose rate on biological effect. However, some of the relevant biophysical damage mechanisms need to be covered to appreciate the processes important in energy deposition. Incident ionizing radiation can interact with matter by being either 194 Table 2 Ionizing Radiation as a Carcinogen Quality factors associated with various types of radiation Source/occurrence X-ray machine and accelerators, Van Allen belts, solar radiation, electromagnetic processes Radioisotopes decay, Van Allen belts, solar radiation, electromagnetic processes Radioisotopes decay, Van Allen belts, solar radiation, galactic cosmic radiation Nuclear reactor, accelerators, radiation therapy, atmosphere, Van Allen belts, solar radiation, galactic cosmic radiation Penetration properties in human X- and g-rays penetrate deeply (only a fraction of the rays interact with each layer of tissue) Quality factor, Q 1 Radiation type and energy range X-rays g-rays b-particles Neutrons: <10 keV the level of penetration depends on the energy but is usually limited to less than 8 mm in tissue Neutrons penetrate deeply (only a fraction of the neutrons interact with each layer tissue) 1 5 Neutrons:10­100 keV Neutrons: 100 keV to 2 MeV Neutrons:2­20 MeV Neutrons: >20 MeV Protons of energy > 2 MeV a-Particles, fission fragments, heavy nuclei 10 20 10 5 2! Additionally, it can also interact with atomic components that usually change the target atoms and lose energy via a complex chain reaction of radiation events (Jones et al. The transfer of energy from an incident photon or particle to atoms of an absorber. The process of excitation involves the addition of energy to an atomic or molecular system, thereby transferring it from its ground or stable state to an excited or unstable state. Depending upon the type of interaction, either the atomic nucleus or one of its orbital electrons may absorb the excitation energy. An excited electron will not retain its energy but will tend to return to its original energy level either by emitting the excess energy in the form of a photon. As indicated previously, ionization is any process that results in the removal of an electron from an atom or molecule, thereby leaving the atom or molecule with a net positive charge. Ionization occurs if a- or b-particles, or gphotons, transfer sufficient energy to dislodge one of the electrons from the outer orbital shells of the target atom. Each ionization event produces an ion pair consisting of a free electron and the positively charged remainder of the atom. In the interactions of photons with matter, the energy of the photons is transferred via collision; usually these collisions occur with orbital electrons in an atom of the absorbing medium. The most relevant energy transfer processes whereby photons of sufficient energy eject electrons from an atom, which can then interact with other atoms and molecules to produce a cascade of alterations that ultimately lead to observable biological effects, will be described. A photon interacts with and ejects an electron from one of the inner shells of an atom. The photon is extinguished, and most of its energy is imparted to the ejected electron as kinetic energy. As outer electrons fill the vacancy, this energy change is balanced by the emission of a photon. In this case, the energy of the incoming photon is converted into the kinetic energy of an ejected electron and a secondary "scattered" photon. Hence the products of Compton interactions are a scattered, less energetic photon of reduced wavelength, a high-speed electron, and an ionized atom. The ejected electron will travel some distance in matter, producing ionizations along its track. In the course of this travel, the photon Ionizing Radiation as a Carcinogen 195 may undergo additional Compton collisions until its energy is sufficiently degraded for the photoelectric process to predominate. Thus, the photons in this energy range have their energy distributed over a relatively large volume of matter and may therefore have significant biological effects. A photon interacts with an atomic nucleus, and the photon energy is converted into a positron and an electron. The electron and the positron interact with and can ionize other molecules until the excess kinetic energy is exhausted. Energy from a heavy ion is deposited along the core of the track, where the ionization events produced in glancing collisions are quite dense. These features allow even a single heavy ion particle to affect many cells in an irradiated tissue, which make the biological effects of heavy ions different from those of other radiation phenomena. People working in medical facilities, mining, milling, or with nuclear material are required to protect themselves from occupational exposures to radiation. As we have seen earlier, predicting the risks associated with exposure of biological tissue to a given quantity of radiation is a complicated process. The figure depicted here illustrates the relative contributions of natural sources to the global population exposure. More than half of the total exposure comes from exposure to radon gas and its decay products. Cosmic radiation is subsequently the next highest percentage of natural ionizing radiation exposure. Medical X-rays and nuclear medicine account for about 79% of the man-made radiation exposure. Elements in consumer products, such as tobacco and domestic water supply, account for 16%. Occupational exposures, fallout, and nuclear fuel cycle account for the remaining. The timing of irradiation also affects the progression of the cell through the cell cycle in a way that is dependent upon the normal rate of division in a given cell line; for example, low dose radiation stops slowly dividing cellsdbut not rapidly dividing onesdin G1. With regard to cell state, cells irradiated in vitro are more radiosensitive than those irradiated in vivo (Jones et al. Redundancy in the number of mitochondria may confer radioresistance; for example, lymphocytes contain few mitochondria and are exquisitely sensitive to irradiation. Another factor affecting radiation-induced cell death or inactivation is the oxygen tension in the cellular environment; many cells are more sensitive to irradiation under normoxic conditions as compared to hypoxic environments (Jones et al. Space radiation, as opposed to typical terrestrial sources, contains a much greater proportion of particulate radiation. Cells exposed to radiation have one of four fates: (1) complete recovery to the preradiation state; (2) partial recovery with repair of injury but with diminished functionality; (3) mutations caused by incomplete or erroneous repair; or (4) cell death (Jones et al.

Syndromes

• Location of the tumor and how far it has spread
• Know what you are taking. Look at the list of ingredients and choose products that have fewer items listed.
• You may be asked to stop taking drugs that make it hard for your blood to clot. Some of these are aspirin, ibuprofen (Advil, Motrin), vitamin E, warfarin (Coumadin), clopidogrel (Plavix), or ticlopidine (Ticlid).
• Dilated eye exam
• Do you use douches or feminine hygiene spray?
• Using the wrong word, not pronouncing words correctly, speaking in confusing sentences
• Constipation
• Bone biopsy
• Damage to brain tissue
• Head CT scan

To date erectile dysfunction drugs at cvs generic 100 mg viagra super active with amex, 15 calpain-like genes have been described for mammals erectile dysfunction shake drink viagra super active 25 mg buy amex, 4 in Drosophila erectile dysfunction naturopathic treatment 100 mg viagra super active buy fast delivery, 12 in Caenorhabditis elegans erectile dysfunction treatment in rawalpindi viagra super active 25 mg order with amex, and 1 in plants (Sorimachi and Suzuki impotence of proofreading viagra super active 50 mg purchase with amex, 2001). Of the 15 mammalian calpain family members, 14 are large subunit isoforms and 1 is a small subunit, and one is an endogenous inhibitor calpastatin (Goll et al. Currently, the mammalian calpain family consists of typical and atypical groups, based on domain structure homology (Table 6). Domain I is a short sequence of 87 (calpain 1) or 76 (calpain 2) amino acids, which are autolytically cleaved during protease activation by Ca2 þ (Goll et al. Cleavage of this domain affords the calpain the ability to function at lower Ca2 þ concentrations and with different substrate affinities, thus it is an important regulatory mechanism of calpain activity. Sequence homology of domain I between species is about 72%­86%; however, this domain is not homologous to any other sequenced protein domains (Goll et al. Ubiquitous No No Yes (8) No Yes (2) Yes (2) No No Yes (2) No No No Yes (8) No No the currently accepted naming system for the calpain family of cysteine proteases is presented. Also, a clear distinction between the classification of typical and atypical calpains is outlined. Tissue-specific distribution is highlighted unless this characteristic has not been determined (n. This Ca2 þ-binding event and folding is proposed to be vital for protease (Hosfield et al. Recent crystallographic structures of calpain 2 have illuminated domain boundaries, and a new domain classification system has been proposed (Goll et al. The new classification system has been slowly accepted in the calpain field of study, but the current literature still uses the conventional classification system, which will be used throughout this discussion. A major issue with in vivo calpain activation is that Ca2 þ activation requirements exceed physiologically attainable concentrations. Normal physiological intracellular Ca2 þ is generally thought to be 50­300 nmol L­1 (Maravall et al. Many investigators have focused on understanding how calpains can become active at Ca2 þ concentration orders of magnitude below their requirements. Some studies have focused on identifying mechanisms that lower the Ca2 þ requirements for autolysis including identification of molecules that would interact with the calpains to reduce requirements (Goll et al. Other proposed mechanisms for calpain activation have included studying microenvironments and the potential of Ca2 þ being much higher in specific subcellular locations. A current hypothesis is that calpain activation could depend on the subcellular localization of enzymes and the local Ca2 þ in those locations. Other investigators have questioned the necessity of calpain to achieve full activation in vivo, as less than half-maximal activation may be sufficient for its presently unidentified physiological functions. Additionally, the full calpain activation may occur only during pathological conditions, for which intracellular Ca2 þ concentrations can be much greater. The role of posttranslational modifications in calpain activation has been explored because regulation of many cellular processes is controlled by phosphorylation and other posttranslational modifications. Studies with phospho-specific antibodies and matrixassisted laser desorption/ionization time-of-flight proteomics have shown that calpains 1 and 2 are phosphorylated at nine and eight sites, respectively (Goll et al. Not all sites are thought to be phosphorylated at once, as only two to four phosphates per molecule are generally found. Calpain phosphorylation is still not clearly understood as more questions about the role of phosphorylation have arisen from these initial detection studies. The prototypical calpains (calpains 1 and 2) have been studied much more extensively and therefore will serve to guide a general discussion of the multiple physiological roles of calpain. Despite great efforts over the last 35 years, exactly how calpains participate in physiological and pathological conditions is elusive (Goll et al. The lack of precise tools, such as specific inhibitors and diagnostic substrates, has delayed our understanding of calpain biology and pathobiology. Calpain is known to cleave a diverse array of substrates without having an apparent specific consensus sequence. In contrast to other protease families, calpain is notorious for cleaving substrates at limited sites, leaving truncated but apparently functional versions of the original substrate (Goll et al. This pattern of specific limited proteolysis has suggested that calpains are not digestive proteases (lysosomal or proteasomal) but are regulators of tightly controlled processes (Goll et al. This important cell cycle transition is known to be controlled by cyclin-dependent kinases, such as cdk2 and cdk-4, in addition to other important molecules such as cyclin D, cyclin E (Nigg, 1995), and p27kip1 which are reported to be degraded by calpain (Carragher, 2006). Other studies indicated that calpain-dependent degradation of p53 was involved 300 Calcium and Proteases in the cell cycle progression, again implicating calpain as a positive regulator of cell cycle progression (Zhang et al. Additionally, a recent study with fibroblasts from a calpain 4 (small subunit) knockout mouse demonstrated that these cells progress through the cell cycle and proliferate at similar rates as their wild-type counterparts (Arthur et al. This would indicate that neither calpain 1 nor 2 is vital for cell cycle progression and suggests that conflicting conclusions arose from investigations with nonspecific calpain inhibitors. In summary, the role of calpains in cell cycle progression and mitosis remains controversial and awaits clarification. However, the proteasome pathway is responsible for degrading these transcription factors (Goll et al. At this time, whether calpain does degrade these transcription factors in vivo or whether these are nonspecific effects arising from inaccurate scientific tools is unclear (Gonen et al. Currently, the accepted hypothesis is that c-Fos, c-Jun, and p53 transcription factors are chiefly degraded by the proteasome pathway, but under certain conditions, calpains can degrade these proteins (Salvat et al. Some reports suggest that calpain promotes apoptosis and others ascribe to it an antiapoptotic role (Goll et al. Caspases, another family of cysteine proteases, are principal regulators of apoptosis (Danial and Korsmeyer, 2004; Thornberry and Lazebnik, 1998). Multiple caspase family members have been shown to inactivate via direct cleavage by calpain (Chua et al. Conversely, calpain 1 has been shown to cleave caspase-12, producing an activated proapoptotic form of the caspase. Additionally, calpain 1 is reported to mediate a cleavage event that transforms the antiapoptotic Bcl-xl into a proapoptotic form (Nakagawa and Yuan, 2000). With these selected examples, it is clear that the role of calpain in apoptosis is not completely understood and requires more investigation to elucidate a specific role. Many other signaling molecules (including kinases, phosphatases, and cytoskeletal proteins) were identified as in vitro calpain substrates, supporting calpain as a regulator of signal transduction; however, none of the molecules could be validated as signal transduction-related calpain substrate in vivo (Goll et al. Most recently, calpain has been implicated in integrin-mediated signal transduction pathwaysdspecifically, b-integrins are cleaved by calpain (Pfaff et al. Multiple cytoskeletal and focal adhesion complex components, such as spectrin, talin, ezrin, focal adhesion kinase, paxillin, vimentin, and desmin (Carragher, 2006), have been confirmed to be in vitro calpain substrates. Additionally, calpain-dependent degradation of focal adhesion attachments at both the leading and trailing edge of motile cells is required for mobility (Glading et al. Furthermore, fibroblasts from calpain 4 (small subunit) knockout mice, as previously mentioned, can proliferate but migration markedly reduced (Arthur et al. Fibroblasts from these mice, which have no detectable calpain activity, cannot degrade talin, whereas their wild-type counterparts retain this ability. Studies of fibroblasts from calpain 4 knockout mice have provided strong molecular support for the role of calpain in cell motility. As alluded to previously, the generation of a genetic calpain small subunit knockout animal has assisted researchers to define a physiological role for calpain. Specifically, the lack of calpain activity caused defects to the fetal cardiovascular system, hemorrhage, and accumulation of erythroid progenitor cells (Arthur et al. Because activity of calpains 1 and 2 was abolished, which one was responsible is uncertain. The calpain 1 knockout mouse was not embryonically lethal but had a phenotype of deficient platelet aggregation (Azam et al. Of these proposed "calpainopathies," limb-girdle muscular dystrophy has been definitively linked to calpain 3 dysfunction and calpain 2 suppression is postulated to contribute to leukemia (Ishihara et al. Much research about calpain and ischemic insults has been performed in model systems of neuronal ischemia, indicating that calpain overactivation, resulting from loss of Ca2 þ homeostasis, facilitates neuronal injury (Bartus et al. Indeed, calpain inhibition has been shown to protect neuronal cells in multiple ischemic in vivo models of stroke (Bartus et al. Specifically, hyperactivation of calpain occurs within minutes after the insult and damages specific brain areas (Cagmat et al. Also, calpain was reported to contribute to tau formation in neurodegenerative models; blocking calpain attenuated disease and extended animal survival in a murine model of tau-induced frontotemporal lobar degeneration (Rao et al. However, data generated with a calpain inhibitor alone must be interpreted cautiously. Calpain has also been implicated in renal proximal tubular ischemia­reperfusion injury, and renal oncosis induced by various model toxicants can be blocked with multiple calpain inhibitors (Harriman et al. Calpain is involved in the promotion of plasma membrane permeability during toxicant-induced oncosis (a model of ischemiainduced cell injury) (Waters et al. Finally, calpain activation is important to myocardial ischemic injury; and calpain inhibition contributes to cardioprotective effects of preconditioning and postconditioning therapeutic strategies (Inserte et al. As evidenced from initial reports of mitochondrial calpain-like activity, multiple sources of calpain-like activity were assumed to be localized to multiple submitochondrial compartments. Additionally, both calpastatin, an endogenous inhibitor of calpain, and calpain 1 have been identified in pulmonary smooth muscle mitochondria (Kar et al. Evidence is mounting that calpain 1 is not an exclusively cytosolic protease but is likely targeted to the mitochondria. As predicted in early mitochondrial calpain-like protease studies, another calpain isoform, calpain 1, has been identified and virtually simultaneous to this, our laboratory identified a separate calpain isoform, calpain 10, in rabbit renal cortex mitochondria (Arrington et al. Calpain 10 has Ca2 þ-inducible activity (not Ca2 þ dependent) and inhibited by calpain inhibitors, calpeptin and E-64, at submicromolar concentrations in isolated mitochondria. Mitochondrial calpain 10 was positively identified in all mitochondrial subfractions but was primarily active in the mitochondrial matrix and contained N-terminal 15 amino acids as a mitochondrial targeting sequence (Arrington et al. Functionally, mitochondrial calpain 10 has been implicated in Ca2 þ-induced mitochondrial dysfunction as measured by mitochondrial swelling and decreased mitochondrial respiration. Reduction of renal mitochondrial calpain 10 led to accumulation of its substrates and increased cell death. Overexpression of calpain 10 caused mitochondrial swelling and cell death (Covington et al. Thus, both reduced and excessive calpain 10 cause cellular dysfunction and death, suggesting a need for tight regulation of calpain 10 for normal cellular function. Disruption in calcium concentrations causes direct cellular dysfunction or protease activation and insufficient or increased protease activation can also contribute to cellular dysfunction, so calcium must be tightly regulated within the cell. Induction of the mitochondrial permeability transition by protease activity in rats: a mechanism of hepatocyte necrosis. Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration. Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division. A general framework to characterize inhibitors of calmodulin: use of calmodulin inhibitors to study the interaction between calmodulin and its calmodulin binding domains. Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. The biochemistry and molecular biology of the dihydropyridine-sensitive calcium channel. The critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. Tributylin increases cytosolic free Ca2 þ concentration in thymocytes by mobilizing intracellular Ca2 þ, activating a Ca2 þ entry pathway, and inhibiting Ca2 þ efflux. Identification of calcineurin as a key signaling enzyme of T-lymphocyte activation. Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injury. Calcium-dependent proteolytic activity in the rat liver: identification of two proteases with different calcium requirements. Reduced cell migration and disruption of the actin cytoskeleton in calpaindeficient embryonic fibroblasts. Emerging functions of the calpain superfamily of cysteine proteases in neuroendocrine secretory pathways. Functional co-localization of transfected Ca2 þ-stimulable adenylyl cyclases with capacitative Ca2 þ entry sites. Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas. Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin On the involvement of calpains in the degradation of the tumor suppressor protein p53. Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases. Cadmium toxicity in rat pheochromocytoma cells: studies on the mechanism of uptake. Crystal structure of calpain reveals the structural basis for Ca2 þ-dependent protease activity and a novel mode of enzyme activation. Preapoptotic protease calpain-2 is frequently suppressed in adult T-cell leukemia. Mitochondrial micro-calpain is not involved in the processing of apoptosis-inducing factor.

Ca2 þ clearly stimulates numerous cellular processes erectile dysfunction effects on women generic viagra super active 25 mg buy line, such as muscle contraction erectile dysfunction underwear generic viagra super active 100 mg buy, cellular proliferation erectile dysfunction non organic purchase viagra super active 25 mg fast delivery, gene expression impotence venous leakage ligation viagra super active 100 mg without a prescription, hormone and neurotransmitter secretion erectile dysfunction drugs muse viagra super active 100 mg buy otc, exocytosis, and chemotaxis, but Ca2 þ is also toxic. Thus, free intracellular Ca2 þ ([Ca2 þ]i) must be tightly regulated to properly balance Ca2 þ-mediated cell function and Ca2 þ-mediated cell injury and death. Intracellular cytoplasmic Ca2 þ ($ 10À 8­10À 7 mol LÀ 1) is maintained well below the extracellular concentration 10À 3 mol LÀ 1, creating a gradient across the cell membrane. Consequently, a steep electrochemical gradient of rv 104 mol LÀ 1 exists for Ca2 þ between the cytoplasm and cell exterior and between the cytoplasm and certain organelle interiors. Electrochemical gradient maintenance is necessary for second messenger roles of Ca2 þ and prevention of Ca2 þ-mediated cell injury. Once stimulated by Ca2 þ-elevating agonists, the average [Ca2 þ]i can rise $ 10­100-fold, to low micromolar ranges. These Ca2 þ signals have a complex temporal and spatial organization, and pulsatile Ca2 þ elevations occur frequently in the cytoplasm in the form of baseline Ca2 þ spikes or oscillations. Additionally, other intracellular organelles and Ca2 þ-binding proteins serve to buffer the cytoplasmic Ca2 þ concentration, albeit with lower affinity. For example, the inner mitochondrial membrane contains a low-affinity uniport carrier that allows the electrogenic entry of Ca2 þ due to the negative transmembrane potential. The importance of intracellular calcium homeostasis is appreciated in light of the numerous subcellular compartments that participate in regulating [Ca2 þ]i as well as the diversity of cellular processes controlled by Ca2 þ signaling pathways. Each of these subcellular compartments can be targeted by chemicals or drugs to imbalance intracellular Ca2 þ homeostasis, resulting in toxicity manifested as impaired cellular function or cell death. The Ca2 þ-binding sensor protein calmodulin is ubiquitous, evolutionarily conserved, and well-characterized in its role of enabling cells to detect elevated [Ca2 þ]i and subsequently transducing this signal to diverse cellular processes. The molecular mechanism attributed to the transduction of this Ca2 þ-mediated activation of calmodulin lies in the conformational change induced by Ca2 þ binding. Through its actions on these target enzymes, Ca2 þ-activated calmodulin is involved in the regulation of many cellular processes including cell cycle progression, exocytosis, and ion transport. Many of these inhibitory drugs are functionally selective with respect to impairment of calmodulin-dependent processes, and thus may serve as molecular probes of calmodulin-dependent pathways to study cell functions. For example, lead is reported to occupy the Ca2 þ-binding sites of calmodulin as well as an allosteric-potentiating binding site (Chao et al. Calmodulin is the primary intracellular receptor for Ca2 þ and is involved in the regulation of numerous enzymes, many of which are Ca2 þ-binding proteins that are regulated, in some way, upon interaction with calmodulin. For example, a Ca2 þ/ calmodulin-regulated enzyme is the cysteine protease calpain. Calpain is an important Ca2 þ-binding protease functioning in necrosis in various cell types (Squier et al. For instance, retinal cell ganglion explant cell apoptosis is induced by caplain (McKernan et al. Also, calpainmediated cell death was attributed to nonapoptotic cell death of photoreceptors in all major types of hereditary blindness (Arango-Gonzalez, 2014). Thus, calmodulin is often the primary decoder of elevated intracellular Ca2 þ and it acts as a molecular switch for activation of many Ca2 þ-dependent signaling enzymes. Analysis of Ca2 þ/calmodulin and Ca2 þ-binding proteins has aided our understanding of cellular processes associated with disease. Both drugs bind to and inhibit immunophilins, which catalyze cis-/trans-peptidylprolyl isomerase reactions. Immunosuppressant inhibition of isomerase arises from the immunosuppressive immunophilin­drug complex binding specifically to and inhibiting calcineurin. In addition to its importance in T-cell activation, Ca2 þ-induced activation of calcineurin is important in regulating apoptosis underscoring that immunosuppressants block apoptosis (Fruman et al. Many pathological states may arise from Ca2 þ binding protein activity alteration and this emphasizes the biomedical importance of intracellular Ca2 þ homeostasis (Table 4; Berridge, 1994). Calcium permeability control through plasma membrane calcium-selective channels is a chief route by which cells regulate [Ca2 þ]i. Different calcium channels are characterized by unique gating properties, ion selectivity, and toxicant sensitivity (Chang et al. Most ion channels have four functional characteristics: ion selectivity, electrical conductance, ion-gating kinetics, and chemical or electrical signal sensing. Ion selectivity is accomplished by steric constraints and more importantly by the relative binding strength of ions to sites within the channel. Channel conductance is a measure of the ease with which ions pass through the channel. Ion-gating characteristics include the three distinguishable processes of activation, deactivation, and inactivation of the gate function. Finally, Ca2 þ channels are divided into four major classes based on sensing mechanisms. Each of these major classes is extensively further subdivided based on function and molecular cloning. These channels are distinguished by several properties, including differential sensitivity to 1,4-dihydropyridines (Varadi et al. The best-characterized and most numerous Ca2 þ channels are the L-type Ca2 þ, which mediate long-lasting depolarization. The L-type Ca2 þ channel is a heteropentameric complex of a1, a2, b, c, and N-type polypeptides highly expressed in skeletal muscle. Cloning studies identified six a1 gene transcripts and numerous a2, b, and c gene transcripts (Perez-Reyes et al. L-type channels are blocked by dihydropyridines, phenylalkylamines, and benzothiazepines as discussed elsewhere in this series. First, different valences, ionic forms, and metal­ligand complexes in physiological solutions partially determine with which channel component a given metal may react. Second, metals or their complexes may react specifically with the cell membrane (cadmium), at the Ca2 þ channel entrance (lead or zinc), or within the Ca2 þ channel (mercury, methyl mercury, aluminum) (Busselberg et al. In contrast, Ca2 þ entry may arise from a simple sensing of the intracellular Ca2 þ pool storage state. In most cases, the influx of external Ca2 þ lags temporally behind intracellular Ca2 þ release. An increase in [Ca2 þ]i due to external Ca2 þ influx are usually smaller than that released from intracellular stores. This sustained small increase in 292 Calcium and Proteases [Ca2 þ]i is a necessary intermediate for long-term maintenance of cellular response but how agonists acting on receptors increase Ca2 þ influx is not well defined. Most evidence suggests that lead does not block the channel per se, but rather alters the binding of agonists. It is the only high-affinity Ca2 þ transporting system present in plasma membranes, and it is ubiquitous in all animal and plant cells (Carafoli, 1991, 1994). The Ca2 þ pump interacts with high affinity with Ca2 þ but has a low total Ca2 þ transporting capacity. The pump, originally discovered in erythrocyte membrane preparations, is present in the plasma membrane in very small amounts, representing less than 0. Each of these isogenes produces additional isoforms through alternative transcript splicing. The four isogene products and their splicing variants among human tissues show that gene products 1 and 4 are expressed in all tissues, with isogene 1 generally being more abundant and required for survival. The other gene products (2 and 3) are expressed in a relatively tissue-specific manner in muscle, brain, and kidney. Tissue specificity of the various splice variants of the four isogenes has been described especially in the central nervous system. The affinity of the pump for calmodulin differs among the various isoforms, indicating that tissue-selective mechanisms of inhibition by toxic chemicals or drugs may exist. Phosphorylation tends to increase Vmax and/ or Km (Ca2 þ) of the isolated pump; however, whether phosphorylation also occurs in vivo or whether the various pump isoforms have kinase specificities remains to be determined. This intracellular store compartmentalization plays an important role in maintaining Ca2 þ homeostasis and in regulating Ca2 þ signaling functions. Intracellular compartmentalization is necessary to enable pulsatile Ca2 þ signals to be propagated and to maintain nontoxic (submicromolar) cytosolic Ca2 þ. The most popular inhibitory compound is the sesquiterpene lactone thapsigargin, which is a root extract from the plant Thapsia garganica. Thus, thapsigargin can be used to study the relationship between intracellular Ca2 þ release and Ca2 þ entry. The observation that thapsigargin reproduces the effects of agonists on Ca2 þ entry provides strong evidence to support the capacitative entry hypothesis first postulated by Putney and colleagues (Putney, 1990; Putney and Bird, 1993a,b, 1994; Takemura et al. By mechanisms similar but not identical to thapsigargin, the hydroquinone 2,5-di-(t-butyl)-1,4-benzohydroquinone has been shown to stimulate capacitative Ca2 þ entry in hepatocytes or lymphocytes (Llopis et al. Increases in cytosolic free Ca2 þ can activate a number of degradative Ca2 þ-dependent enzymes, such as phospholipases and proteinases. These enzymes can produce abnormalities in the structure and function of cytoskeletal elements. In lethally injured cells, mitochondria are known to accumulate Ca2 þ through a low-affinity, high-capacity Ca2 þ transport system. In renal cells, substantial mitochondrial Ca2 þ uptake occurs after cytosolic concentrations reach 400 nmol LÀ 1 or greater, usually seen only during cell injury (Weinberg, 1991). In summary, oxidative stress and Ca2 þ dysregulation converge on mitochondria and induce dysfunction, which can lead to either type of cell death. After this initial isolation, calpain was renamed m-calpain (calpain 2), and two other calpain family members were identified, m-calpain (calpain 1) and calpastatin, an endogenous inhibitor of calpain (Dayton et al. Since these founding members of the calpain family were identified, numerous ubiquitous (Thompson and Goll, 2000) or tissue-specific (Sorimachi et al. Identification of calpastatin and mu-calpain and studies of their association in pulmonary smooth muscle mitochondria. Calcium-dependent neural proteases, widespread occurrence of a species of protease active at lower concentrations of calcium. Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain). Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability. Comparison between the effects of the microsomal Ca2 þ-translocase inhibitors thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone on cellular calcium fluxes. Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps. Estimating intracellular calcium concentrations and buffering without wavelength ratioing. Canine cardiac calcium-dependent proteases: resolution of two forms with different requirements for calcium. Evidence for participation of a calpain-like cysteine protease in cell cycle progression through late G1 phase. Proceedings of the National Academy of Sciences of the United States of America, 85(8), 2499­2503. Intracellular Ca2 þ-dependent protease (calpain) and its high-molecular-weight endogenous inhibitor (calpastatin). The cytosol of human erythrocytes contains a highly Ca2 þ-sensitive thiol protease (calpain I) and its specific inhibitor protein (calpastatin). Proceedings of the National Academy of Sciences of the United States of America, 86(2), 453­457. Glycine blocks opening of a death channel in cultured hepatic sinusoidal endothelial cells during chemical hypoxia. The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational determinants of the monomers and not on formation of dimers. Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel. Cytoskeletal derangements of cortical neuronal processes three hours after traumatic brain injury in rats: an immunofluorescence study. Emptying of intracellular Ca2 þ stores releases a novel small messenger that stimulates Ca2 þ influx. Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. Are there multiple proteolytic pathways contributing to c-Fos, c-Jun and p53 protein degradation in vivo Distinct regulatory functions of calpain 1 and 2 during neural stem cell self-renewal and differentiation. Proteases in renal cell death: calpains mediate cell death produced by diverse toxicants. Mitochondrial m-calpain opens the mitochondrial permeability transition pore in ischemia-reperfusion. Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle. A novel tissue-specific calpain species expressed predominantly in the stomach comprises two alternative splicing products with and without Ca2 þ-binding domain. The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proceedings of the National Academy of Sciences of the United States of America, 97, 588­592. Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons. Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane. American Journal of Physiology Heart and Circulatory Physiology, 310(3), H376­H384. Permeation of Pb2 þ through calcium channels: fura-2 measurements of voltageand dihydropyridine-sensitive Pb2 þ entry in isolated bovine chromaffin cells.

Numerous crosses of these mice have been instrumental in defining the importance of the aforementioned complexes erectile dysfunction mental treatment order viagra super active amex. For example erectile dysfunction bipolar medication purchase cheap viagra super active line, while Ripk1À/À erectile dysfunction blue pill generic viagra super active 100 mg buy on-line, FaddÀ/À erectile dysfunction herbal generic 50 mg viagra super active overnight delivery, casp8À/À erectile dysfunction doctor washington dc buy viagra super active without prescription, FlipÀ/À, and cIap1/2À/À mice all die during embryonic development (E10. At this stage, dozens of compound mutant mice have been generated and the following review articles offer a detailed description of the resulting phenotypes (Dillon et al. However, once activated, active caspases can cleave Grim at Asp132, removing both the lysine necessary for its ubiquitination as well as existing ubiquitin chains. Consequently, cleavage of Grim by caspases enhances its stability and initiates a feed-forward caspase amplification loop that results in still greater cell death (Yeh and Bratton, 2013). While clinical studies are ongoing, Smac mimetics, perhaps in combination with caspase inhibitors, may prove effective in treating various cancers through the induction of apoptosis and/or necroptosis (Brumatti et al. Regardless of the stimulus, in most cases, the engaged pathways eventually converge and culminate in the formation of caspase-activating complexes that ultimately activate caspases and dismantle the cell. Lack of release of cytochrome C from mitochondria into cytosol early in the course of Fas-mediated apoptosis of Jurkat cells. Dissociation of Bak alpha1 helix from the core and latch domains is required for apoptosis. Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2. A biotin switch-based proteomics approach identifies 14-3-3zeta as a target of Sirt1 in the metabolic regulation of caspase-2. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Calpains mediate epithelial-cell death during mammary gland involution: Mitochondria and lysosomal destabilization. Proceedings of the National Academy of Sciences of the United States of America, 103, 10283­10288. Mechanism of the t(14;18) chromosomal translocation: Structural analysis of both derivative 14 and 18 reciprocal partners. Proceedings of the National Academy of Sciences of the United States of America, 84, 2396­2400. Role of prodomain in importin-mediated nuclear localization and activation of caspase-2. Bax-type apoptotic proteins porate pure lipid bilayers through a mechanism sensitive to intrinsic monolayer curvature. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Caspase-2-induced apoptosis requires bid cleavage: A physiological role for bid in heat shock-induced death. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. Caspase activation involves the formation of the aposome, a large ($ 700 kDa) caspase-activating complex. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Different subcellular distribution of caspase-3 and caspase-7 following Fas-induced apoptosis in mouse liver. Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome c and inhibiting apoptosome. Engineering a dimeric caspase-9: A re-evaluation of the induced proximity model for caspase activation. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. The ribonucleotide reductase R1 subunits of herpes simplex virus 1 and 2 protect cells against poly(I. Highly conserved caspase and Bcl-2 homologues from the sea anemone Aiptasia pallida: Lower metazoans as models for the study of apoptosis evolution. Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis. Caspase 7 can cleave tumor necrosis factor receptor-I (p60) at a non-consensus motif, in vitro. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. The protein structures that shape caspase activity, specificity, activation and inhibition. A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Visual and functional demonstration of growing Bax-induced pores in mitochondrial outer membranes. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Proceedings of the National Academy of Sciences of the United States of America, 95, 570­575. The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: Implications for therapeutic applications. Bid is upstream of lysosome-mediated caspase 2 activation in tumor necrosis factor alphainduced hepatocyte apoptosis. Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Proceedings of the National Academy of Sciences of the United States of America, 101, 12461­12466. Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proceedings of the National Academy of Sciences of the United States of America, 108, 20054­20059. Proceedings of the National Academy of Sciences of the United States of America, 111, 15072­15077. Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. Proceedings of the National Academy of Sciences of the United States of America, 106, 5336­5341. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proceedings of the National Academy of Sciences of the United States of America, 94, 12401­12406. Proteolytic processing of the caspase-9 zymogen is required for apoptosome-mediated activation of caspase-9. Proceedings of the National Academy of Sciences of the United States of America, 111, 16254­16261. Glycogen synthase kinase-3beta mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia. Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 94, 10717­10722. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. Proceedings of the National Academy of Sciences of the United States of America, 95, 4997­5002. The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. Proceedings of the National Academy of Sciences of the United States of America, 102, 17545­17550. Bcl-rambo induces apoptosis via interaction with the adenine nucleotide translocator. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 95, 5156­5160. Targeting of the transcription factor Max during apoptosis: Phosphorylation-regulated cleavage by caspase-5 at an unusual glutamic acid residue in position P1. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Endocytotic routes of cobra cardiotoxins depend on spatial distribution of positively charged and hydrophobic domains to target distinct types of sulfated glycoconjugates on cell surface. Proceedings of the National Academy of Sciences of the United States of America, 100, 2432­2437. Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Proceedings of the National Academy of Sciences of the United States of America, 105, 2169­2174. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Glycogen Synthase Kinase-3beta and Caspase-2 Mediate Ceramide- and Etoposide-Induced Apoptosis by Regulating the Lysosomal-Mitochondrial Axis. Cytolytic enzymes in relation to the breakdown of the intersegmental muscles of silkmoths. Proceedings of the National Academy of Sciences of the United States of America, 108, 813­822. Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. The Apaf-1 procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer. Bcl-2-regulated apoptosis and cytochrome c release can occur independently of both caspase-2 and caspase-9.

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