Apoptosis-induced compensatory proliferation (AiP) is a form of compensatory proliferation that is triggered by apoptotic cell death to maintain tissue homeostasis. As such, AiP is essential for many ...tissue repair processes including regeneration. The apoptotic effectors, termed caspases, not only execute apoptosis, but are also directly involved in the generation of the signals required for AiP. Reactive oxygen species (ROS) play an important role for regenerative processes. Recently, it was shown in Drosophila that apoptotic caspases can mediate the generation of ROS for promoting AiP. This review summarizes and discusses these findings in the context of regenerative processes and cancer.
Although there are over a dozen types of cell death known, there is clearly more to discover in this field. In this issue of PLOS Biology, erebosis is identified as a new type of cell death involved ...in tissue homeostasis of the adult Drosophila intestine.
Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ...("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging the BM, which recruits macrophages to the tissue. We propose a model where macrophage recruitment to and activation at overgrowing tissue is a multi-step process requiring ROS- and JNK-mediated Mmp2 upregulation and BM damage. These findings have implications for understanding the role of the tumor microenvironment for macrophage activation.
Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement ...and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in response to external injury, wounding, or amputation (epimorphic regeneration). Model organisms that display remarkable regenerative capacity include amphibians, planarians, Hydra, and the vertebrate liver. In addition, several mammalian organs--including the skin, gut, kidney, muscle, and even the human nervous system--have some ability to replace spent or damaged cells. Although the regenerative response is complex, it typically involves the induction of new cell proliferation through formation of a blastema, followed by cell specification, differentiation, and patterning. Stem cells and undifferentiated progenitor cells play an important role in both tissue homeostasis and tissue regeneration. Stem cells are typically quiescent or passing slowly through the cell cycle in adult tissues, but they can be activated in response to cell loss and wounding. A series of studies, mostly performed in Drosophila as well as in Hydra, Xenopus, and mouse, has revealed an unexpected role of apoptotic caspases in the production of mitogenic signals that stimulate the proliferation of stem and progenitor cells to aid in tissue regeneration. This Review summarizes some of the key findings and discusses links to stem cell biology and cancer.
In multi-cellular organisms, activation of apoptosis can trigger compensatory proliferation in surrounding cells to maintain tissue homeostasis. Genetic studies in Drosophila have indicated that ...distinct mechanisms of compensatory proliferation are employed in apoptotic tissues of different developmental states. In proliferating eye and wing tissues, the initiator caspase Dronc coordinates cell death and compensatory proliferation through the Jun N-terminal kinase and p53. The mitogens Decapentaplegic and Wingless are induced in this process. By contrast, in differentiating eye tissues, the effector caspases DrICE and Dcp-1 activate the Hedgehog signaling pathway to induce compensatory proliferation. In this review, we summarize these findings and discuss how activation of apoptosis is linked to the process of compensatory proliferation. The developmental and pathological relevance of compensatory proliferation is also discussed.
In multicellular organisms, apoptotic cells induce compensatory proliferation of neighboring cells to maintain tissue homeostasis. In the
Drosophila wing imaginal disc, dying cells trigger ...compensatory proliferation through secretion of the mitogens Decapentaplegic (Dpp) and Wingless (Wg). This process is under control of the initiator caspase Dronc, but not effector caspases. Here we show that a second mechanism of apoptosis-induced compensatory proliferation exists. This mechanism is dependent on effector caspases which trigger the activation of Hedgehog (Hh) signaling for compensatory proliferation. Furthermore, whereas Dpp and Wg signaling is preferentially employed in apoptotic proliferating tissues, Hh signaling is activated in differentiating eye tissues. Interestingly, effector caspases in photoreceptor neurons stimulate Hh signaling which triggers cell-cycle reentry of cells that had previously exited the cell cycle. In summary, dependent on the developmental potential of the affected tissue, different caspases trigger distinct forms of compensatory proliferation in an apparent nonapoptotic function.
A key objective of government accounting and reporting has been to achieve accountability and its use in that respect has been well documented, however its use for decision-making has had less ...coverage. This article addresses the latter issue, providing evidence from Switzerland that the accounting basis used (accrual versus cash) influences decision-making. This is the result of the effect that the different approaches have on the nature of the information used for decision-making. Switzerland was among the first western democracies to adopt accrual accounting at both state (canton) and local levels of government in the 1980s. The Swiss federal government followed in 2007. The main examples of the use of accrual information in decision-making are: the focus on self-financing of investments in order to control borrowing, as well as the fiscal policy targets of debt reduction and maintenance of capital. All three require accrual basis information. Therefore accrual basis information is key in fiscal decision-making in Switzerland.
C-terminal α-amidation is the final and essential step in the biosynthesis of several peptide hormones. Peptidylglycine α-amidating monooxygenase (PAM) is the only known enzyme to catalyse this ...reaction. PAM amidating activity (AMA) is known to be present in human circulation, but its physiological role and significance as a clinical biomarker remains unclear. We developed a PAM-specific amidation assay that utilizes the naturally occurring substrate Adrenomedullin-Gly (ADM-Gly, 1-53). Using our amidation assay we quantified serum amidating activities in a large population-based cohort of more than 4900 individuals. A correlation of serum amidating activity with several clinical parameters including high blood pressure was observed. Increasing PAM-AMA was an independent predictor of hard outcomes related to hemodynamic stress such as cardiovascular mortality, atrial fibrillation and heart failure during long-term follow-up (8.8 ± 2.5 years). Moreover, results from an animal study in rats utilizing recombinant human PAM provide novel insights into the physiological role of circulating PAM and show its potential significance in circulating peptide amidation.
Objectives The purpose of this study was to examine the incremental value of copeptin for rapid rule out of acute myocardial infarction (AMI). Background The rapid and reliable exclusion of AMI is a ...major unmet clinical need. Copeptin, the C-terminal part of the vasopressin prohormone, as a marker of acute endogenous stress may be useful in this setting. Methods In 487 consecutive patients presenting to the emergency department with symptoms suggestive of AMI, we measured levels of copeptin at presentation, using a novel sandwich immunoluminometric assay in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists using all available data. Results The adjudicated final diagnosis was AMI in 81 patients (17%). Copeptin levels were significantly higher in AMI patients compared with those in patients having other diagnoses (median 20.8 pmol/l vs. 6.0 pmol/l, p < 0.001). The combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (95% confidence interval: 0.95 to 0.98), which was significantly higher than the 0.86 (95% confidence interval: 0.80 to 0.92) for troponin T alone (p < 0.001). A copeptin level <14 pmol/l in combination with a troponin T ≤0.01 μg/l correctly ruled out AMI with a sensitivity of 98.8% and a negative predictive value of 99.7%. Conclusions The additional use of copeptin seems to allow a rapid and reliable rule out of AMI already at presentation and may thereby obviate the need for prolonged monitoring and serial blood sampling in the majority of patients. (Advantageous Predictors of Acute Coronary Syndromes Evaluation APACE; NCT00470587 )
Selenoprotein-P (SELENOP) is the main carrier of selenium to target organs and reduces tissue oxidative stress both directly and by delivering selenium to protective selenoproteins. We tested if the ...plasma concentration of SELENOP predicts cardiovascular morbidity and mortality in the primary preventive setting. SELENOP was measured from the baseline exam in 2002-2006 of the Malmö Preventive Project, a population-based prospective cohort study, using a validated ELISA. Quintiles of SELENOP concentration were related to the risk of all-cause mortality, cardiovascular mortality, and a first cardiovascular event in 4366 subjects during a median (interquartile range) follow-up time of 9.3 (8.3-11) years using Cox proportional Hazards Model adjusting for cardiovascular risk factors. Compared to subjects in the lowest quintile of SELENOP, the risk of all three endpoints was significantly lower in quintiles 2-5. The risk (multivariate adjusted hazard ratio, 95% CI) decreased gradually with the lowest risk in quintile 4 for all-cause mortality (0.57, 0.48-0.69) (
< 0.001), cardiovascular mortality (0.52, 0.37-0.72) (
< 0.001), and first cardiovascular event (0.56, 0.44-0.71) (
< 0.001). The lower risk of a first cardiovascular event in quintiles 2-5 as compared to quintile 1 was significant for both coronary artery disease and stroke. We conclude that the 20% with lowest SELENOP concentrations in a North European population without history of cardiovascular disease have markedly increased risk of cardiovascular morbidity and mortality, and preventive selenium supplementation studies stratified for these subjects are warranted.
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