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Biochimica Et Biophysica Acta Oct 1996Understanding the processes and events that occur when a cell undergoes a prelethal injury or that lead the cell to death following a lethal injury has been the aim of... (Review)
Review
Understanding the processes and events that occur when a cell undergoes a prelethal injury or that lead the cell to death following a lethal injury has been the aim of our research for a number of years. Throughout this period much has been learned, recently at rapid rates, not only by us but by many other investigators as well. Based on the data gathered, we proposed a working hypothesis over a decade ago and have since continually updated it as new experimentation is performed. Our laboratory has focused particularly on the role of cytoplasmic ionized calcium ([Ca2+]i) and the effects of its deregulation on prelethal events, including oncosis and apoptosis, and lethal events (necrosis) following cell death. [Ca2+]i appears to be a major link and signalling event. Understanding the mechanisms involved by using a variety of in vivo and in vitro models, coupled with state-of-the-art methodologies, should now allow us to prevent cell death by killing cells when necessary through gene therapy and cancer chemotherapy.
Topics: Animals; Calcium; Cell Death; Cytoplasm
PubMed: 8898851
DOI: 10.1016/0167-4889(96)00086-9 -
Life Sciences May 2022Multiple mitochondrial dysfunction (MMD) can lead to complex damage of mitochondrial structure and function, which then lead to the serious damage of various metabolic...
AIMS
Multiple mitochondrial dysfunction (MMD) can lead to complex damage of mitochondrial structure and function, which then lead to the serious damage of various metabolic pathways including cerebral abnormalities. However, the effects of MMD on heart, a highly mitochondria-dependent tissue, are still unclear. In this study, we use iron-sulfur cluster assembly 1 (Isca1), which has been shown to cause MMD syndromes type 5 (MMDS5), to verify the above scientific question.
MAIN METHODS
We generated myocardium-specific Isca1 knockout rat (Isca1/α-MHC-Cre) using CRISPR-Cas9 technology. Echocardiography, magnetic resonance imaging (MRI), histopathological examinations and molecular markers detection demonstrated phenotypic characteristics of our model. Immunoprecipitation, immunofluorescence co-location, mitochondrial activity, ATP generation and iron ions detection were used to verify the molecular mechanism.
KEY FINDINGS
This study was the first to verify the effects of Isca1 deficiency on cardiac development in vivo, that is cardiomyocytes suffer from mitochondria damage and iron metabolism disorder, which leads to myocardial oncosis and eventually heart failure and body death in rat. Furthermore, forward and reverse validation experiments demonstrated that six-transmembrane epithelial antigen of prostate 3 (STEAP3), a new interacting molecule for ISCA1, plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency.
SIGNIFICANCE
This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching clinical therapeutic targets of MMDS.
Topics: Animals; Cardiomyopathies; Iron Metabolism Disorders; Male; Mitochondria; Myocardium; Myocytes, Cardiac; Rats
PubMed: 35304126
DOI: 10.1016/j.lfs.2022.120485 -
American Journal of Physiology. Lung... Apr 2008Apoptosis has been considered as an underlying mechanism in acute lung injury/acute respiratory distress syndrome and multiorgan dysfunction syndrome. Recently, several... (Review)
Review
Apoptosis has been considered as an underlying mechanism in acute lung injury/acute respiratory distress syndrome and multiorgan dysfunction syndrome. Recently, several alternative pathways for cell death (such as caspase-independent cell death, oncosis, and autophagy) have been discovered. Evidence of these pathways in the pathogenesis of acute lung injury has also come into light. In this article, we briefly introduce cell death pathways and then focus on studies related to lung injury. The different types of cell death that occur and the underlying mechanisms utilized depend on both experimental and clinical conditions. Lipopolysaccharide-induced acute lung injury is associated with apoptosis via Fas/Fas ligand mechanisms. Hyperoxia and ischemia-reperfusion injury generate reactive oxidative species, which induce complex cell death patterns composed of apoptosis, oncosis, and necrosis. Prolonged overexpression of inflammatory mediators results in increased production and activation of proteases, especially cathepsins. Activation and resistance to death of neutrophils also plays an important role in promoting parenchymal cell death. Knowledge of the coexisting multiple cell death pathways and awareness of the pharmacological inhibitors targeting different proteases critical to cell death may lead to the development of novel therapies for acute lung injury.
Topics: Apoptosis; Caspases; Cell Death; Enzyme Activation; Humans; Lung; Lysosomes; Multiple Organ Failure; Permeability; Respiratory Distress Syndrome
PubMed: 18203816
DOI: 10.1152/ajplung.00262.2007 -
Experimental and Molecular Pathology Aug 2021This review explores the developments leading up to the establishment of the cell theory and cellular pathology and their subsequent refinements and applications while... (Review)
Review
This review explores the developments leading up to the establishment of the cell theory and cellular pathology and their subsequent refinements and applications while focusing on the individuals who have made seminal advances in the field. The links between cell biology, cell pathology and cell injury research are emphasized. Recognition also is given to the importance of technological advances in microscopy, histology, biochemical and molecular methods for discovery in cell biology and cell pathology. Particular attention is focused on the work of Rudolph Virchow and his former students in the formulation of the cell theory in biology and pathology and John F. R. Kerr and colleagues who identified and developed a comprehensive characterization of apoptosis, thereby giving impetus to the contemporary field of cell injury research. Cell injury research remains an important and fruitful field of ongoing inquiry and discovery.
Topics: Animals; Biology; Cell Death; Humans; Medicine; Necrosis
PubMed: 34116021
DOI: 10.1016/j.yexmp.2021.104660 -
Frontiers in Oncology 2017Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity... (Review)
Review
Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity profiles. It is, therefore, an intriguing possibility to consider that oncolytic ("cancer-killing") viruses may act as cancer-selective radiosensitizers, enhancing the therapeutic consequences of radiation treatment on tumors while exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage. Exploiting these abilities to inhibit cellular DNA repair following damage by therapeutic irradiation may well augment the anticancer potency of the approach. In this review, we focus on oncolytic adenovirus, the most widely developed and best understood oncolytic virus, and explore its various mechanisms for modulating cellular DNA repair pathways. The most obvious effects of the various adenovirus serotypes are to interfere with activity of the MRE11-Rad50-Nbs1 complex, temporally one of the first sensors of double-stranded DNA damage, and inhibition of DNA ligase IV, a central repair enzyme for healing double-stranded breaks by non-homologous end joining (NHEJ). There have been several preclinical and clinical studies of this approach and we assess the current state of progress. In addition, oncolytic viruses provide the option to promote a localized proinflammatory response, both by mediating immunogenic death of cancer cells by oncosis and also by encoding and expressing proinflammatory biologics within the tumor microenvironment. Both of these approaches provide exciting potential to augment the known immunological consequences of radiotherapy, aiming to develop systems capable of creating a systemic anticancer immune response following localized tumor treatment.
PubMed: 28791251
DOI: 10.3389/fonc.2017.00153 -
BioMed Research International 2016QC4 is the derivative of rosin's main components dehydroabietic acid (DHA). We investigated the cytotoxic effect of QC4 on gastric cancer cells and revealed the...
AIM
QC4 is the derivative of rosin's main components dehydroabietic acid (DHA). We investigated the cytotoxic effect of QC4 on gastric cancer cells and revealed the mechanisms beneath the induction of cell death.
METHODS
The cytotoxic effect of QC4 on gastric cancer cells was evaluated by CCK-8 assay and flow cytometry. The underlying mechanisms were tested by administration of cell death related inhibitors and detection of apoptotic and oncosis related proteins. Cytomembrane integrity and organelles damage were confirmed by lactate dehydrogenase (LDH) leakage assay, mitochondrial function test, and cytosolic free Ca(2+) concentration detection.
RESULTS
QC4 inhibited cell proliferation dose- and time-dependently and destroyed cell membrane integrity, activated calpain-1 autolysis, and induced apoptotic protein cleavage in gastric cancer cells. The detection of decreased ATP and mitochondrial membrane potential, ROS accumulation, and cytosolic free Ca(2+) elevation confirmed organelles damage in QC4-treated gastric cancer cells.
CONCLUSIONS
DHA derivative QC4 induced the damage of cytomembrane and organelles which finally lead to oncosis and apoptosis in gastric cancer cells. Therefore, as a derivative of plant derived small molecule DHA, QC4 might become a promising agent in gastric cancer therapy.
Topics: Abietanes; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Stomach Neoplasms
PubMed: 27057539
DOI: 10.1155/2016/2581061 -
Bioscience, Biotechnology, and... Mar 2009Cell death can proceed via at least two distinct pathways, apoptosis and oncosis. Apoptosis is an energy-dependent process characterized morphologically by cell...
Cell death can proceed via at least two distinct pathways, apoptosis and oncosis. Apoptosis is an energy-dependent process characterized morphologically by cell shrinkage, whereas oncosis is defined as a prelethal pathway leading to cell death associated with cellular swelling, organelle swelling, and increased membrane permeability. In this study, we found that overexpression of chromatin modifying protein 6 (CHMP6) induced cell death by a series of experiments, including morphological observation, intracellular ATP determination, caspase-3 activity, and flow cytometry. Typical morphological characteristics consistent with oncosis were observed by transmission electron microscopy. Simultaneously, we obtained some results that indicated apoptosis, but the anti-apoptotic gene Bcl-xL and caspase family inhibitor Z-VAD-FMK had little effect on CHMP6-induced cell death. These results suggest that CHMP6 overexpression can cause cell death, predominantly via oncosis and to a certain extent via apoptosis, and that CHMP6 might be a novel regulator involved in both oncosis and apoptosis.
Topics: Adenosine Triphosphate; Apoptosis; Caspases; Endosomal Sorting Complexes Required for Transport; Enzyme Activation; Gene Expression Profiling; Gene Expression Regulation; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Vesicular Transport Proteins
PubMed: 19270365
DOI: 10.1271/bbb.80458 -
Journal of the American College of... Apr 2011The aim of this study was to identify the remodeling parameters cardiomyocyte (CM) damage or death, hypertrophy, and fibrosis that may be linked to outcomes in patients...
OBJECTIVES
The aim of this study was to identify the remodeling parameters cardiomyocyte (CM) damage or death, hypertrophy, and fibrosis that may be linked to outcomes in patients with advanced heart failure (HF) in an effort to understand the pathogenic mechanisms of HF that may support newer therapeutic modalities.
BACKGROUND
There are controversial results on the influence of fibrosis, CM hypertrophy, and apoptosis on outcomes in patients with HF; other modalities of cell damage have been poorly investigated.
METHODS
In endomyocardial biopsy specimens from 100 patients with idiopathic dilated cardiomyopathy and advanced HF, CM diameter and the extent of fibrosis were determined by morphometry. The proportion of CMs with evidence of apoptosis, autophagic vacuolization (AuV), and oncosis was investigated by immunohistochemical methods and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. Those parameters were correlated with mortality in 3 years of follow-up by univariate analysis and with multivariate models incorporating the clinical variables more relevant to the prediction of outcomes.
RESULTS
CM AuV occurred in 28 patients (0.013 ± 0.012%) and oncosis in 41 (0.109 ± 0.139%). Nineteen patients showed both markers. Apoptotic CM nuclei were observed in 3 patients. In univariate analysis, CM diameter and AuV, either alone or associated with oncosis, were predictors of mortality. In multivariate analysis, CM diameter (hazard ratio: 1.37; 95% confidence interval: 1.12 to 1.68; p = 0.002) and simultaneous presence in the same endomyocardial biopsy specimen of AuV and oncosis (hazard ratio: 2.82; 95% confidence interval: 1.12 to 7.13; p = 0.028) were independent predictors of mortality.
CONCLUSIONS
CM hypertrophy and AuV, especially in association with oncosis, are predictors of outcome in patients with idiopathic dilated cardiomyopathy and severe HF.
Topics: Adult; Cardiomyopathy, Dilated; Female; Fibrosis; Heart Failure; Humans; Male; Middle Aged; Myocytes, Cardiac; Predictive Value of Tests; Retrospective Studies; Severity of Illness Index; Ventricular Remodeling
PubMed: 21453830
DOI: 10.1016/j.jacc.2010.09.080 -
Pflugers Archiv : European Journal of... Dec 2012Cell death proceeds by way of a variety of "cell death subroutines," including several types of "apoptosis," "regulated necrosis," and others. "Accidental necrosis" due... (Review)
Review
Cell death proceeds by way of a variety of "cell death subroutines," including several types of "apoptosis," "regulated necrosis," and others. "Accidental necrosis" due to profound adenosine triphosphate (ATP) depletion or oxidative stress is distinguished from regulated necrosis by the absence of death receptor signaling. However, both accidental and regulated necrosis have in common the process of "oncosis," a physiological process characterized by Na(+) influx and cell volume increase that, in necrotic cell death, is required to produce the characteristic features of membrane blebbing and membrane rupture. Here, we review emerging evidence that the monovalent cation channel, transient receptor potential melastatin 4 (TRPM4), is involved in the cell death process of oncosis. Potential involvement of TRPM4 in oncosis is suggested by the fact that the two principal regulators of TRPM4, intracellular ATP and Ca(2+), are both altered during necrosis in the direction that causes TRPM4 channel opening. Under physiological conditions, activation of TRPM4 promotes Na(+) influx and cell depolarization. Under pathological conditions, unchecked activation of TRPM4 leads to Na(+) overload, cell volume increase, blebbing and cell membrane rupture, the latter constituting the irreversible end stage of necrosis. Emerging data indicate that TRPM4 plays a crucial role as end executioner in the accidental necrotic death of ATP-depleted or redox-challenged endothelial and epithelial cells, both in vitro and in vivo. Future studies will be needed to determine whether TRPM4 also plays a role in regulated necrosis and apoptosis.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Calcium; Cell Death; Humans; Necrosis; TRPM Cation Channels
PubMed: 23065026
DOI: 10.1007/s00424-012-1166-z -
Acta Pharmaceutica Sinica. B Sep 2022As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer... (Review)
Review
As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.
PubMed: 36176912
DOI: 10.1016/j.apsb.2022.03.020