scholarly journals Apoptosis and apoptotic body: disease message and therapeutic target potentials

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Xuebo Xu ◽  
Yueyang Lai ◽  
Zi-Chun Hua
Keyword(s):  
Cell Death ◽  
Recombinant Proteins ◽  
Inflammatory Responses ◽  
Apoptotic Bodies ◽  
Apoptotic Body ◽  
Fundamental Process ◽  
Therapeutic Measures ◽  
Membrane Bound ◽  
Dying Cells ◽  
Review Current

AbstractApoptosis is widely known as programmed cell death eliciting no inflammatory responses. The intricacy of apoptosis has been a focus of an array of researches, accumulating a wealth of knowledge which led to not only a better understanding of the fundamental process, but also potent therapies of diseases. The classic intrinsic and extrinsic signaling pathways of apoptosis, along with regulatory factors have been well delineated. Drugs and therapeutic measures designed based on current understanding of apoptosis have long been employed. Small-molecule apoptosis inducers have been clinically used for eliminating morbid cells and therefore treating diseases, such as cancer. Biologics with improved apoptotic efficacy and selectivity, such as recombinant proteins and antibodies, are being extensively researched and some have been approved by the FDA. Apoptosis also produces membrane-bound vesicles derived from disassembly of apoptotic cells, now known as apoptotic bodies (ApoBDs). These little sealed sacs containing information as well as substances from dying cells were previously regarded as garbage bags until they were discovered to be capable of delivering useful materials to healthy recipient cells (e.g., autoantigens). In this review, current understandings and knowledge of apoptosis were summarized and discussed with a focus on apoptosis-related therapeutic applications and ApoBDs.

scholarly journals Unleashing the therapeutic potential of apoptotic bodies

2020 ◽  
Vol 48 (5) ◽  
pp. 2079-2088
Author(s):  
Thanh Kha Phan ◽  
Dilara Ceyda Ozkocak ◽  
Ivan Ka Ho Poon
Keyword(s):  
Drug Delivery ◽  
Cell Death ◽  
Therapeutic Potential ◽  
Predictive Biomarkers ◽  
Distinct Type ◽  
Apoptotic Bodies ◽  
Therapeutic Application ◽  
Effector Molecules ◽  
Membrane Bound ◽  
Shed Light

Extracellular vesicles (EVs), membrane-bound vesicles that are naturally released by cells, have emerged as new therapeutic opportunities. EVs, particularly exosomes and microvesicles, can transfer effector molecules and elicit potent responses in recipient cells, making them attractive therapeutic targets and drug delivery platforms. Furthermore, containing predictive biomarkers and often being dysregulated in various disease settings, these EVs are being exploited for diagnostic purposes. In contrast, the therapeutic application of apoptotic bodies (ApoBDs), a distinct type of EVs released by cells undergoing a form of programmed cell death called apoptosis, has been largely unexplored. Recent studies have shed light on ApoBD biogenesis and functions, promisingly implicating their therapeutic potential. In this review, we discuss many strategies to develop ApoBD-based therapies as well as highlight their advantages and challenges, thereby positioning ApoBD for potential EV-based therapy.

The complement system

2020 ◽  
pp. 315-324
Author(s):  
Marina Botto ◽  
Matthew C. Pickering
Keyword(s):  
Complement System ◽  
Inflammatory Responses ◽  
Membrane Integrity ◽  
Membrane Attack Complex ◽  
Cell Membrane Integrity ◽  
Biological Responses ◽  
Target Cell Membrane ◽  
Membrane Bound ◽  
Dying Cells ◽  
The Complement System

The complement system, consisting of soluble and membrane-bound proteins, is a major effector mechanism of host defence against infection and inflammatory responses. It has an important role in the removal of immune complexes and dying cells, and also modulates humoral and cell-mediated immune responses. Complement activation occurs through three pathways, each generating enzyme complexes, termed C3 convertases. These cleave native C3 to form C3b and C3a. C3b can covalently attach to surfaces (e.g. pathogen surfaces) where it triggers biological responses following interaction with membrane-bound receptors and can also trigger cleavage of native C5 to C5b and C5a. C5b triggers the formation of the membrane attack complex, which disrupts target cell membrane integrity and may result in cell lysis.

scholarly journals Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death

2003 ◽  
Vol 160 (4) ◽  
pp. 577-587 ◽  
Author(s):  
Murray C.H. Clarke ◽  
John Savill ◽  
David B. Jones ◽  
Brendon S. Noble ◽  
Simon B. Brown
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Progenitor Cell ◽  
Caspase 3 ◽  
Transmembrane Potential ◽  
Blood Platelets ◽  
Apoptotic Bodies ◽  
Caspase 9 ◽  
Daughter Cells ◽  
Membrane Bound

Caspase-directed apoptosis usually fragments cells, releasing nonfunctional, prothrombogenic, membrane-bound apoptotic bodies marked for rapid engulfment by macrophages. Blood platelets are functional anucleate cells generated by specialized fragmentation of their progenitors, megakaryocytes (MKs), but committed to a constitutive caspase-independent death. Constitutive formation of the proplatelet-bearing MK was recently reported to be caspase-dependent, apparently involving mitochondrial release of cytochrome c, a known pro-apoptogenic factor. We extend those studies and report that activation of caspases in MKs, either constitutively or after Fas ligation, yields platelets that are functionally responsive and evade immediate phagocytic clearance, and retain mitochondrial transmembrane potential until constitutive platelet death ensues. Furthermore, the exclusion from the platelet progeny of caspase-9 present in the progenitor accounts for failure of mitochondrial release of cytochrome c to activate caspase-3 during platelet death. Thus, progenitor cell death by apoptosis can result in birth of multiple functional anucleate daughter cells.

scholarly journals Apoptotic cell-derived exosomes: messages from dying cells

2020 ◽  
Vol 52 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Ramesh Kakarla ◽  
Jaehark Hur ◽  
Yeon Ji Kim ◽  
Jaeyoung Kim ◽  
Yong-Joon Chwae
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Responses ◽  
Extracellular Vesicles ◽  
Apoptotic Cell ◽  
Active Form ◽  
Live Cells ◽  
Apoptotic Bodies ◽  
Pathological Conditions ◽  
Dying Cells

AbstractApoptosis, a type of programmed cell death that plays a key role in both healthy and pathological conditions, releases extracellular vesicles such as apoptotic bodies and microvesicles, but exosome release due to apoptosis is not yet commonly accepted. Here, the reports demonstrating the presence of apoptotic exosomes and their roles in inflammation and immune responses are summarized, together with a general summary of apoptosis and extracellular vesicles. In conclusion, apoptosis is not just a ‘silent’ type of cell death but an active form of communication from dying cells to live cells through exosomes.

scholarly journals PGE2 induced in and released by dying cells functions as an inhibitory DAMP

2016 ◽  
Vol 113 (14) ◽  
pp. 3844-3849 ◽  
Author(s):  
Sho Hangai ◽  
Tomoka Ao ◽  
Yoshitaka Kimura ◽  
Kosuke Matsuki ◽  
Takeshi Kawamura ◽  
...  
Keyword(s):  
Cell Death ◽  
Wound Repair ◽  
Inflammatory Responses ◽  
Critical Issue ◽  
Protective Role ◽  
The Body ◽  
Lipid Mediator ◽  
Expression Of Genes ◽  
Dying Cells

Cellular components released into the external milieu as a result of cell death and sensed by the body are generally termed damage-associated molecular patterns (DAMPs). Although DAMPs are conventionally thought to be protective to the host by evoking inflammatory responses important for immunity and wound repair, there is the prevailing notion that dysregulated release of DAMPs can also underlie or exacerbate disease development. However, the critical issue for how resultant DAMP-mediated responses are regulated has heretofore not been fully addressed. In the present study, we identify prostaglandin E2 (PGE2) as a DAMP that negatively regulates immune responses. We show that the production of PGE2 is augmented under cell death-inducing conditions via the transcriptional induction of the cyclooxygenase 2 (COX2) gene and that cell-released PGE2 suppresses the expression of genes associated with inflammation, thereby limiting the cell’s immunostimulatory activities. Consistent with this, inhibition of the PGE2 synthesis pathway potentiates the inflammation induced by dying cells. We also provide in vivo evidence for a protective role of PGE2 released upon acetaminophen-induced liver injury as well as a pathogenic role for PGE2 during tumor cell growth. Our study places this classically known lipid mediator in an unprecedented context—that is, an inhibitory DAMP vis-à-vis activating DAMPs, which may have translational implications for designing more effective therapeutic regimens for inflammation-associated diseases.

scholarly journals Regulation of membrane release in apoptosis

1998 ◽  
Vol 334 (2) ◽  
pp. 479-485 ◽  
Author(s):  
Jiandi ZHANG ◽  
Timothy A. DRISCOLL ◽  
Yusuf A. HANNUN ◽  
Lina M. OBEID
Keyword(s):  
Cell Death ◽  
Membrane Lipids ◽  
Morphological Changes ◽  
Membrane Vesicles ◽  
Heterogeneous Population ◽  
Apoptotic Bodies ◽  
Fundamental Process ◽  
Release Assay ◽  
Lymphoid Cell Lines

Apoptosis is a fundamental process of cell regulation whereby cells execute one or more biochemical programs leading to cell death. Several mechanisms have been evaluated and suggested to play roles in the regulation of apoptosis, including the activation of phospholipase A2 (PLA2), usually measured as release of 3H-labelled arachidonic acid (AA) from prelabelled cells. The current study was aimed at examining the role of PLA2 in regulating apoptosis in response to several inducers (such as vincristine and etoposide) in lymphoid cell lines. Cells were labelled with [3H]fatty acids and the released radioactivity was characterized. These studies indicated that the AA release assay did not reflect release of non-esterified fatty acid via activation of the PLA2 pathway. Rather, studies using TLC and electron microscopy showed that AA release reflected a previously unsuspected shedding of a heterogeneous population of membrane vesicles and fragments, probably as components of apoptotic bodies. Further studies demonstrated that this process is an integral part of apoptosis. Overexpression of Bcl-2 or the addition of caspase peptide inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethane prevented the characteristic morphological changes of cell death, and completely inhibited the release of membrane vesicles and fragments. On the other hand, release of membrane vesicles and fragments was caused by various inducers of apoptosis, as measured by release of either 3H-labelled AA or palmitic acid. Thus the present study demonstrates that the release of membrane lipids during apoptosis defines a new assay for apoptosis and has allowed the investigation of the mechanisms regulating formation of apoptotic bodies.

Progress on the Mechanism for Aspirin’s Anti-tumor Effects

2020 ◽  
Vol 22 (1) ◽  
pp. 105-111
Author(s):  
Lin Zheng ◽  
Weibiao Lv ◽  
Yuanqing Zhou ◽  
Xu Lin ◽  
Jie Yao
Keyword(s):  
Platelet Aggregation ◽  
Energy Metabolism ◽  
Side Effects ◽  
Energy Production ◽  
Immune Escape ◽  
Inflammatory Responses ◽  
Mechanisms Of Action ◽  
Proliferation And Metastasis ◽  
Review Current ◽  
Granule Release

: Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review current insights of aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant of aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investi-gations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

scholarly journals The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17

2020 ◽  
Vol 22 (1) ◽  
pp. 118
Author(s):  
Yuanpeng Zheng ◽  
Tessa A. Verhoeff ◽  
Paula Perez Pardo ◽  
Johan Garssen ◽  
Aletta D. Kraneveld
Keyword(s):  
Autism Spectrum Disorder ◽  
Intestinal Tract ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Protein Substrates ◽  
Specific Proteins ◽  
Membrane Bound

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis.

scholarly journals Apoptosis and inflammation

1995 ◽  
Vol 4 (1) ◽  
pp. 5-15 ◽  
Author(s):  
C. Haanen ◽  
I. Vermes
Keyword(s):  
Cell Death ◽  
Inflammatory Reaction ◽  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Target Cells ◽  
Apoptotic Bodies ◽  
Accidental Injury ◽  
Inflammatory Reactions ◽  
Inflammatory Processes

During the last few decades it has been recognized that cell death is not the consequence of accidental injury, but is the expression of a cell suicide programme. Kerr et al. (1972) introduced the term apoptosis. This form of cell death is under the influence of hormones, growth factors and cytokines, which depending upon the receptors present on the target cells, may activate a genetically controlled cell elimination process. During apoptosis the cell membrane remains intact and the cell breaks into apoptotic bodies, which are phagocytosed. Apoptosis, in contrast to necrosis, is not harmful to the host and does not induce any inflammatory reaction. The principal event that leads to inflammatory disease is cell damage, induced by chemical/physical injury, anoxia or starvation. Cell damage means leakage of cell contents into the adjacent tissues, resulting in the capillary transmigration of granulocytes to the injured tissue. The accumulation of neutrophils and release of enzymes and oxygen radicals enhances the inflammatory reaction. Until now there has been little research into the factors controlling the accumulation and the tissue load of granulocytes and their histotoxic products in inflammatory processes. Neutrophil apoptosis may represent an important event in the control of intlamtnation. It has been assumed that granulocytes disintegrate to apoptotic bodies before their fragments are removed by local macrophages. Removal of neutrophils from the inflammatory site without release of granule contents is of paramount importance for cessation of inflammation. In conclusion, apoptotic cell death plays an important role in inflammatory processes and in the resolution of inflammatory reactions. The facts known at present should stimulate further research into the role of neutrophil, eosinophil and macrophage apoptosis in inflammatory diseases.

scholarly journals Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Hironari Nishizawa ◽  
Mitsuyo Matsumoto ◽  
Guan Chen ◽  
Yusho Ishii ◽  
Keisuke Tada ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Peroxide ◽  
Nih3t3 Cells ◽  
Regulated Cell Death ◽  
Primary Mouse ◽  
Ischemic Diseases ◽  
A Chain ◽  
Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

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