scholarly journals Length of intact plasma membrane determines the diffusion properties of cellular water

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Sato Eida ◽  
Marc Van Cauteren ◽  
Yuka Hotokezaka ◽  
Ikuo Katayama ◽  
Miho Sasaki ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Molecular Diffusion ◽  
Apoptotic Cell ◽  
Membrane Integrity ◽  
Biological Tissues ◽  
Critical Determinant ◽  
Adc Value ◽  
Cellular Environment ◽  
Potential Biomarker

Abstract Molecular diffusion in a boundary-free medium depends only on the molecular size, the temperature and medium viscosity. However, the critical determinant of the molecular diffusion property in inhomogeneous biological tissues has not been identified. Here, using an in vitro system and a high-resolution MR imaging technique, we show that the length of the intact plasma membrane is a major determinant of water diffusion in a controlled cellular environment and that the cell perimeter length (CPL) is sufficient to estimate the apparent diffusion coefficient (ADC) of water in any cellular environment in our experimental system (ADC = −0.21 × CPL + 1.10). We used this finding to further explain the different diffusion kinetics of cells that are dying via apoptotic or non-apoptotic cell death pathways exhibiting characteristic changes in size, nuclear and cytoplasmic architectures and membrane integrity. These results suggest that the ADC value can be used as a potential biomarker for cell death.

Quercetin in attenuation of ischemic/reperfusion injury: A review

2020 ◽  
Vol 13 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Saeed Samarghandian ◽  
Kiavash Hushmandi ◽  
Amirhossein Zabolian ◽  
Md Shahinozzaman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Membrane ◽  
Blood Supply ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Membrane Integrity ◽  
Therapeutic Effects ◽  
Molecular Pathways ◽  
Cell Membrane Integrity ◽  
Cell Membrane Disruption

Background: Ischemia/reperfusion (I/R) injury is a serious pathologic event that occurs due to restriction in blood supply to an organ, followed by hypoxia. This condition leads to enhanced levels of pro-inflammatory cytokines such as IL-6 and TNF-, and stimulation of oxidative stress via enhancing reactive oxygen species (ROS) levels. Upon reperfusion, blood supply increases, but it deteriorates condition, and leads to generation of ROS, cell membrane disruption and finally, cell death. Plant derived-natural compounds are well-known due to their excellent antioxidant and anti-inflammatory activities. Quercetin is a flavonoid exclusively found in different vegetables, herbs, and fruits. This naturally occurring compound possesses different pharmacological activities making it appropriate option in disease therapy. Quercetin can also demonstrate therapeutic effects via affecting molecular pathways such as NF-B, PI3K/Akt and so on. Methods: In the present review, we demonstrate that quercetin administration is beneficial in ameliorating I/R injury via reducing ROS levels, inhibition of inflammation, and affecting molecular pathways such as TLR4/NF-B, MAPK and so on. Results and conclusion: Quercetin can improve cell membrane integrity via decreasing lipid peroxidation. Apoptotic cell death is inhibited by quercetin via down-regulation of Bax, and caspases, and upregulation of Bcl-2. Quercetin is able to modulate autophagy (inhibition/induction) in decreasing I/R injury. Nanoparticles have been applied for delivery of quercetin, enhancing its bioavailability and efficacy in alleviation of I/R injury. Noteworthy, clinical trials have also confirmed the capability of quercetin in reducing I/R injury.

scholarly journals Plasma membrane integrity: implications for health and disease

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dustin A. Ammendolia ◽  
William M. Bement ◽  
John H. Brumell
Keyword(s):  
Plasma Membrane ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Whole Body ◽  
Plasma Membrane Integrity ◽  
Plasma Membrane Damage ◽  
Cellular Environment ◽  
Health And Disease ◽  
Repair Pathways ◽  
The Impact

AbstractPlasma membrane integrity is essential for cellular homeostasis. In vivo, cells experience plasma membrane damage from a multitude of stressors in the extra- and intra-cellular environment. To avoid lethal consequences, cells are equipped with repair pathways to restore membrane integrity. Here, we assess plasma membrane damage and repair from a whole-body perspective. We highlight the role of tissue-specific stressors in health and disease and examine membrane repair pathways across diverse cell types. Furthermore, we outline the impact of genetic and environmental factors on plasma membrane integrity and how these contribute to disease pathogenesis in different tissues.

scholarly journals Interactions of the Lysosomotropic Detergent O-Methyl-Serine Dodecylamide Hydrochloride (MSDH) with Lipid Bilayer Membranes—Implications for Cell Toxicity

2020 ◽  
Vol 21 (9) ◽  
pp. 3136 ◽  
Author(s):  
Ana-Maria Villamil Giraldo ◽  
Ida Eriksson ◽  
Stefan Wennmalm ◽  
Timmy Fyrner ◽  
Thomas Ederth ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Lipids ◽  
Apoptotic Cell ◽  
Human Fibroblasts ◽  
Membrane Integrity ◽  
Chemical Properties ◽  
High Ratio ◽  
Lipid Bilayer Membranes ◽  
High Concentration ◽  
Liposome Membrane

O-methyl-serine dodecylamine hydrochloride (MSDH) is a detergent that accumulates selectively in lysosomes, a so-called lysosomotropic detergent, with unexpected chemical properties. At physiological pH, it spontaneously forms vesicles, which disassemble into small aggregates (probably micelles) below pH 6.4. In this study, we characterize the interaction between MSDH and liposomes at different pH and correlate the findings to toxicity in human fibroblasts. We find that the effect of MSDH on lipid membranes is highly pH-dependent. At neutral pH, the partitioning of MSDH into the liposome membrane is immediate and causes the leakage of small fluorophores, unless the ratio between MSDH and lipids is kept low. At pH 5, the partitioning of MSDH into the membrane is kinetically impeded since MSDH is charged and a high ratio between MSDH and the lipids is required to permeabilize the membrane. When transferred to cell culture conditions, the ratio between MSDH and plasma membrane lipids must therefore be low, at physiological pH, to maintain plasma membrane integrity. Transmission electron microscopy suggests that MSDH vesicles are taken up by endocytosis. As the pH of the endosomal compartment progressively drops, MSDH vesicles disassemble, leading to a high concentration of increasingly charged MSDH in small aggregates inside the lysosomes. At sufficiently high MSDH concentrations, the lysosome is permeabilized, the proteolytic content released to the cytosol and apoptotic cell death is induced.

scholarly journals The Calcineurin Pathway Inhibitor Tacrolimus Enhances the In Vitro Activity of Azoles against Mucorales via Apoptosis

2013 ◽  
Vol 12 (9) ◽  
pp. 1225-1234 ◽  
Author(s):  
F. Shirazi ◽  
D. P. Kontoyiannis
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Rhizopus Oryzae ◽  
Apoptotic Cell ◽  
Chromatin Condensation ◽  
Membrane Integrity ◽  
Ros Generation ◽  
Content Type ◽  
Intracellular Ca ◽  
Calcineurin Pathway

ABSTRACT The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales . We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca 2+ , phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 μg/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 μg/ml) for Rhizopus oryzae , Cunninghamella bertholletiae , and Mucor circinelloides . Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca 2+ and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.

scholarly journals Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death

2003 ◽  
Vol 23 (2) ◽  
pp. 665-676 ◽  
Author(s):  
Koh Ono ◽  
Sung O. Kim ◽  
Jiahuai Han
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Tumor Necrosis ◽  
Membrane Integrity ◽  
Membrane Disruption ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Chemical Inhibitors ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Since a release of intracellular contents can induce local inflammatory responses, mechanisms that lead to loss of plasma membrane integrity in cell death are important to know. We showed previously that deficiency of the plasma membrane Ca2+ ATPase 4 (PMCA4) in L929 cells impaired tumor necrosis factor alpha (TNF-α)-induced enlargement of lysosomes and reduced cell death. The lysosomal changes can be determined by measuring the total volume of intracellular acidic compartments per cell (VAC), and we show here that inhibition of the increase in VAC due to PMCA4 deficiency not only reduced cell death but also converted TNF-α-induced cell death from a process involving disruption of the plasma membrane to a cell demise with a nearly intact plasma membrane. The importance of the size of lysosomes in determining plasma membrane integrity during cell death was supported by the observations that chemical inhibitors that reduce VAC also reduced the plasma membrane disruption induced by TNF-α in wild-type L929 cells, while increases in VAC due to genetic mutation, senescence, cell culture conditions, and chemical inhibitors all changed the morphology of cell death from one with an originally nearly intact plasma membrane to one with membrane disruption in a number of different cells. Moreover, the ATP depletion-mediated change from apoptosis to necrosis is also associated with the increases of VAC. The increase in lysosomal size may due to intracellular self-digestion of dying cells. Big lysosomes are easy to rupture, and the release of hydrolytic enzymes from ruptured lysosomes can cause plasma membrane disruption.

scholarly journals The Drosophila TNF Eiger activates caspase-dependent necrosis when apoptosis is blocked

2018 ◽  
Author(s):  
Mingli Li ◽  
Yun Fan
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Membrane Integrity ◽  
Apoptotic Cell Death ◽  
Dual Roles ◽  
Developmental Defects ◽  
Cell Membrane Integrity ◽  
Effector Caspases ◽  
Necrosis Factor ◽  
Cellular Organelles

AbstractEiger (Egr), the homolog of the mammalian tumor-necrosis factor (TNF), is the ligand of the c-Jun N-terminal kinase (JNK) stress response signaling pathway in Drosophila. Although expression of Egr frequently leads to apoptosis, it has also been implicated in activation of non-apoptotic cell death. However, it is not yet clear how Egr can induce both apoptosis and non-apoptotic cell death, and if so, how such processes are coordinated. Here, we show that expression of Egr in the developing Drosophila eye induces apoptosis and non-apoptotic developmental defects, both of which are JNK-dependent. Intriguingly, when apoptotic effector caspases DrICE and Dcp-1 are defective or inhibited, expression of Egr induces necrosis characterized by loss of cell membrane integrity, translucent cytoplasm and aggregation of cellular organelles. Surprisingly, the induction of necrosis depends on the catalytic activity of the initiator caspase Dronc and the input from JNK signaling independently of their roles in apoptosis. Therefore, similar to the mammalian caspase-8, caspases in Drosophila also have dual roles in promoting TNF-mediated apoptosis and inhibiting necrosis.

Adaptive Responses to the Stress Induced by Hyperthermia or Hydrogen Peroxide in Human Fibroblasts

2003 ◽  
Vol 228 (5) ◽  
pp. 491-498 ◽  
Author(s):  
S. Grasso ◽  
C. Scifo ◽  
V. Cardile ◽  
R. Gulino ◽  
M. Renis
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Human Fibroblasts ◽  
Membrane Integrity ◽  
Adaptive Responses ◽  
Mitochondrial Potential ◽  
Cell Membrane Integrity

Perturbation of oxidant/antioxidant cellular balance, induced by cellular metabolism and by exogenous sources, causes deleterious effects to proteins, lipids, and nucleic acids, leading to a condition named “oxidative stress” that is involved in several diseases, such as cancer, ischemia-reperfusion injury, and neurodegenerative disorders. Among the exogenous agents, both H2O2 and hyperthermia have been implicated in oxidative stress promotion linked with the activation of apoptotic or necrotic mechanisms of cell death. The goal of this work was to better understand the involvement of some stress-related proteins in adaptive responses mounted by human fibroblasts versus the oxidative stress differently induced by 42°C hyperthermia or H2O2. The research was developed, switching off inducible nitric oxide synthase (iNOS) expression through antisense oligonucleotide transfection by studying the possible coregulation in the expression of HSP32 (also named HO-1), HSP70, and iNOS and their involvement in the induction of DNA damage. Several biochemical parameters, such as cell viability (MTT assay), cell membrane integrity (lactate dehydrogenase release), reactive oxygen species formation, glutathione levels, immunocytochemistry analysis of iNOS, HSP70, and HO-1 levels, genomic DNA fragmentation (HALO/COMET assay), and transmembrane mitochondrial potential (ΔΨ) were examined. Cells were collected immediately at the end of the stress-inducing treatment. The results, confirming the pleiotropic function of i-NOS, indicate that: (i) HO-1/HSP32, HSP70, and iNOS are finely tuned in their expression to contribute all together, in human fibroblasts, in ameliorating the resistance to oxidative stress damage; (ii) ROS exposure, at least in hyperthermia, in human fibroblasts contributes to growth arrest more than to apoptosis activation; and (iii) mitochondrial dysfunction, in presence of iNOS inhibition seems to be clearly involved in apoptotic cell death of human fibroblasts after H2O2 treatment, but not after hyperthermia.

scholarly journals Apoptosis in Hydra: function of HyBcl-2 like 4 and proteins of the transmembrane BAX inhibitor motif (TMBIM) containing family

2019 ◽  
Vol 63 (6-7) ◽  
pp. 259-270 ◽  
Author(s):  
Mina Motamedi ◽  
Laura Lindenthal ◽  
Anita Wagner ◽  
Margherita Kemper ◽  
Jasmin Moneer ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Epithelial Cells ◽  
Programmed Cell Death ◽  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Family Members ◽  
Sequence Comparisons ◽  
Induced Apoptosis ◽  
Related Proteins

Mechanisms of programmed cell death differ between animals, plants and fungi. In animals, apoptotic cell death depends on caspases and Bcl-2 family proteins. These protein families are only found in multicellular animals, including cnidarians, insects and mammals. In contrast, members of the TMBIM-family of transmembrane proteins are conserved across all eukaryotes. Sequence comparisons of cell death related proteins between phyla indicate strong conservation of the genes involved. However, often it is not known whether this is paralleled by conservation of function. Here we present the first study to support an anti-apoptotic function of Bcl-2 like proteins in the cnidarian Hydra within a physiological context. We used transgenic Hydra expressing GFP-tagged HyBcl-2-like 4 protein in epithelial cells. The protein was localised to mitochondria and able to protect Hydra epithelial cells from apoptosis induced by either the PI(3) kinase inhibitor wortmannin or by starvation. Moreover, we identified members of the TMBIM-family in Hydra including HyBax-Inhibitor-1, HyLifeguard-1a and -1b and HyLifeguard 4. Expressing these TMBIM-family members in Hydra and human HEK cells, we found HyBax-inhibitor-1 protein localised to ER-membranes and HyLifeguard-family members localised to the plasma membrane and Golgi-vesicles. Moreover, HyBax-inhibitor-1 protected human cells from camptothecin induced apoptosis. This work illustrates that the investigated Bcl-2- and TMBIM-family members represent evolutionarily conserved mitochondrial, ER, Golgi and plasma membrane proteins with anti-apoptotic functions. The participation of ER and Golgi proteins in the regulation of programmed cell death might be a very ancient feature.

scholarly journals Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Se-Yeon Park ◽  
Han-Hee Park ◽  
Sang-Yeong Park ◽  
Sun Mi Hong ◽  
Seongmin Yoon ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Membrane Integrity ◽  
Death Receptor ◽  
Kinase Domain ◽  
Death Process ◽  
Endosomal Trafficking ◽  
Independent Manner ◽  
Interacting Protein ◽  
Early Endosomes

Abstract Mixed lineage kinase domain-like (MLKL) is an essential molecule of necroptosis, a cell death process that is initiated by direct disruption of the plasma membrane. During necroptosis, MLKL is phosphorylated by receptor interacting protein kinase-3 (RIPK3 or RIP3), and then translocates to the plasma membrane to disrupt membrane integrity. Recent data suggest that MLKL also has a RIP3-indendent function in the generation of intraluminal and extracellular vesicles (EVs), as well as in myelin sheath breakdown when promoting sciatic nerve regeneration. Here we show that depletion of MLKL enhances TRAIL-induced cell death in a RIP3-independent manner. Depletion of MLKL leads to prolonged cytotoxic signals that increase TRAIL-induced cell death. Initially, TRAIL binds to DR5 at the cell surface and is endocytosed at similar rates in MLKL-expressing and MLKL-depleted cells, eventual degradation of intracellular TRAIL by the lysosome is delayed in MLKL-depleted cells, corresponding with prolonged/enhanced intracellular signals such as p-ERK and p-p38 in these cells. Colocalization of TRAIL with the marker of early endosomes, EEA1 suggests that TRAIL is accumulated in early endosomes in MLKL-depleted cells compared to MLKL-expressing cells. This indicates that depletion of MLKL reduces receptor-ligand endosomal trafficking leading to increased TRAIL-cytotoxicity. An MLKL mutant that compromises its necroptotic function and its function in the generation of EVs was sufficient to rescue MLKL deficiency, suggesting that the N-terminal structural elements necessary for these functions are not required for the function of MLKL in the intracellular trafficking associated with regulating death receptor cytotoxicity. A reduction in MLKL expression in cancer cells would therefore be expected to result in enhanced TRAIL-induced therapeutic efficacy.

scholarly journals NINJ1 mediates plasma membrane rupture during lytic cell death

2020 ◽  
Author(s):  
Nobuhiko Kayagaki ◽  
Opher Kornfeld ◽  
Bettina Lee ◽  
Irma Stowe ◽  
Karen O'Rourke ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Apoptotic Cell ◽  
High Mobility ◽  
Surface Protein ◽  
Underlying Mechanism ◽  
Cell Swelling ◽  
Membrane Pore ◽  
Membrane Rupture ◽  
Ionic Fluxes

Abstract Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules termed damage-associated molecular patterns (DAMPs) that propagate the inflammatory response. The underlying mechanism for PMR, however, is unknown. Here we show that the ill-characterized nerve injury-induced protein 1 (NINJ1) — a cell surface protein with two transmembrane regions — plays an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1–/– macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and failed to release numerous intracellular proteins including High Mobility Group Box 1 (HMGB1, a known DAMP) and Lactate Dehydrogenase (LDH, a standard measure of PMR). Ninj1–/– macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1–/– mice were more susceptible than wild-type mice to Citrobacter rodentium, suggesting a role for PMR in anti-bacterial host defense. Mechanistically, NINJ1 utilized an evolutionarily conserved extracellular α-helical domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held dogma that cell death-related PMR is a passive event. Pyroptosis is a potent inflammatory mode of lytic cell death triggered by diverse infectious and sterile insults1-3. It is driven by the pore-forming fragment of gasdermin D (GSDMD)4-7 and releases two exemplar proteins: interleukin-1β (IL-1β), a pro-inflammatory cytokine, and LDH, a standard marker of PMR and lytic cell death. An early landmark study8 predicted two sequential steps for pyroptosis: (1) initial formation of a small plasma membrane pore causing IL-1β release and non-selective ionic fluxes, and (2) subsequent PMR attributable to oncotic cell swelling. PMR releases LDH (140 kDa) and large DAMPs. While the predicted size of gasdermin pores (~18 nm inner diameter9) is large enough to release IL-1β (17 kDa, ~4.5 nm diameter), the underlying mechanism for subsequent PMR has been considered a passive osmotic lysis event.

Sign in / Sign up

Export Citation Format

Share Document