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Model of cisplatin-induced cytoskeletal remodeling. The model depicts activation of the ASMase/ceramide pathway by cisplatin as a key step upstream of actin rearrangement. The serine/threonine phosphatase PP2A links ceramide generation to ezrin dephosphorylation and cytosolic relocation. Inactivation of ezrin results in dissociation of actin filaments from the plasma membrane and resorption of cellular filopodia.
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The chemotherapeutic agent cisplatin is widely used in treatment of solid tumors. In breast cancer cells, cisplatin produces early and marked changes in cell morphology and the actin cytoskeleton. These changes manifest as loss of lamellipodia/filopodia and appearance of membrane ruffles. Furthermore, cisplatin induces dephosphorylation of the acti...
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... When Mfs engulf larger particles, they require an increased membrane capacity, including ruffled membrane formation, to encapsulate these large particles. Sphingolipids, such as sulfatide and SM, have saturated fatty acids and preferentially self-organize liquid-ordered membrane domains together with cholesterol (63). Ly49Q distributes to liquid-ordered lipid rafts via the CRAC motif and can assemble a panel of signaling molecules to lipid rafts via the ITIM domain. ...
... PEMfs were prepared from Cst +/+ and Cst -/mice, and phagocytosis of IgG-opsonized beads with different diameters was examined. to such stoichiometric assessments of protein−protein interactions, given that sphingolipid, as a saturated fatty acid, can organize a liquid-ordered domain by clustering (63,69), cis-interaction between MHC-I and Ly49Q might incubate multivalent clusters of ITIMs within a limited membrane area. This might promote the formation of a membrane region where a panel of ITIM-interacting molecules are in close proximity to facilitate the construction of a functional lipid raft as a signaling platform for efficient and concerted regulation of complex biological processes, such as highly regulated actin remodeling. ...
Inhibitory natural killer (NK) cell receptors recognize MHC class I (MHC-I) in trans on target cells and suppress cytotoxicity. Some NK cell receptors recognize MHC-I in cis, but the role of this interaction is uncertain. Ly49Q, an atypical Ly49 receptor expressed in non-NK cells, binds MHC-I in cis and mediates chemotaxis of neutrophils and type I interferon production by plasmacytoid dendritic cells. We identified a lipid-binding motif in the juxtamembrane region of Ly49Q and found that Ly49Q organized functional membrane domains comprising sphingolipids via sulfatide binding. Ly49Q recruited actin-remodeling molecules to an immunoreceptor tyrosine-based inhibitory motif, which enabled the sphingolipid-enriched membrane domain to mediate complicated actin remodeling at the lamellipodia and phagosome membranes during phagocytosis. Thus, Ly49Q facilitates integrative regulation of proteins and lipid species to construct a cell type-specific membrane platform. Other Ly49 members possess lipid binding motifs; therefore, membrane platform organization may be a primary role of some NK cell receptors.
... In fact, lipidomics offers mechanistic insight into morphological changes in response to priming. Sphingosine-1-phosphate (S1P), a catabolite of ceramide, is a well-documented regulator of cytoskeletal reorganization in a cell type-specific manner (139,140). Both S1P and ceramide are intermediates in sphingolipid metabolism, along with sphingomyelin (141), which we observed in MSC-EVs. ...
Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function can be mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include ‘priming’ MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.
Graphical Abstract
Highlights
MSCs morphologically respond to inflammatory priming conditions.
Priming ‘hits’ identified from morphological screen increase MSC-EV production.
Priming MSCs in bioreactors enhances MSC-EV modulation of microglia.
Changes in MSC-EV production and potency reflected by lipid content.
First demonstration of effects of priming on MSC production of EVs in a bioreactor.
... Abdel Karim et al. completely overlooked a crucial point and thus were not able to provide an explanation for this apparent paradox. Cisplatin activates ASMase [182][183][184][185] and cisplatininduced apoptosis of different cancer cells is partly or closely mediated by ASMase activation [184,186]. On the other hand, TCAs, e.g. ...
Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.
Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.
Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.
Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca²⁺) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.
Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.
... Ceramide dimers can also be used in the manufacture of pharmaceuticals [10] and other inventions have documented many potential applications of ceramide-based formulations for drug delivery [11]. The fact that ceramides can mediate cell death by triggering apoptosis enhances their utility as a chemotherapeutic agent in cancer treatment [12,13]. In addition, foods containing adequate amounts of ceramides have also been studied for their potential health benefits [14][15][16]. ...
The utilization of ceramides, which are members of the sphingolipid family, has been widely acknowledged in the cosmetic and pharmaceutical industries, along with various other applications as therapeutic agents. Most ceramides currently available on the market are synthetic ceramides created through chemical reactions with precursors resembling the natural precursor of sphingolipid production by living organisms. In fact, many organisms ranging from microbes to higher-order mammals natively use metabolism to produce sphingolipids, including ceramides and their derivatives, to support cell molecular functions. Sphingolipids, for instance, are present in the cell membranes of mammals, plants, and yeast to maintain membrane morphology. As a green alternative to the chemical synthesis method, many studies have been carried out to reveal the diversity and characteristics of biologically produced ceramide derivatives. In this review, we summarized the most important aspects of ceramide biosynthesis in general and provide a quick overview of the common organisms producing ceramides. In addition, a brief discussion regarding the role of ceramides in cells and their risks was included. As the biosynthesis of ceramides is an attractive alternative to current commercial methods, the advances reviewed herein demonstrate the untapped potential for the further development of synthetic pathways to enhance biobased-ceramide production.
... CDDP has been shown to directly interfere with the cytoskeleton network, causing its collapse and subsequent aggregation in the cytoplasm [150] ( Figure 2E). For example, CDDP causes vast remodelling of the actin microfilament network, causing loss of filopodia and an increase in cortical stress fibers [151]. In addition, CDDP causes the destabilization of actin filaments anchored to the plasma membrane, causing its re-localization to the cytoplasm. ...
... In addition, CDDP causes the destabilization of actin filaments anchored to the plasma membrane, causing its re-localization to the cytoplasm. This effect is mediated through ezrin, an actin binding protein with roles in anchoring actin to the plasma membrane, that becomes deactivated by CDDP via CDDPinduced aSMase activity [151]. Indeed, knockdown of aSMase activity abrogates the actin and ezrin re-localization induced by CDDP. ...
... Indeed, knockdown of aSMase activity abrogates the actin and ezrin re-localization induced by CDDP. In addition, treatment with ceramides alone cause the same effects of ezrin inactivation as by CDDP, showing that ceramides produced by CDDP-activated aSMase are responsible for the disruption of the actin network [151]. ...
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
... CDDP has been shown to directly interfere with the cytoskeleton network, causing its collapse and subsequent aggregation in the cytoplasm [149]. For example, CDDP causes vast remodelling of the actin microfilament network, causing loss of filopodia and an increase in cortical stress fibers [150]. In addition, CDDP causes the destabilization of actin filaments anchored to the plasma membrane, causing its re-localization to the cytoplasm. ...
... In addition, CDDP causes the destabilization of actin filaments anchored to the plasma membrane, causing its re-localization to the cytoplasm. This effect is mediated through ezrin, an actin binding protein with roles in anchoring actin to the plasma membrane, that becomes deactivated by CDDP via CDDP-induced aSMase activity [150]. Indeed, knockdown of aSMase activity abrogates the actin and ezrin re-localization induced by CDDP. ...
... Indeed, knockdown of aSMase activity abrogates the actin and ezrin re-localization induced by CDDP. In addition, treatment with ceramides alone cause the same effects of ezrin inactivation as by CDDP, showing that ceramides produced by CDDP-activated aSMase is responsible for the disruption of the actin network [150]. ...
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
... This was supported by a study where aSMase-null lymphoblasts were shown to be insensitive to radiation therapy and to be re-sensitized upon aSMase overexpression [102]. Similar to radiotherapy, cellular actions of chemotherapeutic agents, such as paclitaxel, also involve aSMase-mediated ceramide generation and subsequent cell death in BC cells [103]. Additionally, another study has reported that paclitaxel can also increase de novo ceramide production through activating SPT in breast tumors [55], suggesting that chemotherapeutic agents may promote intracellular ceramide accumulation through a combination of increasing de novo ceramide production and breakdown of downstream sphingolipids. ...
One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.
... Cisplatin (cis-diamminedichloroplatinum II), known as CP, is an anti-cancer drug [12] that has been used for the treatment of different types of cancer (breast, testicular, ovarian, cervical, head, neck, and lung cancers) with excellent clinical outcomes [13,14]. It is generally known that CP promotes DNA damage, which causes a number of signal transduction pathways to be activated [15][16][17]. Nevertheless, it is still unclear as to exactly how cisplatin works and how particular it is. ...
Atriplex halimus L., also known as Mediterranean saltbush, and locally as "Lgtef", an hal-ophytic shrub, is used extensively to treat a wide variety of ailments in Morocco. The present study was undertaken to determine the antioxidant activity and cytotoxicity of the ethanolic extract of A. halimus leaves (AHEE). We first determined the phytochemical composition of AHEE using a liquid chromatography (LC)-tandem mass spectrometry (MS/MS) technique. The antioxidant activity was evaluated using different methods including DPPH scavenging capacity, β-carotene bleaching assay , ABTS scavenging, iron chelation, and the total antioxidant capacity assays. Cytotoxicity was investigated against human cancer breast cells lines MCF-7 and MDA-MB-231. The results showed that the components of the extract are composed of phenolic acids and flavonoids. The DPPH test showed strong scavenging capacity for the leaf extract (IC50 of 0.36 ± 0.05 mg/mL) in comparison to ascorbic acid (IC50 of 0.19 ± 0.02 mg/mL). The β-carotene test determined an IC50 of 2.91 ± 0.14 mg/mL. The IC50 values of ABTS, iron chelation, and TAC tests were 44.10 ± 2.92 TE µmol/mL, 27.40 ± 1.46 mg/mL, and 124 ± 1.27 µg AAE/mg, respectively. In vitro, the AHE extract showed significant inhibitory activity in all tested tumor cell lines, and the inhibition activity was found in a dose-dependent manner. Furthermore, computational techniques such as molecular docking and AD-MET analysis were used in this work. Moreover, the physicochemical parameters related to the compounds' pharmacokinetic indicators were evaluated, including absorption, distribution, metabolism , excretion, and toxicity prediction (Pro-Tox II).
... Both types differ in their trafficking process, utilizing a common protein precursor, ASMase. L-SMase, which is localized in an endolysosomal compartment, is translocated to an extracellular leaflet through the fusion of the lysosome to the plasma membrane for secretion [7,8]. S-Mase, on the other hand, is released extracellularly through the Golgi pathway. ...
Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival “rheostat” between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.
... Thus, interference with actin dynamics would be expected to have a significant impact on viral uptake. In this context, it is noteworthy that the breakdown of actin cytoskeletal protrusions after ASM activation and subsequent ceramide accumulation were observed in MCF-7 breast cancer cells (Zeidan et al., 2008), and, NSM-and ASM-dependently, upon measles virus (MV) interaction with T cells (Gassert et al., 2009;Mueller et al., 2014). ...
Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach.
