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Morphological features of apoptosis, necroptosis, and pyroptosis and their linkages with immunogenicity. (A) Dying cells revealed by scanning electron microscopy. In RAW264.7 cells, apoptosis was induced by TNF+Smac mimetics; necroptosis was induced by TNF+Smac mimetics+zVAD; pyroptosis was induced by LPS priming followed by nigericin treatment. (B) Membrane blebbing followed by formation of apoptotic bodies is commonly observed in apoptosis. Under certain conditions, such as inhibition of PANX1 by trovafloxacin or further combined inhibition of actomyosin contraction by cytochalasin D or GSK 269962, apoptotic cells exhibit two apoptotic body-related morphological changes called apoptopodia and 'beads-on-astring' protrusions. These membrane-enveloped fragments can be immunogenic, non-immunogenic, or even immunosuppressive under different experimental settings. However, the regulated secondary necrosis of apoptotic cells mediated by DFNA5 can be highly inflammatory. In necroptosis, MLKL-mediated plasma membrane rupture leads to release of cellular contents and thus immunogenicity. Pyroptosis results from an inflammatory response induced by inflammasome activation, which is frequently observed in professional phagocytes and tightly associated with IL-1β/IL-18 secretion. Whether GSDMD-mediated pyroptosis itself is immunogenic awaits further investigation.
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Ruptured and intact plasma membranes are classically considered as hallmarks of necrotic and apoptotic cell death, respectively. As such, apoptosis is usually considered a non-inflammatory process while necrosis triggers inflammation. Recent studies on necroptosis and pyroptosis, two types of programmed necrosis, revealed that plasma membrane ruptu...
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... Furthermore, the presence of a homogeneous pink amyloid fluid in tissue samples points to systemic amyloidosis, where acidophilic extracellular protein deposits can inflict damage on surrounding tissues [49]. This condition underscores the systemic impact of renal tubular and vascular damage induced by toxic exposure and metabolic imbalances [50,51]. ...
... Otherwise, loss of membrane integrity leads to a collapse in electrochemical gradients, driving an influx of water through GSDMD pores 38,45 . This causes a characteristic "necrotic" cell death morphology 12 , characterized by cell bloating/swelling and formation of pyroptotic bodies, bubbling membrane protrusions that swell and contract stochastically in response to changing intracellular osmotic conditions 22,31,46 . Late-stage pyroptosis typically involves catastrophic membrane rupture, which releases proinflammatory alarmins (e.g. ...
Antigen-specific cytotoxic T lymphocytes (CTLs) kill targets through rapid release of perforin/granzymes into the lytic synapse. Lethal hit delivery activates programmed cell death in the target, which is classically considered apoptotic, caspase-mediated, and granzyme-dependent. Herein, we propose an unprecedented role for perforin in triggering target cell pyroptosis, complementing its well-documented role as a conduit for granzymes. Utilizing imaging and molecular approaches, we demonstrate that target perforation upon CTL attack elicits swift K+ efflux, triggering the canonical inflammatory pyroptotic signaling cascade defined by activation of the NLRP3 inflammasome, caspase-1, and the pore-forming pyroptotic executioner, gasdermin D (GSDMD); this is followed by pyroptotic body formation, plasma membrane rupture, and release of intracellular contents. Disruption of perforin inhibited this pathway, while recombinant perforin activated caspase-1-dependent pyroptosis. These results reveal that perforin retains the pro-pyroptotic activity of ancestral pore-forming toxins, and highlight a previously unappreciated role for the canonical caspase-1/GSDMD pyroptotic pathway in adaptive immunity.
... It contains protein transporters and channels for the movement of nutrients, inorganic and organic molecules. Hence, membrane disruption would certainly result in cellular death [35]. Plasma membrane of yeast cells has asymmetrical distributions of phospholipids, with most of the PS directed towards the cytoplasm. ...
Introduction. Innovative antifungal therapies are of crucial importance to combat the potentially life-threatening infections linked to the multidrug-resistant fungal pathogen Candida auris . Induction of regulated cell death, apoptosis, could provide an outline for future therapeutics. Human antimicrobial peptides (AMPs), well-known antifungal compounds, have shown the ability to induce apoptosis in pathogenic fungi.
Hypothesis/Gap Statement . Although it is known that AMPs possess antifungal activity against C. auris , their ability to induce apoptosis requires further investigations.
Aim. This study evaluated the effects of AMPs on the induction of apoptosis in C. auris .
Methods. Human neutrophil peptide-1 (HNP-1), human β-Defensins-3 (hBD-3) and human salivary histatin 5 (His 5) were assessed against two clinical C. auris isolates. Apoptosis hallmarks were examined using FITC-Annexin V/PI double labelling assay and terminal deoxynucleotidyl transferase deoxynucleotidyl transferase nick-end labelling (TUNEL) to detect phosphatidylserine externalization and DNA fragmentation, respectively. Then, several intracellular triggers were studied using JC-10 staining, spectrophotometric assay and 2′,7′-dichlorofluorescin diacetate staining to measure the mitochondrial membrane potential, cytochrome-c release and reactive oxygen species (ROS) production, respectively.
Results and conclusion. FITC-Annexin V/PI staining and TUNEL analysis revealed that exposure of C. auris cells to HNP-1 and hBD-3 triggered both early and late apoptosis, while His 5 caused significant necrosis. Furthermore, HNP-1 and hBD-3 induced significant mitochondrial membrane depolarization, which resulted in substantial cytochrome c release. In contrast to His 5, which showed minimal mitochondrial depolarization and no cytochrome c release. At last, all peptides significantly increased ROS production, which is related to both types of cell death. Therefore, these peptides represent promising and effective antifungal agents for treating invasive infections caused by multidrug-resistant C. auris.
... When exposing the TLT cells to 12.5 mM H 2 O 2 , we expected to observe a higher frequency of necroptotic cells [24]. Thus, we expected the inhibition of caspase 8 and the formation of a receptor-interacting protein kinases 1 and 3 (RIP1/RIP3) necrosome that phosphorylates mixed-lineage kinase domain-like pseudo kinase (MLKL), which initiates the characteristic membrane rupture [25,26]. On the other hand, 266 µM TBBPA or 500 µM 5-FU exposure should induce apoptosis on TLT cells [27,28]. ...
The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division, or remain viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids, and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells to rifampicin, ibuprofen, and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds, as it considers the different cellular responses induced by toxic agents.
... The morphological manifestations of apoptosis include DNA fragmentation, cytoplasmic condensation, karyopycnosis, karyorrhexis, and apoptotic body formation. However, the cell membrane remains intact during the process of apoptosis, and thus no contents are released, which does not directly cause further inflammatory response [63]. ...
Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired AKI, which seriously threatens the health of patients. To date, the precise pathogenesis of CI-AKI has remained not clear and may be related to the direct cytotoxicity, hypoxia and ischemia of medulla, and oxidative stress caused by iodine contrast medium, which have diverse physicochemical properties, including cytotoxicity, permeability and viscosity. The latest research shows that microRNAs (miRNAs) are also involved in apoptosis, pyroptosis, and autophagy which caused by iodine contrast medium (ICM), which may be implicated in the pathogenesis of CI-AKI. Unfortunately, effective therapy of CI-AKI is very limited at present. Therefore, effective prevention of CI-AKI is of great significance, and several preventive options, including hydration, antagonistic vasoconstriction, and antioxidant drugs, have been developed. Here, we review current knowledge about the features of iodine contrast medium, the definition, pathogenesis, molecular mechanism, risk factors, prevention and treatment of CI-AKI.
... In contrast, the protein level of BAX in HEP-2 cells was According to Elmore, apoptosis is an organized, energyrequired process that is essential for tissue survival and homeostasis [23]. The morphological signs of apoptosis include cell shrinkage, membrane bleb formation, nuclear condensation, and the development of pyknotic or apoptotic bodies [24,25]. Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. ...
... Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. During the late stages of apoptosis, the nucleus continues to condense and disintegrate within a cell with an intact membrane [24,25]. These morphological signs can be initiated by the cleavage of various proteins by caspase activation [26], which is upregulated upon treatment with citalopram in HEP-2 cells. ...
Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients' overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50-400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram's anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.
... In contrast, the protein level of BAX in HEP-2 cells was According to Elmore, apoptosis is an organized, energyrequired process that is essential for tissue survival and homeostasis [23]. The morphological signs of apoptosis include cell shrinkage, membrane bleb formation, nuclear condensation, and the development of pyknotic or apoptotic bodies [24,25]. Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. ...
... Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. During the late stages of apoptosis, the nucleus continues to condense and disintegrate within a cell with an intact membrane [24,25]. These morphological signs can be initiated by the cleavage of various proteins by caspase activation [26], which is upregulated upon treatment with citalopram in HEP-2 cells. ...
Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients' overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50-400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram's anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.
... In contrast, the protein level of BAX in HEP-2 cells was According to Elmore, apoptosis is an organized, energyrequired process that is essential for tissue survival and homeostasis [23]. The morphological signs of apoptosis include cell shrinkage, membrane bleb formation, nuclear condensation, and the development of pyknotic or apoptotic bodies [24,25]. Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. ...
... Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. During the late stages of apoptosis, the nucleus continues to condense and disintegrate within a cell with an intact membrane [24,25]. These morphological signs can be initiated by the cleavage of various proteins by caspase activation [26], which is upregulated upon treatment with citalopram in HEP-2 cells. ...
Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients’ overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50–400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram’s anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.
... According to Elmore, apoptosis is an organized, energyrequired process that is essential for tissue survival and homeostasis [23]. The morphological signs of apoptosis include cell shrinkage, membrane bleb formation, nuclear condensation, and the development of pyknotic or apoptotic bodies [24,25]. Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. ...
... Citalopram has been shown to cause morphological changes in HEP-2 cells, including the development of apoptotic bodies and progressive chromatin condensation. During the late stages of apoptosis, the nucleus continues to condense and disintegrate within a cell with an intact membrane [24,25]. These morphological signs can be initiated by the cleavage of various proteins by caspase activation [26], which is upregulated upon treatment with citalopram in HEP-2 cells. ...
Human laryngeal squamous carcinoma (LSCC) is a common malignant tumor in the head and neck. Despite the recently developed therapies for the treatment of LSCC, patients’ overall survival rate still did not enhance remarkably; this highlights the need to formulate alternative strategies to develop novel treatments. The antitumor effects of antidepressant drugs such as citalopram have been reported on several cancer cells; however, they have yet to be investigated against LSCC. The current study was directed to explore the possible antitumor effects of citalopram on human laryngeal carcinoma cell lines (HEP-2). HEP-2 cells were cultured and treated with different doses of citalopram (50–400 µM) for 24, 48, and 72 h. The effects of citalopram on the viability of cancer cells were determined by the MTT assay. In addition, apoptosis and cell cycle analysis were performed by flow cytometry. Moreover, evaluation of the expression of proapoptotic and apoptotic proteins, such as cytochrome c, cleaved caspases 3 and 9, Bcl-2, and BAX, was performed by western blotting analysis. Our results revealed that citalopram significantly suppressed the proliferation of HEP-2 cells through the upregulation of p21 expression, resulting in the subsequent arrest of the cell cycle at the G0/G1 phase. Furthermore, citalopram treatment-induced HEP-2 cell apoptosis; this was indicated by the significant increase of cytochrome c, cleaved caspases 3 and 9, and BAX protein expression. On the contrary, Bcl-2 protein expression was significantly downregulated following treatment with citalopram. The ultrastructure studies were in accordance with the protein expression findings and showed clear signs of apoptosis with ring chromatin condensation upon treatment with citalopram. These findings suggest that citalopram’s anti-tumor activities on HEP-2 cells entailed stimulation of the intrinsic apoptotic pathway, which was mediated via Bcl-2 suppression.
... Its N-terminal activating domain becomes inactive upon attachment to the membrane and localization at cell membrane holes (8,9). Members of the gasdermin family promote the formation of pores in the cell membrane, allowing cellular content to leak out and triggering a mild inflammatory response (10,11). Considering the link between pyroptosis genes and the immune response to cancer, these genes could serve as prognostic indicators for GC. ...
Gastric cancer (GC) is a prevalent form of malignancy characterized by significant heterogeneity. The development of a specific prediction model is of utmost importance to improve therapy alternatives. The presence of H. pylori can elicit pyroptosis, a notable carcinogenic process. Furthermore, the administration of chemotherapeutic drugs is often employed as a therapeutic approach to addressing this condition. In the present investigation, it was observed that there were variations in the production of 17 pyroptosis-regulating proteins between stomach tissue with tumor development and GC cells. The predictive relevance of each gene associated with pyroptosis was assessed using the cohort from the cancer genome atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) was utilized to enhance the outcomes of the regression approach. Patients with gastric cancer GC in the cohort from the TCGA were categorized into low-risk or high-risk groups based on their gene expression profiles. Patients with a low risk of gastric cancer had a higher likelihood of survival compared to persons classified as high risk (P<0.0001). A subset of patients diagnosed with GC from a Genes Expression Omnibus (GEO) cohort was stratified according to their overall survival (OS) duration. The statistical analysis revealed a higher significance level (P=0.0063) regarding OS time among low-risk individuals. The study revealed that the GC risk score emerged as a significant independent prognostic factor for OS in patients diagnosed with GC. The results of Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) research revealed that genes associated with a high-risk group had significantly elevated levels of immune system-related activity. Furthermore, it was found that the state of immunity was diminished within this particular group. The relationship between the immune response to cancer and pyroptosis genes is highly interconnected, suggesting that these genes have the potential to serve as prognostic indicators for GC.
