Different Types Of Cell Death Research Articles

NETosis and kidney disease: what do we know?

Neutrophils are the most abundant leukocytes in the blood. They are rapidly mobilized from the circulation to sites of inflammation and/or infection. In affected tissues, neutrophils exhibit some dramatic antimicrobial functions, including degranulation, reactive oxygen species (ROS) production, phagocytosis, and formation of neutrophil extracellular traps (NETs). Like other cells of the immune system, after fulfilling their biological duties, they enter the path of death. Depending on the conditions, they may undergo different types of cell death (apoptosis, necrosis, necroptosis, autophagy, NETosis, and pyroptosis) that require the participation of multiple signaling pathways. NETosis is a unique neutrophil cell death mechanism that gives rise to different inflammatory and autoimmune pathological conditions. Recent studies have shown that NETosis also plays a role in the formation and/or progression of kidney diseases. This review discusses the underlying mechanism of NETosis and its relationship with some major kidney diseases in light of the current knowledge.

Flow Cytometric Analysis of Regulated Cell Death.

Cell death is a crucial and fundamental process in the biology of all living organisms and plays an essential role in developmental, cellular, and molecular biology. With a deeper understanding of the mechanisms of different types of cell death, quantitative experiments are becoming increasingly necessary to analyze the dynamic changes and coordinate physiological processes. Flow cytometry is the most widely used method for detecting and quantifying cell processes in mammalian cells, providing a comprehensive and high-throughput approach, even at the single-cell level. This chapter provides a brief overview of guidelines for performing flow cytometry in the detection of regulated cell deaths, including apoptosis, autophagy, ferroptosis, pyroptosis, and immunogenic cell death.

ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications

Cell death is a fundamental pathophysiological process in human disease. The discovery of necroptosis, a form of regulated necrosis that is induced by the activation of death receptors and formation of necrosome, represents a major breakthrough in the field of cell death in the past decade. Z-DNA-binding protein (ZBP1) is an interferon (IFN)-inducing protein, initially reported as a double-stranded DNA (dsDNA) sensor, which induces an innate inflammatory response. Recently, ZBP1 was identified as an important sensor of necroptosis during virus infection. It connects viral nucleic acid and receptor-interacting protein kinase 3 (RIPK3) via two domains and induces the formation of a necrosome. Recent studies have also reported that ZBP1 induces necroptosis in non-viral infections and mediates necrotic signal transduction by a unique mechanism. This review highlights the discovery of ZBP1 and its novel findings in necroptosis and provides an insight into its critical role in the crosstalk between different types of cell death, which may represent a new therapeutic option.

Cathepsins Trigger Cell Death and Regulate Radioresistance in Glioblastoma

Treatment of glioblastoma (GBM) remains very challenging, and it is particularly important to find sensitive and specific molecular targets. In this work, we reveal the relationship between the expression of cathepsins and radioresistance in GBM. We analyzed cathepsins (cathepsin B, cathepsin D, cathepsin L, and cathepsin Z/X), which are highly associated with the radioresistance of GBM by regulating different types of cell death. Cathepsins could be potential targets for GBM treatment.

МОЛЕКУЛЯРНЫЕ И МОРФОЛОГИЧЕСКИЕ МАРКЕРЫ ГИБЕЛИ НЕЙРОНОВ ПРИ ОСТРЫХ НАРУШЕНИЯХ МОЗГОВОГО КРОВООБРАЩЕНИЯ

Acute cerebral circulatory disorders are characterised by various changes in brain cells, often leading to mass death. This review presents a list of markers associated with different types of cell death occurring in acute cerebral circulation disorders and identifies the importance of these markers in the diagnosis of haemorrhagic and ischaemic stroke.Acute cerebral circulation disorder is one of the most debated issues in modern resuscitation and medicine, asit is asevere condition leading to stroke and subsequent patient death, if not treated promptly. However, rapid treatment and diagnosis of stroke is difficult due to the lack of study of morphological signs and biomarkers to reliably determine the nature of the injury. Anin-depth analysis and systematization of the available information on this topic is needed.Purpose of the review:to reveal the correspondence between the molecular mechanisms of cell death in acute disorders ofcerebral circulation and their morphological manifestations.Material and Methods.A total of 50 most relevant sources of information were selected. The sources were selected from the databases of medical and biological publications PubMed, Scopus, Web of Science, RSCI, and fundamental works of scientificliterature on the considered topic were involved.Results.The main mechanisms of cell death in stroke were identified and analyzed, the morphological and histological features ofthe observed processes and their structural manifestations were reviewed. Besides, the most frequently detected molecular markers specific for each type of cell death were listed.Conclusion.The study of molecular pathways andcellular reorganization processes characteristic of different types of cell death as well as their corresponding biological markers is of important diagnostic value in the detection of cerebral circulatory disorders. Determination of morphological and molecular markers typical for this condition will allow a prompt diagnosis ofstroke and minimization of its negative consequences.

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury, uncommon among patients suffering from myocardial infarction, stroke, or acute kidney injury, can result in cell death and organ dysfunction. Previous studies have shown that different types of cell death, including apoptosis, necrosis, and autophagy, can occur during I/R injury. Pyroptosis, which is characterized by cell membrane pore formation, pro-inflammatory cytokine release, and cell burst, and which differentiates itself from apoptosis and necroptosis, has been found to be closely related to I/R injury. Therefore, targeting the signaling pathways and key regulators of pyroptosis may be favorable for the treatment of I/R injury, which is far from adequate at present. This review summarizes the current status of pyroptosis and its connection to I/R in different organs, as well as potential treatment strategies targeting it to combat I/R injury.

The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development.

More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal tubule metabolism. Kidneys have one of the highest mitochondrial densities. Mitochondrial biogenesis, mitochondrial fusion and fission, and mitochondrial recycling, such as mitophagy are critical for proper mitochondrial function. Mitochondrial dysfunction can lead to an energetic crisis, orchestrate different types of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), and influence cellular calcium levels and redox status. Collectively, mitochondrial defects in renal tubules contribute to epithelial atrophy, inflammation, or cell death, orchestrating kidney disease development.

Regulation of Ferroptosis by non-coding RNAs: Mechanistic insights.

Discovery of ferroptosis has paradigmatically shifted our understanding about different types of cell death. Wealth of information gathered over decades of pioneering research has enabled us to develop a better comprehension about versatile regulators of ferroptosis. In this review we have attempted to set spotlight on the indispensable involvement of non-coding RNAs in regulation of ferroptosis. We have exclusively analyzed role of miRNAs, long non-coding RNAs (lncRNAs) and circular RNAs in the regulation of ferroptosis and how inhibition of ferroptosis promoted carcinogenesis and metastasis. Significance Statement The review is written by experts in the field to bring our most recent information about this exciting topic.

461 Identification of Z-DNA, G4-DNA and B-DNA in epidermis: Spatial genomic organization of different DNA structures (Genomesorganizomics)

Human epidermis is an exceptional tissue to examine biological processes, such as mitosis, basal stem cells, cellular differentiation, and two different types of cell death. We wanted to establish, for the first time, the presence and distribution of three totally different types of DNAs in the epidermis of human skin. Nucleic acids are dynamic molecules that can adopt different structural conformations, such as left-handed double-stranded (ds-) Z-DNA, four-stranded G4-quadruplex DNA, and canonical right-handed ds-B-DNA.

Commentary on “PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons”

Commentary on “PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons”

The effect of neoadjuvant chemotherapy on the structural and functional state of tumor cells in the secondary edematous form of breast cancer

Background. Secondary edematous form of breast cancer (SЕF BC) is the most aggressive type of BC that is characterized by rapid progression, high levels of metastasis, significant resistance to chemotherapy and radiotherapy. SЕF BC is not just a combination of cancer and local inflammation, but is a rare phenomenon in which the development of the tumor is primary. The processes of edema and inflammation occur because of lymph flow blockage by the formation of emboli from tumor cells (TC), which have elevated levels of E-cadherin, properties of polyploid cells and show signs of stem cells. Trimodal therapy methods are used for the treatment of SЕF BC, the main components of which are neoadjuvant systemic chemotherapy, surgery and adjuvant radiation therapy. However, the results of treatment remain insufficient, possibly due to the fact that the features of SЕF, the role of stem cells and inflammatory factors are not taken into account. Therefore, further research is needed in various fields of oncology, molecular biology, immunology, genetics, morphology, including electron microscopy, which is an important area for establishing the characteristics of both tumor cells and their environment. Purpose. Study of the neoadjuvant polychemotherapy influence on the structural and functional state of tumor cells of different molecular subtypes in the secondary edematous form of breast cancer.
 Materials and methods. Tumors of 29 patients with normal breast cancer and 32 patients with SЕF BC were studied. Receptors to estrogen (ER), progesterone (PR) and epidermal human growth factor 2 (HER2) were immunohistochemically determined before systemic neoadjuvant polychemotherapy (PCT). According to the receptor status, tumors were divided into 4 groups: 1 – triple negative («3-neg») tumors, 2 – HER2-positive («HER2») tumors, 3 – hormonally receptor («HP») tumors, 4 – tumorswith co-expression of hormonal receptors and HER2 («HR + HER2»). For polychemotherapy (PCT) the regimen (AСx4–Рx4) was used.The ultrastructure of the tumor cells (TC) was examined using standard electron microscopy methods. In all study groups, the frequency of cases with pronounced therapeutic pathomorphosis (PTPM) was determined, as well as the frequency of tumors with luminal and non-luminal symptoms after treatment. The obtained data were calculated using non-parametric methods with the software package for PC «Biostat» application and using a non-parametric criterion of the most plausible assessment of reliability for small selections (Pmp).
 Results. It was found that PCT in patients with conventional BC causes a pronounced therapeutic pathomorphosis (РТPM) of most tumors of the receptor groups «3-neg», «HER2» and «HR+HER2», compared with the group «HR», where no case of РTPM was observed. At SЕF BC the frequency of tumors with the pronounced pathomorphosis in groups with nonluminal subtypes and co-expression of receptors decreases, that for group «3-neg» is reliable. This indicates increased chemoresistance of triple negative tumors. In the group of hormone receptor tumors at SEF, this index increases significantly. Analysis of the ultrastructure of tumors of different molecular subtypes showed that most of the processes of damage and accompanying reactions to the action of PCT are identical for both forms of BC. Thus, in response to chemotherapy, different types of cell death: necrotic, dark cell, apoptotic; processes of cell nucleus damage: presence of dinuclear PCs, cells with micronuclei; disturbance of the microvessels structure: edema and condensation of the endothelial cells cytoplasm and their exfoliation; activation of phagocytosis and immune processes are observed. Only SЕF is characterized by the presence of TCs and emboli in capillaries, as well as a significantly increased frequency of giant polyploid tumor cells. It was also found that after PCT in patients with normal BC preserved tumor cells show mainly luminal signs (72.7–100%). However, in SЕF BC such reaction occurs only for hormone-receptor subtypes and the group with co-expression of receptors, whereas for tumors of three negative and HER2-positive subtypes the frequency of luminal signs is lower than in conventional BC and is 33.3%, p ≤ 0.05 and 66.7%, respectively.
 Conclusions. Peculiarities of SЕF BC in contrast to the usual form of BC are significantly reduced sensitivity of 3-negative cancer to chemotherapy and the tendency to chemoresistance of molecular subtypes with the presence of HER2; significant survival after PCT tumors with non-luminal cells characteristic in the group of 3-negative cancer, while in other receptor subtypes most tumors have luminal features; probably increased after chemotherapy the number of tumors with giant polyploid cells. It is possible that the features of SЕF BC are associated with the presence of polyploid TCs resistant to chemotherapy, and both inflammation and chemotherapy may play a role in stimulating their formation.

Programmed Cell Death of Endothelial Cells in Myocardial Infarction and Its Potential Therapeutic Strategy.

Cardiovascular disease, especially coronary artery disease and stroke, kills around one-third of the world's population, and myocardial infarction, a primary symptom of coronary heart disease, is a major worldwide health problem. Cardiovascular disease research has historically focused on promoting angiogenesis following myocardial damage. Myocardial vascular repair is crucial for improving myocardial infarction prognosis. Endothelial cells, the largest population of nonmyocytes within myocardial tissue, play an important role in angiogenesis. In recent years, different types of programmed cell death such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy have been described and found to be linked with cardiovascular diseases such as myocardial infarction, heart failure, and myocarditis. This will have important implications for reforming the treatment strategy of cardiovascular diseases. Different types of cell death of endothelial cells in myocardial infarction have been proposed, the roles and mechanisms of endothelial cell death in myocardial infarction are summarized in this review, and endothelial cell death inhibition as a therapeutic technique for treating myocardial infarction might be advantageous to human health.

Programmed Cell Death-Dependent Host Defense in Ocular Herpes Simplex Virus Infection.

Herpes simplex virus type 1 (HSV1) remains one of the most ubiquitous human pathogens on earth. The classical presentation of HSV1 infection occurs as a recurrent lesions of the oral mucosa commonly refer to as the common cold sore. However, HSV1 also is responsible for a range of ocular diseases in immunocompetent persons that are of medical importance, causing vision loss that may result in blindness. These include a recurrent corneal disease, herpes stromal keratitis, and a retinal disease, acute retinal necrosis, for which clinically relevant animal models exist. Diverse host immune mechanisms mediate control over herpesviruses, sustaining lifelong latency in neurons. Programmed cell death (PCD) pathways including apoptosis, necroptosis, and pyroptosis serve as an innate immune mechanism that eliminates virus-infected cells and regulates infection-associated inflammation during virus invasion. These different types of cell death operate under distinct regulatory mechanisms but all server to curtail virus infection. Herpesviruses, including HSV1, have evolved numerous cell death evasion strategies that restrict the hosts ability to control PCD to subvert clearance of infection and modulate inflammation. In this review, we discuss the key studies that have contributed to our current knowledge of cell death pathways manipulated by HSV1 and relate the contributions of cell death to infection and potential ocular disease outcomes.

Nobiletin as an inducer of programmed cell death in cancer: a review

Cancer resistance to therapy is a big issue in cancer therapy. Tumours may develop some mechanisms to reduce the induction of cell death, thus stimulating tumour growth. Cancer cells may show a low expression and activity of tumour suppressor genes and a low response to anti-tumour immunity. These mutations can increase the resistance of cancer cells to programmed cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, autophagic cell death, and some others. The upregulation of some mediators and transcription factors such as Akt, nuclear factor of κB, signal transducer and activator of transcription 3, Bcl-2, and others can inhibit cell death in cancer cells. Using adjuvants to induce the killing of cancer cells is an interesting strategy in cancer therapy. Nobiletin (NOB) is a herbal-derived agent with fascinating anti-cancer properties. It has been shown to induce the generation of endogenous ROS by cancer cells, leading to damage to critical macromolecules and finally cell death. NOB may induce the activity of p53 and pro-apoptosis mediators, and also inhibit the expression and nuclear translocation of anti-apoptosis mediators. In addition, NOB may induce cancer cell killing by modulating other mechanisms that are involved in programmed cell death mechanisms. This review aims to discuss the cellular and molecular mechanisms of the programmed cell death in cancer by NOB via modulating different types of cell death in cancer.

Revisiting Minocycline in Intracerebral Hemorrhage: Mechanisms and Clinical Translation.

Intracerebral hemorrhage (ICH) is an important subtype of stroke with an unsatisfactory prognosis of high mortality and disability. Although many pre-clinical studies and clinical trials have been performed in the past decades, effective therapy that meaningfully improve prognosis and outcomes of ICH patients is still lacking. An active area of research is towards alleviating secondary brain injury after ICH through neuroprotective pharmaceuticals and in which minocycline is a promising candidate. Here, we will first discuss new insights into the protective mechanisms of minocycline for ICH including reducing iron-related toxicity, maintenance of blood-brain barrier, and alleviating different types of cell death from preclinical data, then consider its shortcomings. Finally, we will review clinical trial perspectives for minocycline in ICH. We hope that this summary and discussion about updated information on minocycline as a viable treatment for ICH can facilitate further investigations.

Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties.

Due to its chemical properties and multiple molecular effects on different tumor cell types, the sesquiterpene lactone parthenolide (PN) can be considered an effective drug with significant potential in cancer therapy. PN has been shown to induce either classic apoptosis or alternative caspase-independent forms of cell death in many tumor models. The therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT). This review focuses on the molecular mechanisms of both PN and analogues action in tumor models, highlighting their effects on gene expression, signal transduction and execution of different types of cell death. Recent findings indicate that these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs but can also determine the activation of specific death pathways, increasing intracellular reactive oxygen species (ROS) production and modifications of Bcl-2 family members. An intriguing property of these compounds is its specific targeting of cancer stem cells. The unusual actions of PN and its analogues make these agents good candidates for molecular targeted cancer therapy.

A proteomic perspective on TNF-mediated signalling and cell death.

The tumour necrosis factor (TNF) is the most potent inducer of cell death amongst cytokines. It is crucial for processes including homeostasis, the development of the immune system and fighting infections. However, high levels of TNF due to genetic disorders or persistent infections can contribute to autoinflammatory and autoimmune diseases or life-threatening conditions like sepsis. These diseases generally display increased levels of cell death, which, downstream of the TNF receptor, can either be caspase-dependent (apoptosis) or caspase-independent (necroptosis). Significant efforts have been invested in unravelling and manipulating signalling mechanisms regulating these two different types of cell death. Here I discuss how modern proteomic approaches like phosphoproteomics and secretomics provide a novel perspective on this central cytokine and its effect on inflammation and cell survival.

Involvement of calcium signaling in different types of cell death in cancer.

Programmed cell death is a basic feature of chemotherapeutic (and also radiotherapeutic) intervention. Induction of cell death in tumor cells aims to kill preferentially the tumor cells, with minimal impact on the normal cells. Although apoptosis is the most obvious type of cell death induced by chemotherapeutics, several other types can also be activated, especially in conditions, where cells are resistant to apoptosis induction. Calcium signaling was shown to play an indisputable role in the activation of different types of cell death. Local increase of the calcium in time and precise place of this increase is secured by calcium transport systems. In this review, we summarized the involvement of some calcium transport systems in apoptosis, autophagy, necroptosis, ferroptosis, and mitophagy during cancer development and treatment.

Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies

Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

Anticancer potential and through study of the cytotoxicity mechanism of ionic liquids that are based on the trifluoromethanesulfonate and bis(trifluoromethylsulfonyl)imide anions

Ionic liquids (ILs) are known for their unique physicochemical properties. However, despite the great number of published papers, still little attention has been paid to their biological activity. Anticancer potential and the molecular mechanisms underlying the toxicity of these compounds are especially interesting and still unexplored. In the current work, a broad analysis of the cytotoxicity towards colon and breast cancers as well as glioblastoma of the ILs with pyridinium, piperidinium, pyrrolidinium, and imidazolium cations and trifluoromethanesulfonate or bis(trifluoromethylsulfonyl)imide anions indicated previously as the most toxic for normal human dermal fibroblasts were presented. In the case of MCF-7 cells, the activity of 1-decyl-3-methylimidazolium trifluoromethanesulfonate was more than twice as high as cisplatin. It was found that the inhibition of the cell cycle of colon cancer and glioblastoma cells occurs in different phases. More importantly, the different types of cell death were detected for both selected ILs, namely 1-hexyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide and 1-hexyl-3-methylimidazolium trifluoromethane-sulfonate, on colon cancer and glioblastoma, respectively, apoptosis and autophagy, confirmed at the gene and protein levels. Additionally, kinetic studies of the reactive oxygen species indicated that the tested ILs disturbed the cellular redox homeostasis.