Editorial

4 pages, 194 KiB

Open AccessEditorial

Programmed Cell Death in Health and Disease

by Lara Gibellini and Loredana Moro

Cells 2021, 10(7), 1765; https://doi.org/10.3390/cells10071765 - 13 Jul 2021

Cited by 25 | Viewed by 2579

Programmed cell death is a conserved evolutionary process of cell suicide that is central to the development and integrity of eukaryotic organisms [...] Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

Research

Jump to: Editorial, Review

15 pages, 6522 KiB

Open AccessArticle

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

by Antonio Gil, Elisa Martín-Montañez, Nadia Valverde, Estrella Lara, Federica Boraldi, Silvia Claros, Silvana-Yanina Romero-Zerbo, Oscar Fernández, Jose Pavia and Maria Garcia-Fernandez

Cells 2021, 10(1), 34; https://doi.org/10.3390/cells10010034 - 29 Dec 2020

Cited by 9 | Viewed by 2714

Abstract

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential [...] Read more.

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential to preserve neuronal function. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of multiple sclerosis. This work was performed in a model of oxidative damage on neuronal cell cultures exposed to menadione in the presence or absence of fingolimod phosphate. We studied the mitochondrial function, antioxidant enzymes, protein nitrosylation, and several pathways related with glucose metabolism and glycolytic and pentose phosphate in neuronal cells cultures. Our results showed that menadione produces a decrease in mitochondrial function, an imbalance in antioxidant enzymes, and an increase in nitrosylated proteins with a decrease in glycolysis and glucose-6-phosphate dehydrogenase. All these effects were counteracted when fingolimod phosphate was present in the incubation media. These effects were mediated, at least in part, by the interaction of this drug with its specific S1P receptors. These actions would make this drug a potential tool in the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Graphical abstract

21 pages, 3936 KiB

Open AccessArticle

ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance

by Mélody Caillot, Florence Zylbersztejn, Elsa Maitre, Jérôme Bourgeais, Olivier Hérault and Brigitte Sola

Cells 2020, 9(11), 2357; https://doi.org/10.3390/cells9112357 - 26 Oct 2020

Cited by 14 | Viewed by 3022

Abstract

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable due to innate or acquired resistance. Although MM cells produce high intracellular levels of reactive oxygen species (ROS), we hypothesised that they could remain sensitive to ROS unbalance. We tested if the [...] Read more.

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable due to innate or acquired resistance. Although MM cells produce high intracellular levels of reactive oxygen species (ROS), we hypothesised that they could remain sensitive to ROS unbalance. We tested if the inhibition of ROS, on one hand, or the overproduction of ROS, on the other, could (re)sensitise cells to bortezomib (BTZ). Two drugs were used in a panel of MM cell lines with various responses to BTZ: VAS3947 (VAS), an inhibitor of NADPH oxidase and auranofin (AUR), an inhibitor of thioredoxin reductase (TXNRD1), an antioxidant enzyme overexpressed in MM cells. We used several culture models: in suspension, on a fibronectin layer, in coculture with HS-5 mesenchymal cells, and/or in 3-D culture (or spheroids) to study the response of MM primary cells and cell lines. Several MM cell lines were sensitive to VAS but the combination with BTZ showed antagonistic or additive effects at best. By contrast, in all culture systems studied, the combined AUR/BTZ treatment showed synergistic effects on cell lines, including those less sensitive to BTZ and primary cells. MM cell death is due to the activation of apoptosis and autophagy. Modulating the redox balance of MM cells could be an effective therapy for refractory or relapse post-BTZ patients. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

21 pages, 8060 KiB

Open AccessFeature PaperReview

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

by Annamaria Paolini, Rebecca Borella, Sara De Biasi, Anita Neroni, Marco Mattioli, Domenico Lo Tartaro, Cecilia Simonini, Laura Franceschini, Gerolamo Cicco, Anna Maria Piparo, Andrea Cossarizza and Lara Gibellini

Cells 2021, 10(7), 1585; https://doi.org/10.3390/cells10071585 - 23 Jun 2021

Cited by 30 | Viewed by 6624

Abstract

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some [...] Read more.

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

17 pages, 1882 KiB

Open AccessReview

Cell Death and Inflammation: The Role of Mitochondria in Health and Disease

by Anna Picca, Riccardo Calvani, Hélio José Coelho-Junior and Emanuele Marzetti

Cells 2021, 10(3), 537; https://doi.org/10.3390/cells10030537 - 03 Mar 2021

Cited by 81 | Viewed by 8763

Abstract

Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard [...] Read more.

Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell’s fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy–apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

29 pages, 4739 KiB

Open AccessReview

Unraveling Cell Death Pathways during Malaria Infection: What Do We Know So Far?

by Camille Sena-dos-Santos, Cíntia Braga-da-Silva, Diego Marques, Jhully Azevedo dos Santos Pinheiro, Ândrea Ribeiro-dos-Santos and Giovanna C. Cavalcante

Cells 2021, 10(2), 479; https://doi.org/10.3390/cells10020479 - 23 Feb 2021

Cited by 18 | Viewed by 5247

Abstract

Malaria is a parasitic disease (caused by different Plasmodium species) that affects millions of people worldwide. The lack of effective malaria drugs and a vaccine contributes to this disease, continuing to cause major public health and socioeconomic problems, especially in low-income countries. Cell [...] Read more.

Malaria is a parasitic disease (caused by different Plasmodium species) that affects millions of people worldwide. The lack of effective malaria drugs and a vaccine contributes to this disease, continuing to cause major public health and socioeconomic problems, especially in low-income countries. Cell death is implicated in malaria immune responses by eliminating infected cells, but it can also provoke an intense inflammatory response and lead to severe malaria outcomes. The study of the pathophysiological role of cell death in malaria in mammalians is key to understanding the parasite–host interactions and design prophylactic and therapeutic strategies for malaria. In this work, we review malaria-triggered cell death pathways (apoptosis, autophagy, necrosis, pyroptosis, NETosis, and ferroptosis) and we discuss their potential role in the development of new approaches for human malaria therapies. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

18 pages, 1042 KiB

Open AccessFeature PaperReview

Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment

by Aleksandra Gruevska, Ángela B. Moragrega, Andrea Cossarizza, Juan V. Esplugues, Ana Blas-García and Nadezda Apostolova

Cells 2021, 10(2), 410; https://doi.org/10.3390/cells10020410 - 16 Feb 2021

Cited by 8 | Viewed by 3441

Abstract

Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency [...] Read more.

Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15–17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

12 pages, 2362 KiB

Open AccessReview

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

by Stefania Fiorcari, Rossana Maffei, Claudio Giacinto Atene, Leonardo Potenza, Mario Luppi and Roberto Marasca

Cells 2021, 10(2), 217; https://doi.org/10.3390/cells10020217 - 22 Jan 2021

Cited by 18 | Viewed by 4250

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to [...] Read more.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to the host”; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells’ survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

29 pages, 1981 KiB

Open AccessReview

Apoptosis in the Extraosseous Calcification Process

by Federica Boraldi, Francesco Demetrio Lofaro and Daniela Quaglino

Cells 2021, 10(1), 131; https://doi.org/10.3390/cells10010131 - 12 Jan 2021

Cited by 24 | Viewed by 3756

Abstract

Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including [...] Read more.

Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

15 pages, 725 KiB

Open AccessReview

Antitumor Effects of PRIMA-1 and PRIMA-1^Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

by Paola Menichini, Paola Monti, Andrea Speciale, Giovanna Cutrona, Serena Matis, Franco Fais, Elisa Taiana, Antonino Neri, Riccardo Bomben, Massimo Gentile, Valter Gattei, Manlio Ferrarini, Fortunato Morabito and Gilberto Fronza

Cells 2021, 10(1), 98; https://doi.org/10.3390/cells10010098 - 07 Jan 2021

Cited by 24 | Viewed by 4357

Abstract

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% [...] Read more.

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1^Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1^Met/APR246 and describes their potential use in hematological malignancies. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

62 pages, 3171 KiB

Open AccessReview

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

by Anna Atlante, Giuseppina Amadoro, Antonella Bobba and Valentina Latina

Cells 2020, 9(11), 2347; https://doi.org/10.3390/cells9112347 - 23 Oct 2020

Cited by 27 | Viewed by 6519

Abstract

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence [...] Read more.

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

45 pages, 3586 KiB

Open AccessReview

The Role of Caspase-2 in Regulating Cell Fate

by Vasanthy Vigneswara and Zubair Ahmed

Cells 2020, 9(5), 1259; https://doi.org/10.3390/cells9051259 - 19 May 2020

Cited by 43 | Viewed by 9753

Abstract

Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation [...] Read more.

Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

19 pages, 3249 KiB

Open AccessReview

Putting the Brakes on Tumorigenesis with Natural Products of Plant Origin: Insights into the Molecular Mechanisms of Actions and Immune Targets for Bladder Cancer Treatment

by Qiushuang Wu, Janet P. C. Wong and Hang Fai Kwok

Cells 2020, 9(5), 1213; https://doi.org/10.3390/cells9051213 - 13 May 2020

Cited by 19 | Viewed by 3803

Abstract

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. Although the incidence in men is 4 times higher than that in women, the diagnoses are worse for women. Over the past 30 years, the treatment for bladder cancer has not achieved a [...] Read more.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. Although the incidence in men is 4 times higher than that in women, the diagnoses are worse for women. Over the past 30 years, the treatment for bladder cancer has not achieved a significant positive effect, and the outlook for mortality rates due to muscle-invasive bladder cancer and metastatic disease is not optimistic. Phytochemicals found in plants and their derivatives present promising possibilities for cancer therapy with improved treatment effects and reduced toxicity. In this study, we summarize the promising natural products of plant origin with anti-bladder cancer potential, and their anticancer mechanisms—especially apoptotic induction—are discussed. With the developments in immunotherapy, small-molecule targeted immunotherapy has been promoted as a satisfactory approach, and the discovery of novel small molecules against immune targets for bladder cancer treatment from products of plant origin represents a promising avenue of research. It is our hope that this could pave the way for new ideas in the fields of oncology, immunology, phytochemistry, and cell biology, utilizing natural products of plant origin as promising drugs for bladder cancer treatment. Full article

(This article belongs to the Special Issue Programmed Cell Death in Health and Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Programmed Cell Death in Health and Disease

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (13 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI