Induction of cell death by adenoviruses

Adenoviruses have proved to be excellent tools for gaining insight into the regulation, and deregulation, of the mammalian cell cycle. With the widespread clinical use of gene therapy fast approaching, there comes a need for a better understanding of how the cell death process is regulated. A greater understanding will allow the development of therapeutic approaches that both maximise transgene expression while minimising cytotoxicity to the target cell. Consequently, much adenovirus research has centered on understanding the mechanisms governing adenovirus induced cell death or apoptosis. This review discusses recent advances in the field of adenovirus cell death regulation and evaluates the roles of implicated gene products and their respective data. The data suggest the existence of multiple virus gene products involved in cell death regulation and point towards several distinct, yet related, cell death pathways. A discussion of the shortcomings of current adenoviral research, along with a proposed model based upon the data is also given.     

Programmed cell death in the ovary: insights and future prospects using genetic technologies

Programmed cell death (PCD) plays a prominent role in development of the fetal ovaries and in the postnatal ovarian cycle. As is the case with other major organ systems, an evolutionarily conserved framework of genes and signaling pathways has been implicated in determining whether or not ovarian germ cells and somatic cells will die in response to either developmental cues or pathological insults. However, the identification of increasing numbers of potential ovarian cell death regulatory factors over the past several years has underscored the need for studies to now separate correlation (e.g. endogenous gene expression) from function (e.g. requirement of the gene product for the execution of PCD). In this regard, genetic technologies have recently been used to examine the functional significance of specific proteins and signaling molecules to the regulation of PCD in the female gonad in vivo. In addition to the more classic approaches, such as the use of genetic null and transgenic mice, methods that achieve cell lineage-selective and/or developmentally timed gene targeting are on the horizon for use by reproductive biologists to more accurately dissect the mechanisms by which PCD is controlled in the ovary. This minireview will highlight some of the advances that have already been made using gene knockout and transgenic mice, as well as provide an overview of the current and future status of cell lineage-selective gene disruption, in the context of PCD and ovarian function.     

A mitochondrial perspective on cell death

The role of mitochondria as crucial participants in cell death programs is well established, yet the mechanisms responsible for the release of mitochondrial activators and the role of BCL2 family proteins in this process remain controversial. Here, we point out the limitations of current approaches used to monitor the physiological responses of mitochondria during cell death, the implications arising from modern views of mitochondrial structure, and briefly assess two proposed mechanisms for the release of mitochondrial proteins during apoptosis.     

Juglone–ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities

Anaplastic thyroid carcinoma (ATC) requires more innovative approaches as the current regimes for therapy are inadequate, also most anticancer drugs cause general suppression of physiological functions. However, therapy with limited nontarget tissue damage is desirable. In the present study, we show prooxidant ability of ascorbic acid, which enhances cytotoxicity induced by juglone. We decipher that juglone–ascorbate combination induces reactive oxygen species‐mediated apoptosis leading to cell death in ARO cell line originated from ATC. This combination also affects enzyme activity of catalase, glutathione reductase, and superoxide dismutase destabilizing redox balance in cell and thereby making juglone effective at a lower dose. We also show that juglone–ascorbate combination suppresses cell migration, invasion, and expression of tumor‐promoting, and angiogenic genes in ARO cell line, thereby disrupting epithelial–mesenchymal transition ability of the cells. Overall, we show that ascorbic acid increases cytotoxic potency of juglone through redox cycling when used in synergy.     

Programmed cell death in fission yeast Schizosaccharomyces pombe

Yeasts have proven to be invaluable, genetically tractable systems to study various fundamental biological processes including programmed cell death. Recent advances in the elucidation of the molecular pathways underlying apoptotic cell death in yeasts have revealed remarkable similarities to mammalian apoptosis at cellular, organelle and macromolecular levels, thus making a strong case for the relevance of yeast models of regulated cell death. Programmed cell death has been reported in fission yeast Schizosaccharomyces pombe, primarily in the contexts of perturbed intracellular lipid metabolism, defective DNA replication, improper mitotic entry, chronological and replicative aging. Here we review the current understanding of the programmed cell death in fission yeast, paying particular attention to lipid-induced cell death. We discuss our recent findings that fission yeast exhibits plasticity of apoptotic and non-apoptotic modes of cell death in response to different lipid stimuli and growth conditions, and that mitochondria, reactive oxygen species and novel cell death mediators including metacaspase Pca1, SpRad9 and Pck1 are involved in the lipotoxic cell death. We also present perspectives on how various aspects of the cell and molecular biology of this organism can be explored to shed light on the governing principles underlying lipid-mediated signaling and cell demise.     

Emerging frontiers in immuno- and gene therapy for cancer

Background aimsThe field of cell and gene therapy in oncology has moved rapidly since 2017 when the first cell and gene therapies, Kymriah followed by Yescarta, were approved by the Food and Drug Administration in the United States, followed by multiple other countries. Since those approvals, several new products have gone on to receive approval for additional indications. Meanwhile, efforts have been made to target different cancers, improve the logistics of delivery and reduce the cost associated with novel cell and gene therapies. Here, we highlight various cell and gene therapy-related technologies and advances that provide insight into how these new technologies will speed the translation of these therapies into the clinic.ConclusionsIn this review, we provide a broad overview of the current state of cell and gene therapy-based approaches for cancer treatment – discussing various effector cell types and their sources, recent advances in both CAR and non-CAR genetic modifications, and highlighting a few promising approaches for increasing in vivo efficacy and persistence of therapeutic drug products.     

Cell death in hematological tumors

Evasion of apoptosis is a hallmark of human cancers, for example in hematological malignancies. Apoptosis is an intrinsic cell death program that is crucial to maintain tissue homeostasis, for example in the hematopoietic system where there is a high turnover rate of cells. As a result, a decrease in the rate of apoptosis besides an increase in proliferation favors tumorigenesis as well as tumor progression. Further, the anti-leukemic action of current treatment approaches, including chemo-, radio- or immunotherapy, critically relies on intact cell death programs in cancer cells. Therefore, defects in apoptosis pathways are frequently associated with the resistance to anticancer therapies. In recent years, the identification and characterization of the molecules and pathways that are involved in the regulation and execution of cell death in leukemia and lymphoma cells have set the ground for the development of novel diagnostic tools and molecular therapeutics targeting apoptosis pathways in hematological malignancies.     

Role of apoptotic and necrotic cell death under physiologic conditions

Apoptosis is considered to be a programmed and controlled mode of cell death, whereas necrosis has long been described as uncontrolled and accidental cell death resulting from extremely harsh conditions. In the following review, we will discuss the features and physiological meanings as well as recent advances in the elucidation of the signaling pathways of both apoptotic cell death and programmed necrotic cell death.     

Better together: Strategies based on magnetic particles and quantum dots for improved biosensing

Novel technologies and strategies for sensitive detection of biological responses in healthcare, food and environmental monitoring continue to be a priority. The present review focuses on bioassay development based on the simultaneous use of quantum dots and magnetic beads. Due to the outstanding characteristics of both particles for biosensing applications and the large number of publications using a combined approach, we aim to provide a comprehensive overview of the literature on different bioassays, the most recent advances and innovative strategies on the topic, together with an analysis of the main drawbacks encountered and potential solutions offered, with a special emphasis on the requirements that the transfer of technologies from the laboratory to the market will demand for future commercialization of biodevices. Several procedures used in immunoassays and nucleic acid-based bioassays for the detection of pathogens and biomarkers are discussed. The improvement of current approaches together with novel multiplex detection systems and nanomaterials-based research, including the use of multimodal nanoparticles, will contribute to simpler and more sensitive bioanalyses.     

Cell death in early neural life

Programmed cell death is a relevant process in the physiology and pathology of the nervous system. Neuronal cell death during development is well characterized, and studies of this process have provided valuable information regarding the regulatory mechanisms of cell death in the nervous system. In the last few years, cell death occurring at earlier developmental stages and affecting proliferating neuroepithelial cells and recently born neuroblasts has been recognized. In this review we cover the observations on cell death in the early, proliferating stages of vertebrate neural development. Genetically modified mouse model systems and complementary in vivo approaches in other vertebrates have provided a solid basis for its relevance and contribution to normal neural development, as well as for the pathological consequences of its deregulation. However, the precise functional role of cell death remains a topic of debate.     

Emerging tools for real-time label-free detection of interactions on functional protein microarrays

The availability of extensive genomic information and content has spawned an era of high-throughput screening that is generating large sets of functional genomic data. In particular, the need to understand the biochemical wiring within a cell has introduced novel approaches to map the intricate networks of biological interactions arising from the interactions of proteins. The current technologies for assaying protein interactions--yeast two-hybrid and immunoprecipitation with mass spectrometric detection--have met with considerable success. However, the parallel use of these approaches has identified only a small fraction of physiologically relevant interactions among proteins, neglecting all nonprotein interactions, such as with metabolites, lipids, DNA and small molecules. This highlights the need for further development of proteome scale technologies that enable the study of protein function. Here we discuss recent advances in high-throughput technologies for displaying proteins on functional protein microarrays and the real-time label-free detection of interactions using probes of the local index of refraction, carbon nanotubes and nanowires, or microelectromechanical systems cantilevers. The combination of these technologies will facilitate the large-scale study of protein interactions with proteins as well as with other biomolecules.     

Programmed cell death: alive and well in the new millennium

Research performed over the past decade has transformed apoptosis from a distinctive form of cell death known only by its characteristic morphology and genomic destruction to an increasingly well understood cellular disassembly pathway remarkable for its complex and multifaceted regulation. Here, we summarize current understanding of apoptotic events, note recent advances in this field and identify questions that might help guide research in the coming years.     

Programmed cell death in the developing limb

The sculpturing of shape in the developing limb together with the regression of the tail in anuran tadpoles constitute, perhaps, the most paradigmatic processes of programmed cell death. The study of these model systems has been of fundamental importance to support the idea that cell death is a physiological behavior of cells in multicellular organisms. Furthermore, different experimental approaches, including comparative analyses of the pattern of cell death in different avian species (i.e. chick interdigits versus duck interdigital webs) and in chick mutants with different limb phenotypes, provided the first evidence for the occurrence of a genetic program underlying the control of cell death. Two well known research groups in the field of limb development, the USA group headed first by John Saunders and next by John Fallon and the group of Donald Ede and Richard Hinchliffe in the U.K. provided a remarkable contribution to this topic. In spite of the historical importance of the developing limb in establishing the concept of programmed cell death, this model system of tissue regression has been largely neglected in recent studies devoted to the analysis of the molecular control of self-induced cell death (apoptosis). However, a considerable amount of information concerning this topic has been obtained in the last few years. Here we will review current information on the control of limb programmed cell death in an attempt to stimulate further molecular studies of this process of tissue regression.     

Cell death in maize

Cell death occurs in plants as a part of normal development and as a response to toxins, pathogens and other environmental stimuli or insults. When cell death occurs as an orderly disassembly of the cell under the control of a genetically determined program, the process is referred to as programmed cell death (PCD). The PCD mechanisms of plants show many striking similarities to, but also intriguing differences from, those of animals. The extensive genetic, developmental and physiological characterizations of maize have made it an excellent system for the study of cell death. We describe the recent advances in the study of cell death in maize in light of what is known in plants and animals.     

Mitochondria and cell death. Mechanistic aspects and methodological issues.

Mitochondria are involved in cell death for reasons that go beyond ATP supply. A recent advance has been the discovery that mitochondria contain and release proteins that are involved in the apoptotic cascade, like cytochrome c and apoptosis inducing factor. The involvement of mitochondria in cell death, and its being cause or consequence, remain issues that are extremely complex to address in situ. The response of mitochondria may critically depend on the type of stimulus, on its intensity, and on the specific mitochondrial function that has been primarily perturbed. On the other hand, the outcome also depends on the integration of mitochondrial responses that cannot be dissected easily. Here, we try to identify the mechanistic aspects of mitochondrial involvement in cell death as can be derived from our current understanding of mitochondrial physiology, with special emphasis on the permeability transition and its consequences (like onset of swelling, cytochrome c release and respiratory inhibition); and to critically evaluate methods that are widely used to monitor mitochondrial function in situ.     

Cell death induction by CTL: perforin/granzyme B system dominantly acts for cell death induction in human hepatocellular carcinoma cells

Cell death induction by cytotoxic T lymphocytes (CTLs) is an important thesis for the understanding of tumor immunotherapy. In the current study we investigated the molecular machinery of CTL-induced cell death in human hepatocellular carcinoma cell lines (HCC lines). CTLs prepared from human peripheral blood induced cell death in all tested HCC lines. As the CTL-induced death system, the effectiveness of Fas ligand/Fas and/or Perforin/Granzyme B systems has been suggested, whereas cell death induction by CTLs was shown independently on Fas expression in the current study. Using various tetrapeptide inhibitors for caspase and its associated factor, we additionally demonstrated that inhibitors for caspase 3 (Ac-DEVD-CHO) and caspase 8/granzyme B (Ac-IETD-CHO) suppressed CTL-induced cell death, but an inhibitor for Fas-activated serine proteinase, which acts for the caspase 3 activator, did not, suggesting that CTL-induced cell death was initiated by the Perforin/Granzyme B system, rather than the Fas ligand/Fas system. On the basis of our current results, we report here that the Perforin/Granzyme B system acts dominantly for the cell death induction of HCC lines.     

MicroRNAs and the regulation of cell death

Programmed cell death, or apoptosis, is ubiquitous, both during development and in the adult. Many components of the evolutionarily conserved machinery that brings about and regulates cell death have been identified, and all of these are proteins. However, in the past three years it has become clear that roughly 1% of predicted genes in animals encode small noncoding RNAs known as microRNAs, which regulate gene function. Here we review the recent identification of microRNA cell death regulators in Drosophila, hints that such regulators are also likely to exist in mammals, and more generally the approaches and tools that are now available to probe roles for noncoding RNAs in the control of cell death.     

Mitochondrial complex I and cell death: a semi-automatic shotgun model

Mitochondrial dysfunction often leads to cell death and disease. We can now draw correlations between the dysfunction of one of the most important mitochondrial enzymes, NADH:ubiquinone reductase or complex I, and its structural organization thanks to the recent advances in the X-ray structure of its bacterial homologs. The new structural information on bacterial complex I provide essential clues to finally understand how complex I may work. However, the same information remains difficult to interpret for many scientists working on mitochondrial complex I from different angles, especially in the field of cell death. Here, we present a novel way of interpreting the bacterial structural information in accessible terms. On the basis of the analogy to semi-automatic shotguns, we propose a novel functional model that incorporates recent structural information with previous evidence derived from studies on mitochondrial diseases, as well as functional bioenergetics.