Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 3, 2008


Contents


Mechanisms of Cell Death: Biomedical Implications
Executive Editor: E. Ottaviani


Editorial Pp. 197


Viral Manipulation of Cell Death Pp. 198-220
J.E. McLean, A. Ruck, A. Shirazian, F. Pooyaei-Mehr and Z.F. Zakeri
[Abstract]


Endothelial Cell Aging and Apoptosis in Prevention and Disease: E-Selectin Expression and Modulation As A Model Pp. 221-225
N. Vannini, U. Pfeffer, G. Lorusso, D. Noonan and A. Albini
[Abstract]


Different Types of Cell Death in Organismal Aging and Longevity: State of the Art and Possible Systems Biology Approach Pp. 226-236
S. Salvioli, M. Capri, P. Tieri, J. Loroni, C. Barbi, L. Invidia, S. Altilia, A. Santoro, C. Pirazzini, M. Pierini, E. Bellavista, L. Alberghina and C. Franceschi
[Abstract]


Apoptosis and HIV Infection: About Molecules and Genes Pp. 237-244
A. Cossarizza
[Abstract]


Xeno-Cannibalism as an Exacerbation of Self-Cannibalism: A Possible Fruitful Survival Strategy for Cancer Cells Pp. 245-252
P. Matarrese, L. Ciarlo, A. Tinari, M. Piacentini and W. Malorni
[Abstract]


Apoptosis in the Homeostasis of the Immune System and in Human Immune Mediated Diseases Pp. 253-268
A. Giovannetti, M. Pierdominici, A. Di Iorio, R. Cianci, G. Murdaca, F. Puppo, F. Pandolfi and R. Paganelli
[Abstract]


Cell Death: Tipping the Balance of Autoimmunity and Tissue Repair Pp. 269-277
P. Rovere-Querini, S. Brunelli, E. Clementi and A.A. Manfredi
[Abstract]


Type 2 Transglutaminase in Neurodegenerative Diseases: the Mitochondrial Connection Pp. 278-288
W. Malorni, M.G. Farrace, C. Rodolfo and M. Piacentini
[Abstract]


General Articles


Correlating Low-Similarity Peptide Sequences and Allergenic Epitopes Pp. 289-295
D. Kanduc
[Abstract]


Integrins: A Method of Early Intervention in the Treatment of Colorectal Liver Metastases Pp. 296-305
J.H. Robertson, A.M. Iga, K. M. Sales, M.C. Winslet and A.M. Seifalian
[Abstract]




Abstracts


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Editorial: Mechanisms of Cell Death: Biomedical Implications

Cell death is a basic element occurring not only in the normal organism functioning but also in many forms of aging and pathologies. The reviews here collected focus on the important role that the different types of cell death, or the interplay among them, can play in many forms of aging and pathologies discussing also how cell death may be exploited for therapeutic purposes in human diseases.

McLean et al. focus on the most recent and important advances in understanding how a wide range of viruses manipulate the survival and death of their hosts. Viruses appear to be able to intervene at all steps of eukaryotic cell death, both to prevent death and ultimately to provoke it. By unraveling the specific details surrounding virus-host interactions, novel therapeutic targets, and aid in improved vaccine design, as well as a clearer insight into the complex machinery of eukaryotic cell death have been reported.

Vannini et al. describe some functional changes encountered by endothelial cells during the aging process that predispose these cells to apoptosis. It is clear how inflammation and redox imbalance are the main features involved in this death process thus they propose a dietary use of safe anti-oxidants as NAC as suitable tool in the prevention of endothelium aging and subsequently in the prevention of cancer and cardiovascular disease.

Salvioli et al. discuss how cell death phenomena are modulated during aging and what is their possible role in the aging process. Since the "decisional process" that leads the cell to death is very complex, the systems biology approach has been shown to be effective in giving structure and increasing understanding of both apoptosis and cell senescence, thus offering a promising tool to disentangle the inherent complexity of the biochemical decision processes that lead to cell death or survival.

Cossarizza focuses on the relationship between apoptosis and HIV. The infection with HIV is characterized by the activation of several molecular and cellular mechanisms that the organism triggers to cope with the virus and eliminate dangerous, infected cells. The virus can play different parts, because immune cells devoted to its control have to be killed, but such cells are often required for viral replication. In such a complex equation, the action of different antiretroviral drugs and cytokines can significantly influence apoptosis.

Matarrese et al. in their review summarize the findings reported in literature on a phagic process that appears to be related to self-cannibalism: the xeno-cannibalism. This was described as the ability of certain cells, e.g. metastatic cells, to cannibalize their siblings as well as cells from the immune system. Furthermore, they suggest a pathogenetic role for cannibalic behavior in human pathology and point at this surprising cellular aggressiveness as an innovative pharmacological target in the clinical management of metastatic disease.

Giovannetti et al. consider some key facts on the relationship of lymphopenia to autoreactivity, the mechanisms controlling positive and negative selection in the thymus, the role of apoptosis in selected primary immunodeficiency states and in systemic and organ-specific autoimmunity, with examples from human diseases and their animal models.

Rovere-Querini et al. report recent developments on the control of apoptosis induction and execution, discussing how cell death may be exploited for therapeutic purposes. The links among cell death, persisting inflammation, stem cell recruitment and activation in experimental models of complex human diseases are also analyzed.

Malorni et al. review the recent developments in the comprehension of the role played by type 2 transglutaminase (TG2) in eukaryotic cells, focusing on the role exerted by TG2 on mitochondrial physiology and on the regulation of cell death pathways at the basis of neurodegenerative diseases.

References
[1] McLean JE, Ruck A, Shirazian A, Pooyaei-Mehr F, Zakeri ZF. Viral Manipulation of Cell Death. Curr Pharm Des 2008; 14(3): 198-220.

[2] Vannini N, Pfeffer U, Lorusso G, Noonan D, Albini A. Endothelial Cell Aging and Apoptosis in Prevention Disease: E-Selectin Expression and Modulation As A Model. Curr Pharm Des 2008; 14(3): 221-225.

[3] Salvioli S, Capri M, Tieri P, Loroni J, Barbi C, Invidia L, Altilia S, Santoro A, Pirazzini C, Pierini M, Bellavista E, Alberghina L, Franceschi C. Different Types of Cell Death in Organismal Aging and Longevity: State of the Art and Possible Systems Biology Approach. Curr Pharm Des 2008; 14(3): 226-236.

[4] Cossarizza A. Apoptosis and HIV Infection: About Molecules and Genes. Curr Pharm Des 2008; 14(3): 237-244.

[5] Matarrese P, Ciarlo L, Tinari A, Piacentini M, Malorni W. Xeno-Cannibalism As an Exacerbation of Self-Cannibalism: A Possible Fruitful Survival Strategy for Cancer Cells. Curr Pharm Des 2008; 14(3): 245-252.

[6] Giovannetti A, Pierdominici M, Di Iorio A, Cianci R, Murdaca G, Puppo F, Pandolfi F, Paganelli R. Apoptosis in the Homeostasis of the Immune System and in Human Immune Mediated Diseases. Curr Pharm Des 2008; 14(3): 253-268.

[7] Rovere-Querini P, Brunelli S, Clementi E, Manfredi A.A. Cell Death: Tipping the Balance of Autoimmunity and Tissue Repair. Curr Pharm Des 2008; 14(3): 269-277.

[8] Malorni W, Farrace MG, Rodolfo C, Piacentini M. Type 2 Transglutaminase in Neurodegenerative Diseases: the Mitochondrial Connection. Curr Pharm Des 2008; 14(3): 278-288.


Enzo Ottaviani
E-mail: enzo.ottaviani@unimore.it


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Viral Manipulation of Cell Death
J.E. McLean, A. Ruck, A. Shirazian, F. Pooyaei-Mehr and Z.F. Zakeri

Elucidation of the mechanisms behind cell death has brought with it an appreciation for viral strategies that target these pathways as a means to promote viral propagation while avoiding or slowing the host immune response. Several redundant anti-viral pathways have evolved in eukaryotic cells that are designed to minimize the damage due to viral infection while quickly clearing the invading pathogen. Cell death is a commonly employed immune defense against viral infection, and many viruses potently induce or suppress cell death during infection. The past decade has seen an incredible increase in our understanding of how cell death assists in host immune response, as well as how viruses have evolved to hijack or disengage these systems. By targeting components of host cell death pathways, viruses have developed the ability to control host survival and death, ensuring efficient propagation while inactivating or avoiding the immune system consequences of infection. This review focuses on the most recent and important advances in our understanding of how a wide range of viruses manipulate the survival and death of their hosts.


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Endothelial Cell Aging and Apoptosis in Prevention and Disease: E-Selectin Expression and Modulation As A Model
N. Vannini, U. Pfeffer, G. Lorusso, D. Noonan and A. Albini

Endothelial cell senescence and apoptosis are features of numerous human pathologies including atherosclerosis, allograft vasculopathy, heart failure, diabetic retinopathy and scleroderma. In contrast, endothelial cell activation and replication associated with vessel proliferation and angiogenesis are now therapeutic targets in other diseases such as cancer and macular dystrophy. Finally, preventive medicine, in particular cardiovascular and cancer chemoprevention, commonly involve the endothelium. Here we discuss several aspects of the interplay between endothelial cell aging, apoptosis and senescence. Further, we show novel microarray data on endothelial cells “aged” in culture, and note that many genes regulated by the aging process are also modulated by a chemopreventive anti-angiogenic and anti-apoptotic drug, N-acetyl-cysteine (NAC). Focusing on one of these genes, the leukocyte adhesion protein E-selectin, we show that E-selectin is down-modulated with time in culture and upon treatment with NAC at mRNA and protein levels. This correlates with reduced adhesion of breast cancer cells and NF-κB activation in NAC treated endothelial cells. These data underscore the effects of a chemoprevention agent in modulating parameters associated with endothelial cell aging.


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Different Types of Cell Death in Organismal Aging and Longevity: State of the Art and Possible Systems Biology Approach
S. Salvioli, M. Capri, P. Tieri, J. Loroni, C. Barbi, L. Invidia, S. Altilia, A. Santoro, C. Pirazzini, M. Pierini, E. Bellavista, L. Alberghina and C. Franceschi

Cell death is as important as cell proliferation for cell turn-over, and susceptibility to cell death is affected by a number of parameters that change with time. A time-dependent derangement of such a crucial process, or even the simple cell loss mediated by cell death impinges upon aging and longevity. In this review we will discuss how cell death phenomena are modulated during aging and what is their possible role in the aging process. We will focus on apoptosis and autophagy, which affect mostly proliferating and post-mitotic cells, respectively, and on mitochondrial degradation in long living cells. Since the "decisional process" that leads the cell to death is very complex, we will also discuss the possibility to address this topic with a systems biology approach.


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Apoptosis and HIV Infection: About Molecules and Genes
A. Cossarizza

During the evolution, the immune system has developed several strategies to fight viral infections. Apoptosis, autophagy and necrosis are different types of cell death that play a main role in the interactions between infective agents and the host, since they are often important defence mechanisms that have to avoid the spreading of the infection. In turn, viruses have evolved numerous ways to evade the host immune system by influencing the behaviour and functionality of several components.

HIV infects and kills CD4+ T helper lymphocytes, preferentially those that are antigen-specific, but also encodes proteins with apoptotic capacities, including gp120, gp160, Tat, Nef, Vpr, Vpu, Vif and, last but not least, the viral protease. This latter protein can kill infected and uninfected lymphocytes through the action of several host molecules, mainly members of the tumor necrosis factor family, or via the mitochondrial apoptotic pathway. The proinflammatory state that is characteristic of both the acute and chronic phase of HIV infection facilitates cell death, and is an additional cause of immune damage.

Potent antiretroviral drugs that are largely use in therapy can reduce apoptosis by different mechanisms, that not only include the diminished production of the virus by infected cells and the subsequent reduction of inflammation, but also a direct action on the viral protease. The role of the host genetic background is finally crucial in understanding the process of cell death in HIV infection.


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Xeno-Cannibalism as an Exacerbation of Self-Cannibalism: A Possible Fruitful Survival Strategy for Cancer Cells
P. Matarrese, L. Ciarlo, A. Tinari, M. Piacentini and W. Malorni

The term self-cannibalism, or autophagy, was coined to describe the ability of the cells to cannibalize their own damaged organelles or proteins. It was morphologically described as the presence of double-membraned autophagic vesicles filled with diverse cellular materials or debris inside the cells. Hence, more recently, the presence of autophagic vacuoles has been associated with cell survival, including cell senescence and cancer and appears to be activated by nutrient deprivation. The occurrence of autophagic processes can also lead, as final event, to the death of the cell. In this review we summarize the results reported in literature on a phagic process that appears to be related to self-cannibalism: the xeno-cannibalism. This was described as the ability of certain cells, e.g. metastatic cells, to cannibalize their siblings as well as cells from the immune system. Interestingly, metastatic tumor cells are also able to engulf and digest living cells, including autologous lymphocytes that should kill them, i.e. CD8⁺ cytotoxic lymphocytes. This can represent a formidable opportunity for metastatic cells to survive in adverse conditions such as those they encounter in their “journey” towards the target organ to establish a colony. Altogether these findings seem to suggest a pathogenetic role for cannibalic behavior in human pathology and point at this surprising cellular aggressiveness as an innovative pharmacological target in the clinical management of metastatic disease.


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Apoptosis in the Homeostasis of the Immune System and in Human Immune Mediated Diseases
A. Giovannetti, M. Pierdominici, A. Di Iorio, R. Cianci, G. Murdaca, F. Puppo, F. Pandolfi and R. Paganelli

The immune system has evolved sophisticate mechanisms controlling the development of responses to dangerous antigens while avoiding unnecessary attacks to innocuous, commensal or self antigens. The risk of autoimmunity is continuously checked and balanced against the risk of succumbing to exogenous infectious agents. It is therefore of paramount importance to understand the molecular events linking the breakdown of tolerance and the development of immunodeficiency. Apoptotic mechanisms are used to regulate the development of thymocytes, the shaping of T cell repertoire, its selection and the coordinate events leading to immune responses in the periphery. Moreover, they are at the heart of the homeostatic controls restoring T cell numbers and establishing T cell memory. T lymphocytes shift continuously from survival to death signals to ensure immune responsiveness without incurring in autoimmune damage. In this review we shall consider some key facts on the relationship of lymphopenia to autoreactivity, the mechanisms controlling positive and negative selection in the thymus, the role of apoptosis in selected primary immunodeficiency states and in systemic and organ-specific autoimmunity, with examples from human diseases and their animal models.


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Cell Death: Tipping the Balance of Autoimmunity and Tissue Repair
P. Rovere-Querini, S. Brunelli, E. Clementi and A.A. Manfredi

Inflammation is a key homeostatic process elicited by microbial components and by tissue damage. Increasing evidence indicates that the outcomes either tissue repair or persistent inflammatory damage and degeneration tightly depend on the pattern of cell death in situ and on infiltrating leukocytes and antigen presenting cells. Defects in the initiation and execution steps of programmed cell death such as in the clearance of cell debris are indeed often associated to inflammation defective repair and autoimmunity. Here we report recent developments on the control of apoptosis induction and execution discussing how cell death may be exploited for therapeutic purposes and the links between cell death persisting inflammation and stem cell recruitment and activation in experimental models of complex human diseases such as muscular dystrophy and cancer.


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Type 2 Transglutaminase in Neurodegenerative Diseases: the Mitochondrial Connection
W. Malorni, M.G. Farrace, C. Rodolfo and M. Piacentini

“Tissue” or type 2 Transglutaminase (TG2) is a peculiar multifunctional enzyme able to catalyse Ca²⁺ -dependent post-translational modification of proteins, by establishing covalent bonds between peptide-bound glutamine residues and either lysine residues or mono- and poly-amines. In addition, it may act also as a G protein in transmembrane signalling, as a kinase, as a protein disulphide isomerase and as a cell surface adhesion mediator. The vast array of biochemical functions exerted by TG2 characterises and distinguishes it from all the other members of the transglutaminase family. Multiple lines of evidence suggest an involvement of the enzyme in neurodegenerative diseases, such as Huntington's (HD) and Parkinson (PD), and that its inhibition, either via drug treatments or genetic approaches, might be beneficial for the treatment of these syndromes.

This review will exploit the recent developments in the comprehension of the role played by type 2 transglutaminase in eukaryotic cells, focusing on the role exerted by TG2 on mitochondrial physiology and on the regulation of cell death pathways at the basis of neurode-generative diseases.


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Correlating Low-Similarity Peptide Sequences and Allergenic Epitopes
D. Kanduc

Although a high number of allergenic peptide epitopes has been experimentally identified and defined, the molecular basis and the precise mechanisms underlying peptide allergenicity are unknown. This issue was analyzed exploring the relationship between peptide allergenicity and sequence similarity to the human proteome. The structured analysis of the data reported in literature put into evidence that the most part of IgE-binding epitopes are (or harbor) pentapeptide unit(s) with no/low similarity to the human proteome, this way suggesting that no or low sequence similarity to the host proteome might represent a minimum common denominator identifying allergenic peptides. The present literature analysis might be of relevance in devising and designing short amino acid modules to be used for blocking pathogenic IgE.


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Integrins: A Method of Early Intervention in the Treatment of Colorectal Liver Metastases
J.H. Robertson, A.M. Iga, K. M. Sales, M.C. Winslet and A.M. Seifalian

The integrin family of cell surface receptors were principally thought to be involved in cell adhesion. Intense study has shown that these glycoproteins also regulate a diverse range of physiological processes. Inappropriate activation of integrins has been implicated in many pathological processes. Recent studies have shown that these molecules play a key role in the early stages of liver metastasis in colorectal cancer. In vivo experiments have demonstrated that integrins are involved in tumour cell targeting, arrest, adhesion and migration within the hepatic microcirculation. Indeed functional blocking of specific integrins has been shown to significantly impair these early stages of metastasis development. This review examines the current knowledge of integrin participation in this area and highlights the future therapeutic implications. Future targeted therapy against specific integrins would allow not only functional blocking but would provide the potential to deliver specific anti-cancer therapy.