http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Mon, 20 May 2013 14:28:03 +0000 http://www.hindawi.com/journals/ijcb/2013/647975/ The prevalence of obesity has given rise to significant global concerns as numerous population-based studies demonstrate an incontrovertible association between obesity and breast cancer. Mechanisms proposed to account for this linkage include exaggerated levels of carbohydrate substrates, elevated levels of circulating mitogenic hormones, and inflammatory cytokines that impinge on epithelial programming in many tissues. Moreover, recently many scientists have rediscovered the observation, first described by Otto Warburg nearly a century ago, that most cancer cells undergo a dramatic metabolic shift in energy utilization and expenditure that fuels and supports the cellular expansion associated with malignant proliferation. This shift in substrate oxidation comes at the cost of sharp changes in the levels of the high energy intermediate, nicotinamide adenine dinucleotide (NADH). In this review, we discuss a novel example of how shifts in the concentration and flux of substrates metabolized and generated during carbohydrate metabolism represent components of a signaling network that can influence epigenetic regulatory events in the nucleus. We refer to this regulatory process as “metabolic transduction” and describe how the C-terminal binding protein (CtBP) family of NADH-dependent nuclear regulators represents a primary example of how cellular metabolic status can influence epigenetic control of cellular function and fate. Jung S. Byun and Kevin Gardner Copyright © 2013 Jung S. Byun and Kevin Gardner. All rights reserved. Thu, 16 May 2013 17:59:51 +0000 http://www.hindawi.com/journals/ijcb/2013/639401/ Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration) and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism. Claudia Cerella, Flavia Radogna, Mario Dicato, and Marc Diederich Copyright © 2013 Claudia Cerella et al. All rights reserved. Tue, 30 Apr 2013 10:00:52 +0000 http://www.hindawi.com/journals/ijcb/2013/231279/ Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors. Xiaodong Feng, Marcia G. Tonnesen, Shaker A. Mousa, and Richard A. F. Clark Copyright © 2013 Xiaodong Feng et al. All rights reserved. Sun, 28 Apr 2013 14:38:37 +0000 http://www.hindawi.com/journals/ijcb/2013/435981/ Malaria is an infectious disease that results in serious health problems in the countries in which it is endemic. Annually this parasitic disease leads to more than half a million deaths; most of these are children in Africa. An effective vaccine is not available, and the treatment of the disease is solely dependent on chemotherapy. However, drug resistance is spreading, and the identification of new drug targets as well as the development of new antimalarials is urgently required. Attention has been drawn to a variety of essential plasmodial proteins, which are targeted to intra- or extracellular destinations, such as the digestive vacuole, the apicoplast, or into the host cell. Interfering with the action or the transport of these proteins will impede proliferation of the parasite. In this mini review, we will shed light on the present discovery of chemotherapeutics and potential drug targets involved in protein trafficking processes in the malaria parasite. Jasmin Lindner, Kamila Anna Meissner, Isolmar Schettert, and Carsten Wrenger Copyright © 2013 Jasmin Lindner et al. All rights reserved. Thu, 18 Apr 2013 17:05:15 +0000 http://www.hindawi.com/journals/ijcb/2013/960378/ Insulin-like growth factor I (IGF-I) is implicated in breast cancer development and 1, 25-dihydroxyvitamin D3 (1, 25-D3) has been shown to attenuate prosurvival effects of IGF-I on breast cancer cells. In this study the role of IGF binding protein-3 (IGFBP-3) in 1, 25-D3-induced apoptosis was investigated using parental MCF-7 breast cancer cells and MCF-7/VDR cells, which are resistant to the growth inhibitory effects of 1, 25-D3. Treatment with 1, 25-D3 increased IGFBP-3 mRNA expression in both cell lines but increases in intracellular IGFBP-3 protein and its secretion were observed only in MCF-7. 1, 25-D3-induced apoptosis was not associated with activation of any caspase but PARP-1 cleavage was detected in parental cells. IGFBP-3 treatment alone produced cleavage of caspases 7, 8, and 9 and PARP-1 in MCF-7 cells. IGFBP-3 failed to activate caspases in MCF-7/VDR cells; however PARP-1 cleavage was detected. 1, 25-D3 treatment inhibited IGF-I/Akt survival signalling in MCF-7 but not in MCF-7/VDR cells. In contrast, IGFBP-3 treatment was effective in inhibiting IGF-I/Akt pathways in both breast cancer lines. These results suggest a role for IGFBP-3 in 1, 25-D3 apoptotic signalling and that impaired secretion of IGFBP-3 may be involved in acquired resistance to vitamin D in breast cancer. C. Brosseau, G. Pirianov, and K. W. Colston Copyright © 2013 C. Brosseau et al. All rights reserved. Thu, 18 Apr 2013 13:57:02 +0000 http://www.hindawi.com/journals/ijcb/2013/273086/ Over the lifespan of therapeutic proteins, from the point of biosynthesis to the complete clearance from tested subjects, they undergo various biological modifications. Therapeutic influences and molecular mechanisms of these modifications have been well appreciated for some while remained less understood for many. This paper has classified these modifications into multiple categories, according to their processing locations and enzymatic involvement during the trafficking events. It also focuses on the underlying mechanisms and structural-functional relationship between modifications and therapeutic properties. In addition, recent advances in protein engineering, cell line engineering, and process engineering, by exploring these complex cellular processes, are discussed and summarized, for improving functional characteristics and attributes of protein-based biopharmaceutical products. Xiaotian Zhong and Jill F. Wright Copyright © 2013 Xiaotian Zhong and Jill F. Wright. All rights reserved. Tue, 09 Apr 2013 18:14:58 +0000 http://www.hindawi.com/journals/ijcb/2013/243876/ Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells. Roberta Palorini, Tiziana Simonetto, Claudia Cirulli, and Ferdinando Chiaradonna Copyright © 2013 Roberta Palorini et al. All rights reserved. Sun, 31 Mar 2013 10:59:55 +0000 http://www.hindawi.com/journals/ijcb/2013/757148/ Virulent microorganisms, such as pathogenic bacteria and viruses, are recognized by pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and nucleotide-binding oligomerization-domain proteins (NODs), and induce inflammatory responses in mammalian hosts. Conversely, commensal bacteria and probiotics, which symbiotically confer health benefits on the host organisms, can lodge in the host intestinal tract without inducing intestinal inflammation. Recent advances in investigations concerning host-microbial interactions have shown that some effector molecules secreted from beneficial bacteria activate cell survival pathways, such as those mediated by p38 MAPK and Akt, and bring health benefits to mammalian hosts. It is noteworthy that such bacteria-derived molecules are taken into the intestinal epithelia through a transport or endocytosis system, thereafter exhibiting their beneficial effects. Understanding this traffic control process can aid in the comprehension of host and microbe interactions and may provide new insight to clarify the pathogenesis of intestinal disorders. This paper highlights the intestinal trafficking systems of bacteria-derived molecules that affect the bacterial functions and modulate epithelial signaling cascades. The latter mechanism may contribute to the maintenance of intestinal homeostasis by improving the host damage induced by virulence factors and various disease states. Hiroaki Konishi, Mikihiro Fujiya, and Yutaka Kohgo Copyright © 2013 Hiroaki Konishi et al. All rights reserved. Thu, 28 Mar 2013 11:21:16 +0000 http://www.hindawi.com/journals/ijcb/2013/705027/ As most proteoglycans exert their biological activities in the pericellular region, circulating Endocan has appeared since its discovery as an atypical dermatan sulfate proteoglycan, with distinctive structural and functional properties. Endocan is naturally expressed by endothelial cells, highly regulated in presence of proinflammatory and proangiogenic molecules, binds to matrix proteins, growth factors, integrin, and cells, and may be then considered as an accurate marker of endothelial activation. Consequently, Endocan expression has been associated with a growing number of pathological conditions where endothelium gets challenged and notably in highly vascularized cancers. In this context, Endocan has indeed been rapidly emerging as a promising tissue- and blood-based marker of the vascular growth and neoangiogenesis during cancer progression. Furthermore, very recent studies have reported an expression of Endocan by the tumor cells themselves. This highlights Endocan as a multifaceted molecule with a great interest for researchers and clinicians to better understand tumor development, from the bench to the clinics. With promising perspectives of clinical applications, Endocan thus appears as an exciting model for on going and future developments of proteoglycan-based approaches in cancer diagnostics and/or therapy. Maryse Delehedde, Lucie Devenyns, Claude-Alain Maurage, and Romain R. Vivès Copyright © 2013 Maryse Delehedde et al. All rights reserved. Tue, 19 Mar 2013 10:46:20 +0000 http://www.hindawi.com/journals/ijcb/2013/834684/ Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of “old players” for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer. Jennifer H. Gunter, Phoebe L. Sarkar, Amy A. Lubik, and Colleen C. Nelson Copyright © 2013 Jennifer H. Gunter et al. All rights reserved. Tue, 05 Mar 2013 10:29:21 +0000 http://www.hindawi.com/journals/ijcb/2013/604867/ Recombinant immunoglobulins comprise an important class of human therapeutics. Although specific immunoglobulins can be purposefully raised against desired antigen targets by various methods, identifying an immunoglobulin clone that simultaneously possesses potent therapeutic activities and desirable manufacturing-related attributes often turns out to be challenging. The variable domains of individual immunoglobulins primarily define the unique antigen specificities and binding affinities inherent to each clone. The primary sequence of the variable domains also specifies the unique physicochemical properties that modulate various aspects of individual immunoglobulin life cycle, starting from the biosynthetic steps in the endoplasmic reticulum, secretory pathway trafficking, secretion, and the fate in the extracellular space and in the endosome-lysosome system. Because of the diverse repertoire of immunoglobulin physicochemical properties, some immunoglobulin clones’ intrinsic properties may manifest as intriguing cellular phenotypes, unusual solution behaviors, and serious pathologic outcomes that are of scientific and clinical importance. To gain renewed insights into identifying manufacturable therapeutic antibodies, this paper catalogs important intracellular and extracellular phenotypes induced by various subsets of immunoglobulin clones occupying different niches of diverse physicochemical repertoire space. Both intrinsic and extrinsic factors that make certain immunoglobulin clones desirable or undesirable for large-scale manufacturing and therapeutic use are summarized. Haruki Hasegawa Copyright © 2013 Haruki Hasegawa. All rights reserved. Thu, 28 Feb 2013 17:25:12 +0000 http://www.hindawi.com/journals/ijcb/2013/705294/ The BCL-2 homolog BCL-XL, one of the two protein products of BCL2L1, has originally been characterized for its prominent prosurvival functions. Similar to BCL-2, BCL-XL binds to its multidomain proapoptotic counterparts BAX and BAK, hence preventing the formation of lethal pores in the mitochondrial outer membrane, as well as to multiple BH3-only proteins, thus interrupting apical proapoptotic signals. In addition, BCL-XL has been suggested to exert cytoprotective functions by sequestering a cytosolic pool of the pro-apoptotic transcription factor p53 and by binding to the voltage-dependent anion channel 1 (VDAC1), thereby inhibiting the so-called mitochondrial permeability transition (MPT). Thus, BCL-XL appears to play a prominent role in the regulation of multiple distinct types of cell death, including apoptosis and regulated necrosis. More recently, great attention has been given to the cell death-unrelated functions of BCL-2-like proteins. In particular, BCL-XL has been shown to modulate a number of pathophysiological processes, including—but not limited to—mitochondrial ATP synthesis, protein acetylation, autophagy and mitosis. In this short review article, we will discuss the functions of BCL-XL at the interface between cell death and metabolism. Judith Michels, Oliver Kepp, Laura Senovilla, Delphine Lissa, Maria Castedo, Guido Kroemer, and Lorenzo Galluzzi Copyright © 2013 Judith Michels et al. All rights reserved. Sun, 17 Feb 2013 08:08:20 +0000 http://www.hindawi.com/journals/ijcb/2013/162094/ Zinc protoporphyrin IX (ZnPP), a naturally occurring molecule formed in iron deficiency or lead poisoning, is a potent competitive inhibitor of heme oxygenase-1 (HO-1). It also regulates expression of HO-1 at the transcriptional level. However, the effect of ZnPP on HO-1 expression is controversial. It was shown to induce HO-1 expression in some cells, but suppress it in others. The objective of this study is to investigate the effect of ZnPP on HO-1 expression in prostate cancer PC-3 cells. Incubation of PC-3 cells with 10 μM ZnPP for 4 h showed only a slight induction of HO-1 mRNA and protein, but the induction was high after 16 h and was maintained through 48 h of incubation. Of all the known responsive elements in the HO-1 promoter, ZnPP activated mainly the stress response elements. Of the various protein kinase inhibitors and antioxidant tested, only Ro 31-8220 abrogated ZnPP-induced HO-1 expression, suggesting that activation of HO-1 gene by ZnPP may involve protein kinase C (PKC). The involvement of PKC α, β, δ, η, θ, and ζ isoforms was ruled out by the use of specific inhibitors. The isoform of PKC involved and participation of other transcription factors remain to be studied. Simon C. M. Kwok Copyright © 2013 Simon C. M. Kwok. All rights reserved. Thu, 14 Feb 2013 08:31:14 +0000 http://www.hindawi.com/journals/ijcb/2013/242513/ Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis. Nicholas Wong, Jason De Melo, and Damu Tang Copyright © 2013 Nicholas Wong et al. All rights reserved. Tue, 12 Feb 2013 13:31:30 +0000 http://www.hindawi.com/journals/ijcb/2013/805975/ Abnormal metabolism and the evasion of apoptosis are considered hallmarks of cancers. Accumulating evidence shows that cancer stem cells are key drivers of tumor formation, progression, and recurrence. A successful therapy must therefore eliminate these cells known to be highly resistant to apoptosis. In this paper, we describe the metabolic changes as well as the mechanisms of resistance to apoptosis occurring in cancer cells and cancer stem cells, underlying the connection between these two processes. Claire Pecqueur, Lisa Oliver, Kristell Oizel, Lisenn Lalier, and François M. Vallette Copyright © 2013 Claire Pecqueur et al. All rights reserved. Mon, 21 Jan 2013 15:59:38 +0000 http://www.hindawi.com/journals/ijcb/2013/463637/ While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases. Simone Fulda Copyright © 2013 Simone Fulda. All rights reserved. Tue, 25 Dec 2012 09:53:44 +0000 http://www.hindawi.com/journals/ijcb/2012/968586/ Lina Ghibelli and Alina Grzanka Copyright © 2012 Lina Ghibelli and Alina Grzanka. All rights reserved. Thu, 29 Nov 2012 17:11:59 +0000 http://www.hindawi.com/journals/ijcb/2012/471591/ The extracellular matrix (ECM) is known to provide various physicochemical cues in directing cell behavior including composition, topography, and dimensionality. Physical remodeling of the ECM has been documented in a variety of cancers. In breast cancer, the increased deposition of matrix proteins, their crosslinking, and alignment create a stiffer microenvironment that activates cell contractility and promotes cancer invasion. In this paper, we sought to study the collective influence of ECM composition and density on the contractile mechanics of human MDA-MB-231 cells making use of the recently established trypsin deadhesion assay. Using collagen and fibronectin-coated surfaces of varying density, we show that cell contractility is tuned in a density-dependent manner, with faster deadhesion on fibronectin-coated surfaces compared to collagen-coated surfaces under identical coating densities. The deadhesion responses are significantly delayed when cells are treated with the myosin inhibitor blebbistatin. By combining collagen and fibronectin at two different densities, we show that mixed ligand surfaces synergistically modulate cell contractility. Finally, we show that on fibroblast-derived 3D matrices that closely mimic in vivo matrices, cells are strongly polarized and exhibit faster deadhesion compared to the mixed ligand surfaces. Together, our results demonstrate that ECM composition, density, and 3D organization collectively regulate cell contractility. Aastha Kapoor and Shamik Sen Copyright © 2012 Aastha Kapoor and Shamik Sen. All rights reserved. Tue, 27 Nov 2012 11:12:28 +0000 http://www.hindawi.com/journals/ijcb/2012/737421/ To develop and optimize new scaffold materials for tissue engineering applications, it is important to understand how changes to the scaffold affect the cells that will interact with that scaffold. In this study, we used a hyaluronic acid- (HA-) based hydrogel as a synthetic extracellular matrix, containing modified HA (CMHA-S), modified gelatin (Gtn-S), and a crosslinker (PEGda). By varying the concentrations of these components, we were able to change the gelation time, enzymatic degradation, and compressive modulus of the hydrogel. These changes also affected fibroblast spreading within the hydrogels and differentially affected the proliferation and metabolic activity of fibroblasts and mesenchymal stem cells (MSCs). In particular, PEGda concentration had the greatest influence on gelation time, compressive modulus, and cell spreading. MSCs appeared to require a longer period of adjustment to the new microenvironment of the hydrogels than fibroblasts. Fibroblasts were able to proliferate in all formulations over the course of two weeks, but MSCs did not. Metabolic activity changed for each cell type during the two weeks depending on the formulation. These results highlight the importance of determining the effect of matrix composition changes on a particular cell type of interest in order to optimize the formulation for a given application. Thomas Lawyer, Kristen McIntosh, Cristian Clavijo, Lydia Potekhina, and Brenda K. Mann Copyright © 2012 Thomas Lawyer et al. All rights reserved. Tue, 11 Sep 2012 11:28:37 +0000 http://www.hindawi.com/journals/ijcb/2012/659645/ Giuseppe Filomeni, Juan P. Bolaños, and Pier Giorgio Mastroberardino Copyright © 2012 Giuseppe Filomeni et al. All rights reserved. Sun, 09 Sep 2012 15:14:06 +0000 http://www.hindawi.com/journals/ijcb/2012/683897/ Electromagnetic fields (EMFs) originating both from both natural and manmade sources permeate our environment. As people are continuously exposed to EMFs in everyday life, it is a matter of great debate whether they can be harmful to human health. On the basis of two decades of epidemiological studies, an increased risk for childhood leukemia associated with Extremely Low Frequency fields has been consistently assessed, inducing the International Agency for Research on Cancer to insert them in the 2B section of carcinogens in 2001. EMFs interaction with biological systems may cause oxidative stress under certain circumstances. Since free radicals are essential for brain physiological processes and pathological degeneration, research focusing on the possible influence of the EMFs-driven oxidative stress is still in progress, especially in the light of recent studies suggesting that EMFs may contribute to the etiology of neurodegenerative disorders. This review synthesizes the emerging evidences about this topic, highlighting the wide data uncertainty that still characterizes the EMFs effect on oxidative stress modulation, as both pro-oxidant and neuroprotective effects have been documented. Care should be taken to avoid methodological limitations and to determine the patho-physiological relevance of any alteration found in EMFs-exposed biological system. Claudia Consales, Caterina Merla, Carmela Marino, and Barbara Benassi Copyright © 2012 Claudia Consales et al. All rights reserved. Mon, 03 Sep 2012 10:19:06 +0000 http://www.hindawi.com/journals/ijcb/2012/139573/ Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches. Nic E. Savaskan, Günter Fingerle-Rowson, Michael Buchfelder, and Ilker Y. Eyüpoglu Copyright © 2012 Nic E. Savaskan et al. All rights reserved. Sun, 26 Aug 2012 14:54:04 +0000 http://www.hindawi.com/journals/ijcb/2012/367934/ In mammals, the mitochondrial F1Fo-ATPsynthase sets out the energy homeostasis by producing the bulk of cellular ATP. As for every enzyme, the laws of thermodynamics command it; however, it is privileged to have a dedicated molecular regulator that controls its rotation. This is the so-called ATPase Inhibitory Factor 1 (IF1) that blocks its reversal to avoid the consumption of cellular ATP when the enzyme acts as an ATP hydrolase. Recent evidence has also demonstrated that IF1 may control the alignment of the enzyme along the mitochondrial inner membrane, thus increasing the interest for the molecule. We conceived this review to outline the fundamental knowledge of the F1Fo-ATPsynthase and link it to the molecular mechanisms by which IF1 regulates its way of function, with the ultimate goal to highlight this as an important and possibly unique means to control this indispensable enzyme in both physiological and pathological settings. Danilo Faccenda and Michelangelo Campanella Copyright © 2012 Danilo Faccenda and Michelangelo Campanella. All rights reserved. Tue, 21 Aug 2012 15:29:33 +0000 http://www.hindawi.com/journals/ijcb/2012/156272/ Fulvio Reggiori, Masaaki Komatsu, Kim Finley, and Anne Simonsen Copyright © 2012 Fulvio Reggiori et al. All rights reserved. Thu, 16 Aug 2012 11:36:02 +0000 http://www.hindawi.com/journals/ijcb/2012/463756/ Debilitating neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), can be attributed to neuronal cell damage in specific brain regions. An important hallmark of these diseases is increased oxidative and nitrosative stress that occurs via overproduction of highly reactive free radicals known as reactive oxygen species (ROS) and reactive nitrogen species (RNS). These molecules are normally removed by cellular antioxidant systems. Under physiological conditions, ROS/RNS are present at low levels, mediating several neurotrophic and neuroprotective signaling pathways. In contrast, under pathological conditions, there is a pronounced increase in ROS/RNS generation, impairing normal neurological function. Nitric oxide (NO) is one such molecule that functions as a signaling agent under physiological conditions but causes nitrosative stress under pathological conditions due to its enhanced production. As first reported by our group and colleagues, the toxic effects of NO can be in part attributed to thiol S-nitrosylation, a posttranslational modification of cysteine residues on specific proteins. Here, we review several reports appearing over the past decade showing that S-nitrosylation of an increasing number of proteins compromises important cellular functions, including mitochondrial dynamics, endoplasmic reticulum (ER) protein folding, and signal transduction, thereby promoting synaptic damage, cell death, and neurodegeneration. Mohd Waseem Akhtar, Carmen R. Sunico, Tomohiro Nakamura, and Stuart A. Lipton Copyright © 2012 Mohd Waseem Akhtar et al. All rights reserved. Mon, 13 Aug 2012 10:03:06 +0000 http://www.hindawi.com/journals/ijcb/2012/361872/ S-nitrosylation is a posttranslational modification of cysteine residues that has been frequently indicated as potential molecular mechanism governing cell response upon redox unbalance downstream of nitric oxide (over)production. In the last years, increased levels of S-nitrosothiols (SNOs) have been tightly associated with the onset of nitroxidative stress-based pathologies (e.g., cancer and neurodegeneration), conditions in which alterations of mitochondrial homeostasis and activation of cellular processes dependent on it have been reported as well. In this paper we aim at summarizing the current knowledge of mitochondria-related proteins undergoing S-nitrosylation and how this redox modification might impact on mitochondrial functions, whose impairment has been correlated to tumorigenesis and neuronal cell death. In particular, emphasis will be given to the possible, but still neglected implication of denitrosylation reactions in the modulation of mitochondrial SNOs and how they can affect mitochondrion-related cellular process, such as oxidative phosphorylation, mitochondrial dynamics, and mitophagy. Giuseppina Di Giacomo, Salvatore Rizza, Costanza Montagna, and Giuseppe Filomeni Copyright © 2012 Giuseppina Di Giacomo et al. All rights reserved. Thu, 26 Jul 2012 14:25:51 +0000 http://www.hindawi.com/journals/ijcb/2012/849541/ The NF-κB signaling system and the autophagic degradation pathway are crucial cellular survival mechanisms, both being well conserved during evolution. Emerging studies have indicated that the IKK/NF-κB signaling axis regulates autophagy in a context-dependent manner. IKK complex and NF-κB can enhance the expression of Beclin 1 and other autophagy-related proteins and stimulate autophagy whereas as a feedback response, autophagy can degrade IKK components. Moreover, NF-κB signaling activates the expression of autophagy inhibitors (e.g., A20 and Bcl-2/xL) and represses the activators of autophagy (BNIP3, JNK1, and ROS). Several studies have indicated that NF-κB signaling is enhanced both during aging and cellular senescence, inducing a proinflammatory phenotype. The aging process is also associated with a decline in autophagic degradation. It seems that the activity of Beclin 1 initiation complex could be impaired with aging, since the expression of Beclin 1 decreases as does the activity of type III PI3K. On the other hand, the expression of inhibitory Bcl-2/xL proteins increases with aging. We will review the recent literature on the control mechanisms of autophagy through IKK/NF-κB signaling and emphasize that NF-κB signaling could be a potent repressor of autophagy with ageing. Antero Salminen, Juha M. T. Hyttinen, Anu Kauppinen, and Kai Kaarniranta Copyright © 2012 Antero Salminen et al. All rights reserved. Thu, 19 Jul 2012 08:51:38 +0000 http://www.hindawi.com/journals/ijcb/2012/161837/ Inborn defects of the tricarboxylic acid (TCA) cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology. Simone Cardaci and Maria Rosa Ciriolo Copyright © 2012 Simone Cardaci and Maria Rosa Ciriolo. All rights reserved. Mon, 09 Jul 2012 14:42:37 +0000 http://www.hindawi.com/journals/ijcb/2012/179207/ Invading pathogens provoke the autophagic machinery and, in a process termed xenophagy, the host cell survives because autophagy is employed as a safeguard for pathogens that escaped phagosomes. However, some pathogens can manipulate the autophagic pathway and replicate within the niche of generated autophagosome-like vesicles. By automated fluorescence-based high content analyses, we demonstrate that Staphylococcus aureus strains (USA300, HG001, SA113) stimulate autophagy and become entrapped in intracellular PtdIns(3)P-enriched vesicles that are decorated with human WIPI-1, an essential PtdIns(3)P effector of canonical autophagy and membrane protein of both phagophores and autophagosomes. Further, agr-positive S. aureus (USA300, HG001) strains were more efficiently entrapped in WIPI-1 positive autophagosome-like vesicles when compared to agr-negative cells (SA113). By confocal and electron microscopy we provide evidence that single- and multiple-Staphylococci entrapped undergo cell division. Moreover, the number of WIPI-1 positive autophagosome-like vesicles entrapping Staphylococci significantly increased upon (i) lysosomal inhibition by bafilomycin A1 and (ii) blocking PIKfyve-mediated PtdIns(3,5)P2 generation by YM201636. In summary, our results provide evidence that the PtdIns(3)P effector function of WIPI-1 is utilized during xenophagy of Staphylococcus aureus. We suggest that invading S. aureus cells become entrapped in autophagosome-like WIPI-1 positive vesicles targeted for lysosomal degradation in nonprofessional host cells. Mario Mauthe, Wenqi Yu, Oleg Krut, Martin Krönke, Friedrich Götz, Horst Robenek, and Tassula Proikas-Cezanne Copyright © 2012 Mario Mauthe et al. All rights reserved. Sun, 08 Jul 2012 11:35:42 +0000 http://www.hindawi.com/journals/ijcb/2012/759583/ Mitochondrial activity progressively declines during ageing and in many neurodegenerative diseases. Caloric restriction (CR) has been suggested as a dietary intervention that is able to postpone the detrimental aspects of aging as it ameliorates mitochondrial performance. This effect is partially due to increased mitochondrial biogenesis. The nutrient-sensing PGC-1𝛼 is a transcriptional coactivator that promotes the expression of mitochondrial genes and is induced by CR. It is believed that many of the mitochondrial and metabolic benefits of CR are due to increased PGC-1𝛼 activity. The increase of PGC-1𝛼 is also positively linked to neuroprotection and its decrement has been involved in the pathogenesis of many neurodegenerative diseases. This paper aims to summarize the current knowledge about the role of PGC-1𝛼 in neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1𝛼-governed pathways could be used as target for nutritional intervention to prevent neurodegeneration. Daniele Lettieri Barbato, Sara Baldelli, Beatrice Pagliei, Katia Aquilano, and Maria Rosa Ciriolo Copyright © 2012 Daniele Lettieri Barbato et al. All rights reserved.