Giovanni Zummo

Publications of Giovanni Zummo

• The Molecular Anatomy of Human Hsp60 and its Similarity with that of Bacterial Orthologs and Acetylcholine Receptor Reveal a Potential Pathogenetic Role of Anti-Chaperonin Immunity in Myasthenia Gravis.

  Authors: Antonella Marino Gammazza, Fabio Bucchieri, Luigi M E Grimaldi, Arcangelo Benigno, Everly Conway de Macario, Alberto J L Macario, Giovanni Zummo, Francesco Cappello

  Cellular and molecular neurobiology. 01/2012;

  Heat-shock protein 60 (Hsp60) is ubiquitous and highly conserved being present in eukaryotes and prokaryotes, including pathogens. This chaperonin, although typically a mitochondrial protein, canHeat-shock protein 60 (Hsp60) is ubiquitous and highly conserved being present in eukaryotes and prokaryotes, including pathogens. This chaperonin, although typically a mitochondrial protein, can also be found in other intracellular sites, extracellularly, and in circulation. Thus, it can signal the immune system and participate in the development of inflammation and immune reactions. Both phenomena can be elicited by human and foreign Hsp60 (e.g., bacterial GroEL), when released into the blood by infectious agents. Consequently, all these Hsp60 proteins become part of a complex autoimmune response characterized by multiple cross reactions because of their structural similarities. In this study, we demonstrate that Hsp60 proteins from humans and two common pathogens, Chlamydia trachomatis and Chlamydia pneumoniae, share various sequence segments of potentially highly immunogenic epitopes with acetylcholine receptor α1 subunit (AChRα1). The structural data indicate that AChRα1 antibodies, implicated in the pathogenesis of myasthenia gravis, could very well be elicited and/or maintained by self- and/or bacterial Hsp60.

• Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study.

  Authors: Manfredi Rizzo, Francesco Cappello, Rafael Marfil, Luigi Nibali, Antonella Marino Gammazza, Francesca Rappa, Giuseppe Bonaventura, Pablo Galindo-Moreno, Francisco O'Valle, Giovanni Zummo, Everly Conway de Macario, Alberto J L Macario, Francisco Mesa

  Cell stress & chaperones. 01/2012;

  Identification of predictors of cardiovascular risk can help in the prevention of pathologic episodes and the management of patients at all stages of illness. Here, we investigated the relationshipsIdentification of predictors of cardiovascular risk can help in the prevention of pathologic episodes and the management of patients at all stages of illness. Here, we investigated the relationships between serum levels of Hsp60 and dyslipidemia in patients with periodontitis by performing a cross-sectional study of 22 patients with mild periodontitis without any prior treatment for it (i.e., drug naïve) and 22 healthy controls, matched for age and body mass index (BMI). All subjects were evaluated for periodontal status, gingival inflammation, and oral hygiene. Levels of circulating Hsp60, C-reactive protein (CRP), and plasma lipids were measured, and small, dense low-density lipoproteins (LDL) were indirectly assessed by determining the triglycerides/high-density lipoproteins (HDL) cholesterol ratio. We also assessed by immunohistochemistry Hsp60 levels in oral mucosa of patients and controls. No difference was found in CRP levels or plasma lipids between the two groups, but subjects with periodontitis showed, in comparison to controls, higher levels of small, dense LDL (p  = 0.0355) and circulating Hsp60 concentrations (p < 0.0001). However, levels of mucosal Hsp60 did not change significantly between groups. Correlation analysis revealed that circulating Hsp60 inversely correlated with HDL-cholesterol (r  = -0.589, p  = 0.0039), and positively with triglycerides (r  = +0.877, p < 0.0001), and small, dense LDL (r  = +0.925, p < 0.0001). Serum Hsp60 significantly correlated with the degree of periodontal disease (r  = +0.403, p  = 0.0434). In brief, untreated patients with mild periodontitis had increased small, dense LDL and serum Hsp60 concentrations, in comparison to age- and BMI-matched controls and both parameters showed a strong positive correlation. Our data indicate that atherogenic dyslipidemia and elevated circulating Hsp60 tend to be linked and associated to periodontal pathology. Thus, the road is open to investigate the potential value of elevated levels of circulating Hsp60 as predictor of risk for cardiovascular disease when associated to dyslipidemia in periodontitis patients.

• Heat shock protein-60 and risk for cardiovascular disease.

  Authors: Manfredi Rizzo, Alberto J L Macario, Everly Conway de Macario, Ioanna Gouni-Berthold, Heiner K Berthold, Giovam Battista Rini, Giovanni Zummo, Francesco Cappello

  Current pharmaceutical design. 10/2011; 17(33):3662-8.

  Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. There is growing evidence that molecular chaperones, many of which are heat shock proteins HSPs, are involved inCardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. There is growing evidence that molecular chaperones, many of which are heat shock proteins HSPs, are involved in CVD pathogenesis. In this review we focus on HSP60, the human mitochondrial chaperone that also displays extramitochondrial and extracellular functions. HSP60 is typically cytoprotective but a number of stress conditions determine its conversion to a potentially toxic molecule for cells and tissues. We present illustrative examples of specific subtypes of CVD where HSP60 is implicated in the initiation and/or progression of disease. The data not only indicate a pathogenic role for HSP60 but also its potential as a biomarker with applications for diagnosis, assessing prognosis and response to treatment, as well as for preventing and treating CVD.

• Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction.

  Authors: Giuseppina Novo, Francesco Cappello, Manfredi Rizzo, Giovanni Fazio, Sabrina Zambuto, Enza Tortorici, Antonella M Gammazza, Simona Corrao, Giovanni Zummo, Everly C De Macario, Alberto J L Macario, Pasquale Assennato, Salvatore Novo, Giovanni Li Volti, Giovanni L Volti

  Translational research : the journal of laboratory and clinical medicine. 05/2011; 157(5):285-92.

  Heat shock proteins (Hsps) are produced in response to various stressors, including ischemia-reperfusion, and they can exit cells and reach the blood. In this pilot study, we determined serum levelsHeat shock proteins (Hsps) are produced in response to various stressors, including ischemia-reperfusion, and they can exit cells and reach the blood. In this pilot study, we determined serum levels of Hsp60 and heme-oxygenase-1 (HO-1; also named Hsp32) in subjects with acute myocardial infarction (AMI) to assess their clinical significance and potential prognostic value. We also performed a bioinformatics analysis of the 2 molecules in search of structural clues on the mechanism of their release from cells. We studied 40 patients consecutively admitted for AMI (male:female patient ratio=20:20, mean age: 64 ± 13 years) and 40 matched controls. A blood sample was drawn for biochemical analyses within 24 h of symptoms onset, and Hsp60 and HO-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA). All patients were followed up for 6 months to register adverse post-AMI cardiovascular events. A multivariate analysis demonstrated that elevated Hsp60 (P=0.0361), creatine phosphokinase-muscle brain (CK-MB) (P=0.0446), and troponin (P=0.0490) were predictive of post-AMI adverse events. In contrast, increased HO-1 showed a significant association with less severity of coronary artery diseases (P=0.0223). These findings suggest that Hsp60 and HO-1 play distinct roles in the pathogenesis of AMI and subsequent AMI-related pathology. The possibility that these proteins differ in their roles and mechanisms of action in AMI and post-AMI pathology was supported also by the bioinformatics estimates of probability of their localization in various subcellular compartments. The results clear the way for subsequent investigation on the pathogenetic role and clinical significance of Hsp60 and HO-1 in AMI.

• Changes in immunohistochemical levels and subcellular localization after therapy and correlation and colocalization with CD68 suggest a pathogenetic role of Hsp60 in ulcerative colitis.

  Authors: Giovanni Tomasello, Vito Rodolico, Monica Zerilli, Anna Martorana, Fabio Bucchieri, Alessandro Pitruzzella, Antonella Marino Gammazza, Sabrina David, Francesca Rappa, Giovanni Zummo, Provvidenza Damiani, Salvatore Accomando, Manfredi Rizzo, Everly Conway de Macario, Alberto J L Macario, Francesco Cappello

  Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry. 03/2011; 19(6):552-61.

  In an earlier work, the role of heat shock protein (Hsp60) in the pathogenesis of ulcerative colitis (UC) was suggested by its significant increase in the pathological mucosa parallel with anIn an earlier work, the role of heat shock protein (Hsp60) in the pathogenesis of ulcerative colitis (UC) was suggested by its significant increase in the pathological mucosa parallel with an increase in inflammatory cells. More data in this direction are reported in this work. We analyzed by immunohistochemistry biopsies of colon tissue from 2 groups of patients with UC and treated with either 5-aminosalicylic acid (5-ASA) alone or in combination with a probiotic. We looked for inflammatory markers and Hsp60. Both the treatments were effective in reducing symptoms but the group treated with both 5-ASA and probiotics showed better clinical results. Amelioration of symptoms was associated with reduction of both inflammation and Hsp60, a reduction that was most marked in the group treated with 5-ASA and probiotics. The levels of Hsp60 positively correlated with those of CD68-positive cells, and double immunofluorescence showed a high index of colocalization of the chaperonin and CD68 in lamina propria. Immunoelectron microscopy showed that Hsp60-classically a mitochondrial protein-was abundantly also present in cytosol in biopsies taken at the time of diagnosis, but not after the treatment. Our data suggest that Hsp60 is an active player in pathogenesis of UC and it can be hypothesized that the chaperonin is responsible, at least in part, for initiation and maintenance of disease.

• Immunohistochemistry of human Hsp60 in health and disease: from autoimmunity to cancer.

  Authors: Francesco Cappello, Everly Conway de Macario, Giovanni Zummo, Alberto J L Macario

  Methods in molecular biology (Clifton, N.J.). 01/2011; 787:245-54.

  Hsp60 (also called Cpn60) is a chaperonin with essential functions for cell physiology and survival. Additionally, its involvement in the pathogenesis of a number of diseases (e.g., some autoimmuneHsp60 (also called Cpn60) is a chaperonin with essential functions for cell physiology and survival. Additionally, its involvement in the pathogenesis of a number of diseases (e.g., some autoimmune disorders and cancer) is becoming evident with new research. For example, the distribution and levels of Hsp60 in cells and tissues have been found altered in many pathologic conditions, and the significance of these alterations is being investigated in a number of laboratories. The aim of this ongoing research is to determine the meaning of these Hsp60 alterations with regard to pathogenetic mechanisms, diagnosis, classification of lesions, and assessing of prognosis and response to treatment. Hsp60 occurs in the mitochondria, i.e., its typical residence according to classic knowledge, and also in other locales, such as the cytosol, the cell membrane, the intercellular space, and biological fluids (e.g., blood and cerebrospinal fluid). Detection and quantitative determinations in all these locations are becoming essential components of laboratory pathology in clinics and research. Consequently, immunohistochemistry targeting Hsp60 is also becoming essential for pathologists and researchers interested in disorders involving this chaperonin. In this chapter, we briefly summarize some recent discoveries on the participation of Hsp60 in the pathogenesis of human diseases and describe in detail how to perform immunohistochemical reactions for detecting the chaperonin, determining its location, and measuring its levels of expression.

• Hsp60: molecular anatomy and role in colorectal cancer diagnosis and treatment.

  Authors: Francesco Cappello, Sabrina David, Giovanni Peri, Felicia Farina, Everly Conway de Macario, Alberto J L Macario, Giovanni Zummo

  Frontiers in bioscience (Scholar edition). 01/2011; 3:341-51.

  Quantitative changes in Hsp60 during the development of some tumors suggest that this chaperonin plays a role in carcinogenesis. A description of the specific role(s) of Hsp60 in tumor-cell growthQuantitative changes in Hsp60 during the development of some tumors suggest that this chaperonin plays a role in carcinogenesis. A description of the specific role(s) of Hsp60 in tumor-cell growth and proliferation is still incomplete, but it is already evident that monitoring its levels and distribution in tissues and fluids has potential for diagnosis and staging, and for assessing prognosis and response to treatment. Although Hsp60 is considered an intramitochondrial protein, it has been demonstrated in the cytosol, cell membrane, vesicles, cell surface, extracellular space, and blood. The knowledge that Hsp60 occurs at all these locations opens new avenues for basic and applied research. It is clear that elucidating the mechanisms by which the chaperonin arrives at these various locations, and characterizing its functions in each of them will provide information useful for understanding carcinogenesis and for developing diagnostic and therapeutic tools for clinical oncology. Some of these issues pertinent to colorectal cancer (CRC) are discussed in this article.

• Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

  Authors: Francesco Cappello, Gaetano Caramori, Claudia Campanella, Chiara Vicari, Isabella Gnemmi, Andrea Zanini, Antonio Spanevello, Armando Capelli, Giampiero La Rocca, Rita Anzalone, Fabio Bucchieri, Silvestro Ennio D'Anna, Fabio L M Ricciardolo, Paola Brun, Bruno Balbi, Mauro Carone, Giovanni Zummo, Everly Conway de Macario, Alberto J L Macario, Antonino Di Stefano

  PloS one. 01/2011; 6(11):e28200.

  It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonaryIt is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H₂O₂. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H₂O₂ treatment in the absence of cell death. This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COPD.

• Giovanni Filippo Ingrassia: A five-hundred year-long lesson.

  Authors: Francesco Cappello, Aldo Gerbino, Giovanni Zummo

  Clinical anatomy (New York, N.Y.). 08/2010;

  Giovanni Filippo Ingrassia was born five centuries ago in Regalbuto, a small town in the center of Sicily. After his medical course in Padua, under the guidance of Vesalius and Fallopius, he gainedGiovanni Filippo Ingrassia was born five centuries ago in Regalbuto, a small town in the center of Sicily. After his medical course in Padua, under the guidance of Vesalius and Fallopius, he gained international fame as a physician and was recruited as a Professor of human anatomy in Naples and later in Palermo. He is remembered as "the new Galen" or "the Sicilian Hippocrates." He contributed to the knowledge of human anatomy through the description of single bones rather than the whole skeleton. In particular, he was the first to describe the "stapes," the "lesser wings of the sphenoid" and various other structures in the head (probably the pharyngotympanic tube) as well as in the reproductive system (corpora cavernosa and seminal vesicles). He was also a pioneer in the study of forensic medicine, hygiene, surgical pathology, and teratology. As Protomedicus of Sicily, he developed the scientific culture in this country. During those years, he faced the spread of malaria and plague with competence and authoritativeness. Indeed, he was one of the first physicians to suppose that certain diseases could be transmitted between individuals, therefore, introducing revolutionary measures of prevention. He is remembered for his intellectual authority and honesty. Five-hundred years after his birth, his teaching is still alive. In this article, we survey the life and contribution of this pioneer of early anatomical study. Clin. Anat., 2010. (c) 2010 Wiley-Liss, Inc.

• Chaperonopathies of senescence and the scrambling of interactions between the chaperoning and the immune systems.

  Authors: Alberto J L Macario, Francesco Cappello, Giovanni Zummo, Everly Conway de Macario

  Annals of the New York Academy of Sciences. 06/2010; 1197:85-93.

  Aging entails progressive deterioration of molecules and supramolecular structures, including Hsp chaperones and their complexes, paralleled by functional decline. Recent research has changed ourAging entails progressive deterioration of molecules and supramolecular structures, including Hsp chaperones and their complexes, paralleled by functional decline. Recent research has changed our views on Hsp chaperones. They work inside and outside cells in many locations, alone or forming teams, interacting with cells, receptors, and molecules that are not chaperones, in roles that are not typically attributed to chaperones, such as protein folding. Hsp chaperones form a physiological system with a variety of functions and interactions with other systems, for example, the immune system. We propose that chaperone malfunctioning due to structural damage or gene dysregulation during aging has an impact on the immune system, creating the conditions for an overall malfunction of both systems. Pathological chaperones cannot interact with the immune system as normal ones do, and this leads to an overall readjustment of the interactions that is apparent during senescence and is likely to cause many of its manifestations.

• Hsp60 and Hsp10 increase in colon mucosa of Crohn’s disease and ulcerative colitis.

  Authors: Vito Rodolico, Giovanni Tomasello, Monica Zerilli, Anna Martorana, Alessandro Pitruzzella, Antonella Marino Gammazza, Sabrina David, Giovanni Zummo, Provvidenza Damiani, Salvatore Accomando, Everly Conway de Macario, Alberto J L Macario, Francesco Cappello

  Cell stress & chaperones. 04/2010; 15(6):877-84.

  The purpose of this work was to determine in colon mucosa of Crohn’s disease (CD) and ulcerative colitis (UC) in relapse: a) the levels of the chaperonins Hsp60 and Hsp10; b) the quantity ofThe purpose of this work was to determine in colon mucosa of Crohn’s disease (CD) and ulcerative colitis (UC) in relapse: a) the levels of the chaperonins Hsp60 and Hsp10; b) the quantity of inflammatory cells; and c) if the levels of chaperonins parallel those of inflammation cells. Twenty cases of CD and UC and twenty normal controls (NC) were studied using immunohistochemistry, Western blotting and immunofluorescence. Immunohistochemically, Hsp60 and Hsp10 were increased in both inflammatory bowel diseases (IBD) compared to NC. These results were confirmed by Western blotting. Hsp60 and Hsp10 occurred in the cytoplasm of epithelial cells in CD and UC but not in NC. Hsp60 and Hsp10 co-localised to epithelial cells of mucosal glands but not always in connective tissue cells of lamina propria, where only Hsp60 or, less often, Hsp10 was found. Cells typical of inflammation were significantly more abundant in CD and UC than in NC. Since chaperonins are key factors in the activation of the immune system leading to inflammation, we propose that they play a central role in the pathogenesis of the two diseases, which, consequently, ought to be studied as chaperonopathies.

• Adult stem cells, scaffolds for in vivo and in vitro myocardial tissue engineering.

  Authors: Valentina Di Felice, Angela De Luca, Claudia Serradifalco, Patrizia Di Marco, Lucia Verin, Antonella Motta, Annalisa Guercio, Giovanni Zummo

  Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia. 01/2010; 115(1-2):65-9.

  The main goal in the last few years in cardiac research has been to isolate cardiac potential stem cells from adult myocardium and to demonstrate their differentiation potential. We have previouslyThe main goal in the last few years in cardiac research has been to isolate cardiac potential stem cells from adult myocardium and to demonstrate their differentiation potential. We have previously demonstrated that c-Kit positive cardiac stem cells are able to organize themselves into a tissue-like cell mass. In this 3D mass, they can produce a high concentration of natural extracellular matrix, can create vessels, a capsule and, with the help of an Open-pore Polylactic Acid scaffold, many cells can organize an elementary myocardium. Drawing from this background, we decided to design and use poly-lactic scaffolds and the model of the athymic Nude-Foxn1(nu) mouse to evaluate the extent of the myogenic vs endothelial differentiation in vivo, and to evaluate the presence or the absence of a foreign body reaction.

• Hsp60 is actively secreted by human tumor cells.

  Authors: Anna M Merendino, Fabio Bucchieri, Claudia Campanella, Vito Marcianò, Anna Ribbene, Sabrina David, Giovanni Zummo, Giosalba Burgio, Davide F V Corona, Everly Conway de Macario, Alberto J L Macario, Francesco Cappello

  PloS one. 01/2010; 5(2):e9247.

  Hsp60, a Group I mitochondrial chaperonin, is classically considered an intracellular chaperone with residence in the mitochondria; nonetheless, in the last few years it has been foundHsp60, a Group I mitochondrial chaperonin, is classically considered an intracellular chaperone with residence in the mitochondria; nonetheless, in the last few years it has been found extracellularly as well as in the cell membrane. Important questions remain pertaining to extracellular Hsp60 such as how generalized is its occurrence outside cells, what are its extracellular functions and the translocation mechanisms that transport the chaperone outside of the cell. These questions are particularly relevant for cancer biology since it is believed that extracellular chaperones, like Hsp70, may play an active role in tumor growth and dissemination. Since cancer cells may undergo necrosis and apoptosis, it could be possible that extracellular Hsps are chiefly the result of cell destruction but not the product of an active, physiological process. In this work, we studied three tumor cells lines and found that they all release Hsp60 into the culture media by an active mechanism independently of cell death. Biochemical analyses of one of the cell lines revealed that Hsp60 secretion was significantly reduced, by inhibitors of exosomes and lipid rafts. Our data suggest that Hsp60 release is the result of an active secretion mechanism and, since extracellular release of the chaperone was demonstrated in all tumor cell lines investigated, our observations most likely reflect a general physiological phenomenon, occurring in many tumors.

• New emerging potentials for human Wharton's jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity.

  Authors: Rita Anzalone, Melania Lo Iacono, Simona Corrao, Francesca Magno, Tiziana Loria, Francesco Cappello, Giovanni Zummo, Felicia Farina, Giampiero La Rocca

  Stem cells and development. 12/2009;

  In recent years, human mesenchymal stem cells (MSC) have been extensively studied. Their key characteristics of long-term self-renewal and a capacity to differentiate into diverse mature tissuesIn recent years, human mesenchymal stem cells (MSC) have been extensively studied. Their key characteristics of long-term self-renewal and a capacity to differentiate into diverse mature tissues favour their use in regenerative medicine applications. Stem cells can be found in embryonic and extra-embryonic tissues as well as in adult organs. Several reports indicate that cells of Wharton's jelly (WJ), the main component of umbilical cord extracellular matrix, are multipotent stem cells, expressing markers of bone marrow mesenchymal stem cells (BM-MSC), and giving rise to different cellular types of both connective and nervous tissues. Wharton's jelly mesenchymal stem cells (WJ-MSC) express markers previously characterized in embryonic stem cells (ESC), such as Nanog and Oct3/4A. WJ-MSC further emerge as promising hypoimmunogenic cells, due to the expression of molecules able to modulate NK cells and expand regulatory T cells populations. Moreover, it is now accepted that the differentiative capacities of such cells span all the mesoderm-derived tissues, extending to neuroectodermal as well as endodermal lineages. In this review we compare very recent data on the potential of WJ-MSC to undergo hepatocyte-like differentiation with the results obtained from other adult MSC populations. Data in the literature strongly suggest that WJ-MSC can differentiate into diverse cell types, showing a unique ability to cross lineage borders. This, together with their in vitro proliferative potential and their immunoregulatory features, renders these cells extremely promising for regenerative medicine applications in different pathological settings.

• Human Hsp10 and early pregnancy factor (EPF) and their relationship and involvement in cancer and immunity: Current knowledge and perspectives.

  Authors: Simona Corrao, Claudia Campanella, Rita Anzalone, Felicia Farina, Giovanni Zummo, Everly Conway de Macario, Alberto J L Macario, Francesco Cappello, Giampiero La Rocca

  Life sciences. 11/2009;

  This article is about Hsp10 and its intracellular and extracellular forms focusing on the relationship of the latter with Early Pregnancy Factor and on their roles in cancer and immunity. CellularThis article is about Hsp10 and its intracellular and extracellular forms focusing on the relationship of the latter with Early Pregnancy Factor and on their roles in cancer and immunity. Cellular physiology and survival are finely regulated and depend on the correct functioning of the entire set of proteins. Misfolded or unfolded proteins can cause deleterious effects and even cell death. The chaperonins Hsp10 and Hsp60 act together inside the mitochondria to assist protein folding. Recent studies demonstrated that these proteins have other roles inside and outside the cell, either together or independently of each other. For example, Hsp10 was found increased in the cytosol of different tumors (although in other tumors it was found decreased). Moreover, Hsp10 localizes extracellularly during pregnancy and is often indicated as Early Pregnancy Factor (EPF), which is released during the first stages of gestation and is involved in the establishment of pregnancy. Various reports show that extracellular Hsp10 and EPF modulate certain aspects of the immune response with anti-inflammatory effects in patients with autoimmune conditions improving clinically after treatment with recombinant Hsp10. Moreover, Hsp10 and EPF are involved in embryonic development, acting as a growth factor, and in cell proliferation/differentiation mechanisms. Therefore, it becomes evident that Hsp10 is not only a co-chaperonin, but an active player in its own right in various cellular functions. In this article, we present an overview of various aspects of Hsp10 and EPF as they participate in physiological and pathological processes such as the antitumor response and autoimmune diseases.

• OPLA scaffold, collagen I, and horse serum induce an higher degree of myogenic differentiation of adult rat cardiac stem cells.

  Authors: Valentina Di Felice, Nella Maria Ardizzone, Angela De Luca, Vito Marcianò, Antonella Marino Gammazza, Filippo Macaluso, Lucrezia Manente, Francesco Cappello, Antonio De Luca, Giovanni Zummo

  Journal of cellular physiology. 10/2009;

  In the last few years, a major goal of cardiac research has been to drive stem cell differentiation to replace damaged myocardium. Several research groups have attempted to differentiate potentialIn the last few years, a major goal of cardiac research has been to drive stem cell differentiation to replace damaged myocardium. Several research groups have attempted to differentiate potential cardiac stem cells (CSCs) using bi- or three-dimensional systems supplemented with growth factors or molecules acting as differentiating substances. We hypothesize that these systems failed to induce a complete differentiation because they lacked an architectural space. In the present study, we isolated a pool of small proliferating and fibroblast-like cells from adult rat myocardium. The phenotype of these cells was assessed and the characterized cells were cultured in a collagen I/OPLA scaffold with horse serum to obtain fine myocardial differentiation. C-Kit(POS)/Sca-1(POS) CSCs fully differentiated in vitro when an environment more similar to the CSC niche was created. These experiments demonstrated an important model for the study of the biology of CSCs and the biochemical pathways that lead to myocardial differentiation. The results pave the way for a new surgical approach. J. Cell. Physiol. (c) 2009 Wiley-Liss, Inc.

• Chlamydia trachomatis infection and anti-Hsp60 immunity: the two sides of the coin.

  Authors: Francesco Cappello, Everly Conway de Macario, Valentina Di Felice, Giovanni Zummo, Alberto J L Macario

  PLoS pathogens. 09/2009; 5(8):e1000552.

  Chlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As aChlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As a consequence, immune cells will produce anti-CT-Hsp60 antibodies. Hsp60, a ubiquitous and evolutionarily conserved chaperonin, is normally sequestered inside the cell, particularly into mitochondria. However, upon cell stress, as well as during carcinogenesis, the chaperonin becomes exposed on the cell surface (sf-Hsp60) and/or is secreted from cells into the extracellular space and circulation. Reports in the literature on circulating Hsp and anti-Hsp antibodies are in many cases short on details about Hsp60 concentrations, and about the specificity spectra of the antibodies, their titers, and their true, direct, pathogenetic effects. Thus, more studies are still needed to obtain a definitive picture on these matters. Nevertheless, the information already available indicates that the concurrence of persistent CT infection and appearance of sf-Hsp60 can promote an autoimmune aggression towards stressed cells and the development of diseases such as autoimmune arthritis, multiple sclerosis, atherosclerosis, vasculitis, diabetes, and thyroiditis, among others. At the same time, immunocomplexes composed of anti-CT-Hsp60 antibodies and circulating Hsp60 (both CT and human) may form deposits in several anatomical locations, e.g., at the glomerular basal membrane. The opposite side of the coin is that pre-tumor and tumor cells with sf-Hsp60 can be destroyed with participation of the anti-Hsp60 antibody, thus stopping cancer progression before it is even noticed by the patient or physician.

• Tetralogy of fallot as a model to study cardiac progenitor cell migration and differentiation during heart development.

  Authors: Valentina Di Felice, Giovanni Zummo

  Trends in cardiovascular medicine. 05/2009; 19(4):130-5.

  Tetralogy of Fallot (ToF) has long been considered a congenital disorder that occurs due to environmental alterations during gestation. Recently, several mutated genes have been discovered that areTetralogy of Fallot (ToF) has long been considered a congenital disorder that occurs due to environmental alterations during gestation. Recently, several mutated genes have been discovered that are thought to be responsible for the malformations observed in ToF. These genetic mutations, which are microdeletions, are sporadic and are frequently also present in trisomy 21 patients. The ToF malformations can be lethal, but for the last 50 years, surgical repairs that place an artificial patch to repair the four features of ToF have improved the survival of patients with ToF. However, 0.5% to 6% of patients who survive after surgical repair of ToF die of sudden cardiac death caused by ventricular tachycardia. In fact, even if the septum has been repaired, the patch used to close the interventricular defect may cause deformation of the heart, altering the force lines essential for normal function of the right ventricle. In the present review, we hypothesize that mutations in the GATA binding protein 4 (GATA-4)/friend of GATA-2 transcriptional complex and NKX2.5 gene may play a role in the abnormal migration and behavior of precardiac cells during heart development in patients with ToF. An understanding of cardiac precursor cell behavior is needed in order for future research regarding therapeutic approaches to correct the defects seen in ToF without affecting cardiac hemodynamics to be successful.

• Cardiac Stem Cell Research: An Elephant in the Room?

  Authors: Valentina Di Felice, Angela De Luca, Maria Luisa Colorito, Antonella Montalbano, Nella Maria Ardizzone, Filippo Macaluso, Antonella Marino Gammazza, Francesco Cappello, Giovanni Zummo

  Anatomical record (Hoboken, N.J. : 2007). 03/2009; 292(3):449-454.

  Heart disease is the leading cause of death in the industrialized world, and stem cell therapy seems to be a promising treatment for injured cardiac tissue. To reach this goal, the scientificHeart disease is the leading cause of death in the industrialized world, and stem cell therapy seems to be a promising treatment for injured cardiac tissue. To reach this goal, the scientific community needs to find a good source of stem cells that can be used to obtain new myocardium in a very period range of time. Since there are many ethical and technical problems with using embryonic stem cells as a source of cells with cardiogenic potential, many laboratories have attempted to isolate potential cardiac stem cells from several tissues. The best candidates seem to be cardiac "progenitor" and/or "stem" cells, which can be isolated from subendocardial biopsies from the same patient or from embryonic and/or fetal myocardium. Regardless of the technique used to isolate and characterize these cells, it appears that the different cells isolated from adult myocardium to date are all phenotypic variations of a unique cell type that expresses several markers, such as c-Kit, CD34, MDR-1, Sca-1, CD45, nestin, or Isl-1, in various combinations. Anat Rec, 292:449-454, 2009. (c) 2009 Wiley-Liss, Inc.

• Role of endothelial cell stress in the pathogenesis of chronic heart failure.

  Authors: Rita Anzalone, Giampiero La Rocca, Antonino Di Stefano, Francesca Magno, Simona Corrao, Marco Carbone, Tiziana Loria, Melania Lo Iacono, Ermanno Eleuteri, Marilena Colombo, Francesco Cappello, Felicia Farina, Giovanni Zummo, Pantaleo Giannuzzi

  Frontiers in bioscience : a journal and virtual library. 02/2009; 14:2238-47.

  Endothelial cells are key modulators of diverse physiological processes, and their impaired function is a cause of numerous cardiovascular diseases. Under physiologic condition, the reactive oxygenEndothelial cells are key modulators of diverse physiological processes, and their impaired function is a cause of numerous cardiovascular diseases. Under physiologic condition, the reactive oxygen and nitrogen mediators in endothelia lead to the signal propagation of the initial stimulus, by forming molecules with a longer half-life like hydrogen peroxide. Hydrogen peroxide is the focus of growing attention in endothelial biology, and consequently the enzymes involved in its generation and clearance are viewed as novel mediators of great importance. In particular, among peroxidases, myeloperoxidase is recognized as a key enzyme, capable of impairing intracellular NO reservoirs as well as producing oxidized amino acids such as 3-chlorotyrosine or 3-nitrotyrosine. This process switches the functional pathways from normal signalling to a condition characterized by oxidative and/or nitrosative stress. Understanding the molecular mechanisms involved in these stress responses in endothelium will lead to better therapeutic strategies for oxidative stress-driven cardiovascular diseases.