62 results on '"Listì, F"'
Search Results
2. Effects of in vitro treatment with fluticasone propionate on natural killer and lymphokine‐induced killer activity in asthmatic and healthy individuals
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Di Lorenzo, G., primary, Esposito Pellitteri, M., additional, Drago, A., additional, Di Blasi, P., additional, Candore, G., additional, Balistreri, C., additional, Listì, F., additional, and Caruso, C., additional
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- 2001
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3. Biology of longevity: role of the innate immune system.
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Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listì F, Nuzzo D, Vasto S, Lio D, and Caruso C
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- 2006
4. Memory B cell subpopulations in the aged.
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Colonna-Romano G, Aquino A, Bulati M, Di Lorenzo G, Listì F, Vitello S, Lio D, Candore G, Clesi G, and Caruso C
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- 2006
5. Association between the HLA-A2 allele and Alzheimer disease.
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Listì F, Candore G, Balistreri CR, Grimaldi MP, Orlando V, Vasto S, Colonna-Romano G, Lio D, Licastro F, Franceschi C, and Caruso C
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- 2006
6. Immune-inflammatory responses in successful and unsuccessful ageing,Risposte immuno-infiammatorie nell'invecchiamento di e senza successo
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Candore, G., Carmela Rita Balistreri, Bulati, M., Colonna-Romano, G., Bona, D. D. I., Forte, G. I., Lio, D., Listì, F., Pellicanò, M., Scola, L., Vasto, S., and Caruso, C.
7. Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
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Daniela Galimberti, Federica Esposito, Benedetta Nacmias, Michele Mishto, Claudio Franceschi, Sandra D'Alfonso, Elio Scarpini, Elena Cellini, Ulrike Seifert, C. Ligorio, Peter M. Kloetzel, Maurizio Leone, Mara Giordano, Filippo Martinelli-Boneschi, Aurelia Santoro, Maria Pia Amato, Florinda Listì, Chiara Fenoglio, Calogero Caruso, Elena Bellavista, Kathrin Textoris-Taube, Luigi M.E. Grimaldi, Maria Pia Foschini, Mishto M., Bellavista E., Ligorio C., Textoris-Taube K., Santoro A., Giordano M., D'Alfonso S., Listì F., Nacmias B., Cellini E., Leone M., Grimaldi L.M., Fenoglio C., Esposito F., Martinelli-Boneschi F., Galimberti D., Scarpini E., Seifert U., Amato M.P., Caruso C., Foschini M.P., Kloetzel P.M., Franceschi C., Mishto, M, Bellavista, E, Ligorio, C, Textoris-Taube, K, Santoro, A, Giordano, M, D’Alfonso, S, Listì, F, Nacmias, B, Cellini, E, Leone, M, Grimaldi, LME, Fenoglio, C, Esposito, F, Martinelli-Boneschi, F, Galimberti, D, Scarpini, E, Seifert, U, Amato, MP, Caruso, C, Foschini, MP, Kloetze, PM, and Franceschi, C
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Male ,T cells, proteasomes, multiple sclerosis, parietal lobe ,Muscle Proteins ,Immunoproteasome ,Epitope ,Epitopes ,Gene Frequency ,Risk Factors ,Cytotoxic T cell ,Funding: This work was financed in part by the grant Giovani Ricercatori 2007 from Italian Ministry of Health to MM, DG and FMB, by a grant from the European Commission Integrated Project PROTEOMAGE (FP6) to CF, by the finalized projects of Fondazione Italiana Sclerosi Multipla (FISM) cod. 2003/R26 and BioPharmaNet to CF and 2002/R/40 and 2005/R/10, 2008/R/11 (Genoa) to SD'A, by the University of Bologna (FRO) to MPF, by the Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project) to SD'A, by Associazione Amici del Centro Dino Ferrari and IRCCS Ospedale Maggiore Policlinico, Milano to DG and by the grants Sonderforschungsbereich (SFB-507, SFB-421) to PMK and US, the grants TR43 and Neurocure to PMK. MM benefited from the A.V. Humboldt PostDoc fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript ,Multidisciplinary ,Microglia ,Brain ,Middle Aged ,Immunohistochemistry ,Cysteine Endopeptidases ,Oligodendroglia ,medicine.anatomical_structure ,Italy ,multiple sclerosis ,italian population ,multiple sclerosi ,Immunology/Antigen Processing and Recognition ,Medicine ,Female ,Neuroscience/Neurobiology of Disease and Regeneration ,Research Article ,Protein Binding ,Adult ,Proteasome Endopeptidase Complex ,Multiple Sclerosis ,Genotype ,Science ,Molecular Sequence Data ,Immunology/Autoimmunity ,Biology ,Sex Factors ,MHC class I ,HLA-A2 Antigen ,medicine ,Humans ,Amino Acid Sequence ,Allele ,HLA-A Antigens ,Multiple sclerosis ,Macrophages ,Myelin Basic Protein ,medicine.disease ,Myelin basic protein ,Immunology ,biology.protein ,CD8 - Abstract
BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119).Conclusion/significanceThe immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.
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- 2010
8. Role of cyclooxygenae-2 and 5-lypoxygenase polymorphisms in Alzheimer's disease in a population from northern Italy:implications for pharmacogenomics
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Giuseppina Candore, Domenico Lio, Florinda Listì, Martina Chiappelli, Calogero Caruso, Giuseppina Colonna-Romano, Federico Licastro, Listì,F, Caruso,C, Lio,D, Colonna-Romano,G, Chiappelli,M, Licastro,F, Candore,G, Listì F, Caruso C, Lio D, Colonna-Romano G, Chiappelli M, Licastro F, and Candore G.
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Male ,Genotype ,Population ,Single-nucleotide polymorphism ,Disease ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Alzheimer's disease,COX-2, 5-LO, pharmacogenomics ,Gene Frequency ,Population Groups ,Alzheimer Disease ,Genetic variation ,SNP ,Humans ,Settore MED/05 - Patologia Clinica ,Genetic Predisposition to Disease ,Allele ,Age of Onset ,education ,Aged ,Aged, 80 and over ,Settore MED/04 - Patologia Generale ,education.field_of_study ,Arachidonate 5-Lipoxygenase ,General Neuroscience ,General Medicine ,Middle Aged ,Psychiatry and Mental health ,Clinical Psychology ,Italy ,Cyclooxygenase 2 ,Pharmacogenomics ,Female ,Geriatrics and Gerontology - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distribution of the �765G COX-2 and �1708A 5-LO alleles between AD cases and controls (p = 0.03 for �765G/C COX-2 SNP; and p = 0.007 for �1708G/A 5-LO SNP). Hence, COX-2 �765G and 5-LO �1708A alleles were overrepresented in AD patients and underrepresented in controls. Our data suggest that these alleles of COX-2 and 5-LO could be risk factors for AD. These results seem of some importance for a pharmacogenomic approach.
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- 2010
9. Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease
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Federico Licastro, Maria Paola Grimaldi, Carmela Rita Balistreri, Calogero Caruso, Domenico Lio, Sonya Vasto, Giuseppina Candore, Florinda Listì, Martina Chiappelli, Laura Castiglia, Balistreri CR, Grimaldi MP, Chiappelli M, Licastro F, Castiglia L, Listì F, Vasto S, Lio D, Caruso C, Candore G., BALISTRERI, CR, GRIMALDI, MP, CHIAPPELLI M, LICASTRO F, CASTIGLIA L, LISTÌ F, VASTO S, LIO D, CARUSO C, and CANDORE G
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Male ,ALZHEIMER'S DISEASE,INFLAMMATION,INNATE IMMUNITY,TLR4,CD14 ,Lipopolysaccharide Receptors ,Inflammation ,Single-nucleotide polymorphism ,Disease ,Systemic inflammation ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,Degenerative disease ,INFLAMMATION ,Alzheimer Disease ,Risk Factors ,Drug Discovery ,medicine ,Dementia ,SNP ,Humans ,TLR4 ,Aged ,Pharmacology ,Aged, 80 and over ,business.industry ,Middle Aged ,medicine.disease ,Toll-Like Receptor 4 ,Italy ,ALZHEIMER'S DISEASE ,Immunology ,INNATE IMMUNITY ,Female ,medicine.symptom ,Alzheimer's disease ,business ,CD14 - Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.
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- 2008
10. LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects
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Florinda Listì, Calogero Caruso, Giuseppina Colonna-Romano, Domenico Lio, Carmela Rita Balistreri, Giuseppina Candore, Balistreri, CR, Caruso, C, Listì, F, Colonna Romano, G, Lio, D, and Candore, G
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Adult ,Lipopolysaccharides ,Male ,Aging ,Ageing Cytokines Eicosanoids Genetics Inflammation Longevity TLR4 ,Population ,Inflammation ,Single-nucleotide polymorphism ,Biology ,Leukotriene B4 ,Polymorphism, Single Nucleotide ,Dinoprostone ,medicine ,Humans ,SNP ,education ,Receptor ,Settore MED/04 - Patologia Generale ,education.field_of_study ,Middle Aged ,Toll-Like Receptor 4 ,Italy ,Eicosanoid ,Immunology ,TLR4 ,Cytokines ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Developmental Biology ,Eicosanoid Production - Abstract
Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load.
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- 2011
11. Gender-Related Immune-Inflammatory Factors, Age-Related Diseases, and Longevity
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Giuseppina Colonna-Romano, Giuseppina Candore, Carmela Rita Balistreri, Calogero Caruso, Domenico Lio, Sonya Vasto, Florinda Listì, Candore, G, Balistreri, CR, Colonna Romano, G, Lio, D, Listì, F, Vasto, S, and Caruso, C
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Male ,Gerontology ,Aging ,media_common.quotation_subject ,Longevity ,Disease ,gender, inflammation, age-related diseases, longevity ,Immune system ,Alzheimer Disease ,Animals ,Humans ,Immunologic Factors ,Settore MED/05 - Patologia Clinica ,media_common ,Settore MED/04 - Patologia Generale ,Sex Characteristics ,Estrogen Replacement Therapy ,Social constructionism ,Gender psychology ,Sexual dimorphism ,Immune System ,Female ,Inflammation Mediators ,Geriatrics and Gerontology ,Psychology ,Sex characteristics ,Hormone ,Clinical psychology - Abstract
This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer’s disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but rather a question of ‘‘socially constructed sex,’’ a question of gender (i.e., the characteristics that a society or culture delineates as masculine or feminine). In gender medicine, we conclude that it is important to consider the role played both by hormones, customs, and educational levels regarding the different propensity of males and females to fall ill. So, in programming antiaging strategies, we have also to take these aspects into account
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- 2010
12. Genetics of longevity. Data from the studies on Sicilian centenarians
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Matteo Bulati, Marisa Palmeri, Silvio Buffa, M Bova, Loredana Vaccarino, Domenico Lio, Giuseppina Colonna-Romano, Mariavaleria Pellicanò, Giusi Irma Forte, Carmela Rita Balistreri, Giulia Accardi, Giuseppina Candore, Florinda Listì, Letizia Scola, Adriana Martorana, Balistreri, CR, Candore, G, Accardi, G, Bova, V, Buffa, S, Bulati, M, Forte, GI, Listì, F, Martorana, A, Palmeri, M, Pellicanò, M, Vaccarino, L, Scola, L, Lio, D, and Colonna-Romano G
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lcsh:Immunologic diseases. Allergy ,Epigenomics ,Gerontology ,Aging ,medicine.medical_specialty ,Future studies ,Immune system, Genetics, Pro/anti-inflammatory polymorphisms, Epigenomics ,media_common.quotation_subject ,Immunology ,lcsh:Geriatrics ,Biology ,Genetics ,medicine ,Settore MED/05 - Patologia Clinica ,Epigenetics ,Inflammatory genes ,media_common ,Research ,Public health ,Longevity ,Ageing ,lcsh:RC952-954.6 ,Immune system ,Pro/anti-inflammatory polymorphisms ,Life expectancy ,lcsh:RC581-607 - Abstract
The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.
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- 2012
13. A Pilot Study on Prostate Cancer Risk and Pro-Inflammatory Genotypes: Pathophysiology and Therapeutic Implications
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Carmela Rita Balistreri, Calogero Caruso, Florinda Listì, Giuseppe Carruba, Ildegarda Campisi, Vitale Miceli, Domenico Lio, Giuseppina Candore, Giuseppina Colonna-Romano, Balistreri, CR, Caruso, C, Carruba, G, Miceli, V, Campisi, I, Listì, F, Lio, D, Colonna Romano, G, and Candore, G
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Male ,Candidate gene ,Genotype ,Pilot Projects ,Single-nucleotide polymorphism ,Bioinformatics ,Polymorphism, Single Nucleotide ,Prostate cancer ,Risk Factors ,Drug Discovery ,medicine ,Humans ,SNP ,Settore MED/05 - Patologia Clinica ,Gene ,Aged ,Aged, 80 and over ,Inflammation ,Pharmacology ,Settore MED/04 - Patologia Generale ,business.industry ,Prostatic Neoplasms ,Cancer ,Middle Aged ,Prostate cancer (PC), inflammation, genetics, TLR4, TLR2, PTGS2, 5-LO, SNP ,medicine.disease ,Immunology ,TLR4 ,Inflammation Mediators ,business - Abstract
Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and treatment of PC, we have investigated the potential role of common SNPs of a gene cluster (TLR4, TLR2, PTGS2 and 5-Lo), involved in innate and inflammatory response, in PC cases, age-matched controls and centenarians from Sicily. Six SNPs were genotyped and their association with PC risk determined. Statistical analysis evidenced a significant association of some pro-inflammatory gene SNPs with an increased risk of PC. Furthermore, significant differences were observed comparing the three groups in the combined presence of a "high responder" pro-inflammatory profile. Overall, the present results suggest the likely association of these SNPs and PC risk, clearly motivating the need of larger studies to confirm the role of these genes in PC development and/or progression.
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- 2010
14. HLA and KIR Frequencies in Sicilian Centenarians
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Giuseppina Candore, Giuseppina Colonna-Romano, Calogero Caruso, Florinda Listì, Domenico Lio, Domenico Nuzzo, Listì,F, Caruso,C, Colonna-Romano,G, Lio,D, Nuzzo,D, and Candore,G
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Male ,Aging ,media_common.quotation_subject ,Longevity ,Population ,chemical and pharmacologic phenomena ,Human leukocyte antigen ,Biology ,HLA-B8 Antigen ,Immune system ,Gene Frequency ,Receptors, KIR ,Humans ,Settore MED/05 - Patologia Clinica ,Allele ,Receptor ,education ,Sicily ,Gene ,Alleles ,media_common ,Aged, 80 and over ,Genetics ,Settore MED/04 - Patologia Generale ,education.field_of_study ,Haplotype ,HLA-DR Antigens ,HLA, KIR, successful ageing ,Case-Control Studies ,Immunology ,Female ,Geriatrics and Gerontology ,HLA-DRB1 Chains - Abstract
Several studies suggest that human longevity appears to be linked inextricably with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in loci that regulate the immune response, as human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genes. It has been suggested that longevity is associated with positive selection of alleles (i.e., HLA-DR11) or haplotypes (i.e., HLA-B8,DR3) that confer resistance to infectious disease(s). On the other hand, the cytolytic activity of natural killer (NK) cells is controlled by activating and inhibitory cell-surface receptors, including KIR. The genetic diversity of the KIR loci with respect to successful aging has been analyzed only in one study performed in the Irish population. Although two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. We have evaluated by polymerase chain reaction-sequence-specific primers (PCR-SSP) HLA-DRB1 and KIR receptors/HLA ligands frequencies in centenarians and controls from Sicily. Our results demonstrate an increase of the HLA DRB1*18 allele in male centenarians (p = 0.0266, after Bonferroni correction). Concerning KIR, no significant difference was observed after Bonferroni correction. However, our findings suggest that HLA/KIR/longevity associations are population specific, being heavily affected by the population-specific genetic and environmental history. This kind of study is important to better understand aging and longevity, hence enhancing the planning of antiaging strategies.
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- 2010
15. Immune-inflammatory responses in successful and unsuccessful ageing
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CANDORE, Giuseppina, BALISTRERI, Carmela Rita, BULATI, Matteo, COLONNA ROMANO, Giuseppina, FORTE, Giusi Irma, LIO, Domenico, LISTI', Florinda, PELLICANO', Mariavaleria, SCOLA, Letizia, VASTO, Sonya, CARUSO, Calogero, Di Bona, D, Candore, G, Balistreri, CR, Bulati, M, Colonna-Romano, G, Di Bona, D, Forte, GI, Lio, D, Listì, F, Pellicanò, M, Scola, L, Vasto, S, and Caruso, C
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Inflammation ,Settore MED/04 - Patologia Generale ,Ageing ,Immunogenetics - Abstract
A dramatic increase in mean life span and life expectancy, coupled with a significant reduction in early mortality, has lead to a large increase in number of elderly people in modern societies. This demographic phenomenon has been paralleled by an epidemic of chronic diseases associated with advancing age. Both innate and instructive immunity are implicated in almost all age-related diseases. The modifications of the immune system in the elderly are evaluated as a deterioration of the immune system, the so-called immunosenescence, which is thought to be mostly the result of the declining effectiveness of T cells and it is responsible for the increased susceptibility of elderly to infectious diseases. In addition, a low-grade systemic inflammation characterizes ageing and inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and inflammatory age-related diseases are initiated or worsened by systemic inflammation.
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- 2009
16. Inflammation, genes and zinc in Alzheimer's disease
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Danilo Di Bona, Domenico Lio, Marco Malavolta, Domenico Nuzzo, Carmela Rita Balistreri, Giuseppina Colonna-Romano, Calogero Caruso, Eugenio Mocchegiani, Giuseppina Candore, Sonya Vasto, Florinda Listì, VASTO, S, CANDORE, G, LISTÌ, F, BALISTRERI, CR, COLONNA-ROMANO, G, MALAVOLTA, M, LIO, D, NUZZO, D, MOCCHEGIANI, E, DI BONA, D, and CARUSO, C
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BACE1-AS ,Inflammation ,Biology ,Models, Biological ,Biological pathway ,Apolipoproteins E ,Alzheimer Disease ,mental disorders ,medicine ,Animals ,Humans ,Senile plaques ,Inflammation, genes, zinc ,Alzheimer's disease ,Settore MED/04 - Patologia Generale ,Amyloid beta-Peptides ,General Neuroscience ,P3 peptide ,medicine.disease ,Phenotype ,Biochemistry of Alzheimer's disease ,Zinc ,Cholesterol ,Immunology ,Cytokines ,Neurology (clinical) ,Alzheimer's disease ,medicine.symptom - Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.
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- 2007
17. Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity
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Florinda Listì, Maria Paola Grimaldi, Marco Caruso, Enrico Hoffmann, Giuseppe Paolisso, Giuseppina Colonna-Romano, Valentina Orlando, Domenico Lio, Giuseppina Candore, Claudio Franceschi, Calogero Caruso, Listì F., Candore G., Grimaldi M.P., Lio D., Colonna-Romano G., Orlando V., Caruso M., Hoffmann E., Paolisso G., Franceschi C., Caruso C., Listi, F, Candore, G, Grimaldi, Mp, Lio, D, COLONNA ROMANO, G, Orlando, V, Caruso, M, Hoffmann, E, Paolisso, Giuseppe, Franceschi, C, Caruso, C., LISTi' F, CANDORE G, GRIMALDI MP, LIO D, COLONNA-ROMANO G, ORLANDO V, CARUSO M, HOFFMANN E, PAOLISSO G, FRANCESCHI C, and CARUSO C
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Senescence ,Adult ,Male ,medicine.medical_specialty ,Aging ,Heterozygote ,media_common.quotation_subject ,Population ,Longevity ,Myocardial Infarction ,Biology ,Gastroenterology ,Risk Assessment ,Loss of heterozygosity ,Cohort Studies ,Gene Frequency ,Risk Factors ,AAT, Serine-protease inhibitor, AMI, Longevity, Centenarians ,Internal medicine ,Genotype ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Allele ,Risk factor ,education ,Allele frequency ,Sicily ,media_common ,Settore MED/04 - Patologia Generale ,Genetics ,Aged, 80 and over ,education.field_of_study ,Middle Aged ,Settore MED/11 - Malattie Dell'Apparato Cardiovascolare ,Logistic Models ,Case-Control Studies ,alpha 1-Antitrypsin ,Female ,Geriatrics and Gerontology ,Gerontology - Abstract
Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha1-antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AMI patients (1.2%) (P = 0.0000001). The heterozygous MZ genotype was significantly over represented in centenarians (38/143) and under represented in AMI patients (3/127) with intermediate values in young controls (16/255) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a positive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.
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- 2006
18. RP1 Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod-Cone Dystrophy: Potential Founder Effect in Western Sicily.
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D'Esposito F, Randazzo V, Vega MI, Esposito G, Maltese PE, Torregrossa S, Scibetta P, Listì F, Gagliano C, Scalia L, Pioppo A, Marino A, Piergentili M, Malvone E, Fioretti T, Vitrano A, Piccione M, Avitabile T, Salvatore F, Bertelli M, Costagliola C, Cordeiro MF, Maggio A, and D'Alcamo E
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- Humans, Sicily epidemiology, Founder Effect, Eye Proteins, Phenotype, Pedigree, Mutation, DNA Mutational Analysis, Microtubule-Associated Proteins genetics, Cone-Rod Dystrophies genetics, Retinitis Pigmentosa genetics, Retinitis Pigmentosa diagnosis
- Abstract
Background and Objectives . Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1 , which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods . From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions . The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.
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- 2024
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19. Study on the Role of Polymorphisms of the SOX-6 and MYB Genes and Fetal Hemoglobin Levels in Sicilian Patients with β-Thalassemia and Sickle Cell Disease.
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Listì F, Sclafani S, Agrigento V, Barone R, Maggio A, and D'Alcamo E
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- Gene Frequency, Hemoglobinopathies genetics, Humans, Sicily epidemiology, Anemia, Sickle Cell genetics, Fetal Hemoglobin genetics, Genes, myb genetics, Polymorphism, Single Nucleotide, SOXD Transcription Factors genetics, beta-Thalassemia genetics
- Abstract
The hemoglobinopathies, as β-thalassemia (β-thal) and sickle cell disease, are the most common hereditary hemolytic anemias. The increase of fetal hemoglobin (Hb F) levels can ameliorate the symptoms of hemoglobinopathies. There are several transcription factors such as MYB and SOX-6, which are involved in the regulation of Hb F. There are not enough studies investigating the association between single nucleotide polymorphisms (SNPs) of the SOX-6 and MYB genes and the variation of Hb F levels in patients affected by sickle cell disease and β-thal. We therefore decided to analyze the role of four missense variants of MYB and SOX-6 genes in the regulation of Hb F levels. In order to do so, we examinated 30 Sicilian patients affected by sickle cell disease and β-thal, to understand if these variants could also have an influence in our populations. Comparing two groups of patients with low and high levels of Hb F, we found no significant differences in the genetic distribution and allelic frequency of MYB and SOX-6 gene polymorphisms. We also created and compared a 'high producer' and 'low producer' genotype with different genes achieving the same result of no significant difference. Our results may be due either to the fact that the association between these genes and the regulation of Hb F levels are influenced by environmental history and population genetics, or to the small number of samples being analyzed.
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- 2018
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20. Genetics of longevity. data from the studies on Sicilian centenarians.
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Balistreri CR, Candore G, Accardi G, Bova M, Buffa S, Bulati M, Forte GI, Listì F, Martorana A, Palmeri M, Pellicanò M, Vaccarino L, Scola L, Lio D, and Colonna-Romano G
- Abstract
The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.
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- 2012
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21. LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects.
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Balistreri CR, Caruso C, Listì F, Colonna-Romano G, Lio D, and Candore G
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- Adult, Dinoprostone genetics, Female, Humans, Italy, Leukotriene B4 genetics, Male, Middle Aged, Toll-Like Receptor 4 genetics, Cytokines biosynthesis, Dinoprostone biosynthesis, Leukotriene B4 biosynthesis, Lipopolysaccharides pharmacology, Polymorphism, Single Nucleotide, Toll-Like Receptor 4 blood
- Abstract
Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
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- 2011
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22. Gender-related immune-inflammatory factors, age-related diseases, and longevity.
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Candore G, Balistreri CR, Colonna-Romano G, Lio D, Listì F, Vasto S, and Caruso C
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- Aging immunology, Aging metabolism, Aging pathology, Alzheimer Disease drug therapy, Alzheimer Disease etiology, Alzheimer Disease immunology, Animals, Estrogen Replacement Therapy, Female, Humans, Immune System physiology, Immunologic Factors metabolism, Inflammation Mediators immunology, Male, Aging physiology, Disease etiology, Immune System metabolism, Inflammation Mediators metabolism, Longevity physiology, Sex Characteristics
- Abstract
This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer's disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but rather a question of "socially constructed sex," a question of gender (i.e., the characteristics that a society or culture delineates as masculine or feminine). In gender medicine, we conclude that it is important to consider the role played both by hormones, customs, and educational levels regarding the different propensity of males and females to fall ill. So, in programming antiaging strategies, we have also to take these aspects into account.
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- 2010
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23. HLA and KIR frequencies in Sicilian Centenarians.
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Listì F, Caruso C, Colonna-Romano G, Lio D, Nuzzo D, and Candore G
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- Alleles, Case-Control Studies, Female, Gene Frequency, HLA-B8 Antigen genetics, HLA-DRB1 Chains, Humans, Male, Sicily, Aged, 80 and over, HLA-DR Antigens genetics, Longevity genetics, Receptors, KIR genetics
- Abstract
Several studies suggest that human longevity appears to be linked inextricably with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in loci that regulate the immune response, as human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genes. It has been suggested that longevity is associated with positive selection of alleles (i.e., HLA-DR11) or haplotypes (i.e., HLA-B8,DR3) that confer resistance to infectious disease(s). On the other hand, the cytolytic activity of natural killer (NK) cells is controlled by activating and inhibitory cell-surface receptors, including KIR. The genetic diversity of the KIR loci with respect to successful aging has been analyzed only in one study performed in the Irish population. Although two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. We have evaluated by polymerase chain reaction-sequence-specific primers (PCR-SSP) HLA-DRB1 and KIR receptors/HLA ligands frequencies in centenarians and controls from Sicily. Our results demonstrate an increase of the HLA DRB1*18 allele in male centenarians (p = 0.0266, after Bonferroni correction). Concerning KIR, no significant difference was observed after Bonferroni correction. However, our findings suggest that HLA/KIR/longevity associations are population specific, being heavily affected by the population-specific genetic and environmental history. This kind of study is important to better understand aging and longevity, hence enhancing the planning of antiaging strategies.
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- 2010
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24. Association between platelet endothelial cellular adhesion molecule-1 polymorphisms and atherosclerosis: results of a study on patients from northern Italy.
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Listì F, Caruso C, Di Carlo D, Falcone C, Boiocchi C, Cuccia M, and Candore G
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- Aged, Atherosclerosis epidemiology, Case-Control Studies, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Italy epidemiology, Male, Middle Aged, Atherosclerosis genetics, Platelet Endothelial Cell Adhesion Molecule-1 genetics, Polymorphism, Single Nucleotide physiology
- Abstract
Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leukocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule-1 (PECAM-1), involved in this migration, has been associated with the development of atherosclerosis. Studies have investigated an association between coronary artery disease (CAD) and single-nucleotide polymorphisms (SNPs) located in functionally important domains of the PECAM-1 gene with inconsistent results. Thus, we have analyzed the distribution of V125L, N563S, and G670R SNPs in patients and controls from northern Italy, and also analyzed another functional variant identified in the 5'-untranslated region (UTR) of the PECAM-1 gene (53 G-->A). The polymorphisms of PECAM-1 were genotyped by PCR amplification with sequence-specific primers (PCR-SSP) in 119 controls and 431 CAD patients. Our results demonstrate that genotype and allele frequencies for the 53 G/A polymorphism are significantly different in patients affected by CAD compared to healthy controls, whereas, as regards the V125L and N563S polymorphisms, only the allelic frequency is significantly different. We have shown that there were a significant differences for the 53 G/A and V125L and N563S polymorphisms of PECAM-1 in patients affected by CAD compared to controls. This demonstrates a possible involvement of this gene in contributing to the development of CAD. Therefore, an understanding of the role of the PECAM-1 molecule in this complex mechanism is of pivotal significance in further development of innovative and suitable medical therapies in the future.
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- 2010
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25. Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
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Mishto M, Bellavista E, Ligorio C, Textoris-Taube K, Santoro A, Giordano M, D'Alfonso S, Listì F, Nacmias B, Cellini E, Leone M, Grimaldi LM, Fenoglio C, Esposito F, Martinelli-Boneschi F, Galimberti D, Scarpini E, Seifert U, Amato MP, Caruso C, Foschini MP, Kloetzel PM, and Franceschi C
- Subjects
- Adult, Amino Acid Sequence, Brain metabolism, Brain pathology, Cysteine Endopeptidases genetics, Cysteine Endopeptidases metabolism, Epitopes metabolism, Female, Gene Frequency, Genotype, HLA-A Antigens genetics, HLA-A Antigens metabolism, HLA-A2 Antigen, Humans, Immunohistochemistry, Italy, Macrophages metabolism, Macrophages pathology, Male, Microglia metabolism, Microglia pathology, Middle Aged, Molecular Sequence Data, Multiple Sclerosis genetics, Multiple Sclerosis metabolism, Muscle Proteins metabolism, Myelin Basic Protein immunology, Myelin Basic Protein metabolism, Oligodendroglia metabolism, Oligodendroglia pathology, Proteasome Endopeptidase Complex metabolism, Protein Binding, Risk Factors, Sex Factors, Cysteine Endopeptidases immunology, Epitopes immunology, HLA-A Antigens immunology, Multiple Sclerosis immunology
- Abstract
Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis., Methodology/principal Findings: Immunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119)., Conclusion/significance: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.
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- 2010
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26. Role of cyclooxygenase-2 and 5-lipoxygenase polymorphisms in Alzheimer's disease in a population from northern Italy: implication for pharmacogenomics.
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Listì F, Caruso C, Lio D, Colonna-Romano G, Chiappelli M, Licastro F, and Candore G
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- Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease enzymology, Female, Gene Frequency, Genotype, Humans, Italy, Male, Middle Aged, Population Groups, Alzheimer Disease genetics, Arachidonate 5-Lipoxygenase genetics, Cyclooxygenase 2 genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distribution of the -765G COX-2 and -1708A 5-LO alleles between AD cases and controls (p=0.03 for -765G/C COX-2 SNP; and p=0.007 for -1708G/A 5-LO SNP). Hence, COX-2 -765G and 5-LO -1708A alleles were overrepresented in AD patients and underrepresented in controls. Our data suggest that these alleles of COX-2 and 5-LO could be risk factors for AD. These results seem of some importance for a pharmacogenomic approach.
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- 2010
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27. A pilot study on prostate cancer risk and pro-inflammatory genotypes: pathophysiology and therapeutic implications.
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Balistreri CR, Caruso C, Carruba G, Miceli V, Campisi I, Listì F, Lio D, Colonna-Romano G, and Candore G
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- Aged, Aged, 80 and over, Genotype, Humans, Inflammation genetics, Inflammation pathology, Inflammation physiopathology, Inflammation therapy, Male, Middle Aged, Pilot Projects, Prostatic Neoplasms genetics, Prostatic Neoplasms therapy, Risk Factors, Inflammation Mediators physiology, Polymorphism, Single Nucleotide genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms physiopathology
- Abstract
Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and treatment of PC, we have investigated the potential role of common SNPs of a gene cluster (TLR4, TLR2, PTGS2 and 5-Lo), involved in innate and inflammatory response, in PC cases, age-matched controls and centenarians from Sicily. Six SNPs were genotyped and their association with PC risk determined. Statistical analysis evidenced a significant association of some pro-inflammatory gene SNPs with an increased risk of PC. Furthermore, significant differences were observed comparing the three groups in the combined presence of a "high responder" pro-inflammatory profile. Overall, the present results suggest the likely association of these SNPs and PC risk, clearly motivating the need of larger studies to confirm the role of these genes in PC development and/or progression.
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- 2010
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28. Polymorphisms of pro-inflammatory genes and prostate cancer risk: a pharmacogenomic approach.
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Caruso C, Balistreri CR, Candore G, Carruba G, Colonna-Romano G, Di Bona D, Forte GI, Lio D, Listì F, Scola L, and Vasto S
- Subjects
- Aging genetics, Aging immunology, Genetic Predisposition to Disease, Humans, Inflammation genetics, Inflammation immunology, Inflammation Mediators immunology, Male, Pharmacogenetics, Polymorphism, Genetic, Prostatic Neoplasms genetics, Prostatic Neoplasms immunology
- Abstract
In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors' laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical manifestation of the malady, where treatment might play a decisive role in preventing or significantly retarding the manifestation of the disease. The better understanding of the function and the regulation of inflammatory pathway in PCa may help to know the mechanisms of its formation and progression, as well as to identify new targets for the refinement of new treatment such as the pharmacogenomics approach.
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- 2009
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29. Inflammation, genes and zinc in Alzheimer's disease.
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Vasto S, Candore G, Listì F, Balistreri CR, Colonna-Romano G, Malavolta M, Lio D, Nuzzo D, Mocchegiani E, Di Bona D, and Caruso C
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Peptides biosynthesis, Amyloid beta-Peptides metabolism, Animals, Apolipoproteins E metabolism, Cholesterol metabolism, Cytokines biosynthesis, Cytokines genetics, Cytokines metabolism, Humans, Inflammation metabolism, Models, Biological, Zinc metabolism, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Inflammation physiopathology
- Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.
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- 2008
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30. Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease.
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Balistreri CR, Grimaldi MP, Chiappelli M, Licastro F, Castiglia L, Listì F, Vasto S, Lio D, Caruso C, and Candore G
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease physiopathology, Female, Humans, Inflammation genetics, Inflammation physiopathology, Italy epidemiology, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Severity of Illness Index, Alzheimer Disease genetics, Lipopolysaccharide Receptors genetics, Toll-Like Receptor 4 genetics
- Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.
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- 2008
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31. Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics.
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Listì F, Caruso M, Incalcaterra E, Hoffmann E, Caimi G, Balistreri CR, Vasto S, Scafidi V, Caruso C, and Candore G
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- Adult, Age Factors, Aged, 80 and over, Alleles, Drug Delivery Systems, Female, Genetic Predisposition to Disease, Humans, Inflammation genetics, Inflammation physiopathology, Male, Middle Aged, Myocardial Infarction physiopathology, Phenotype, Risk Factors, Young Adult, Arachidonate 5-Lipoxygenase genetics, Cyclooxygenase 2 genetics, Longevity genetics, Myocardial Infarction genetics, Pharmacogenetics
- Abstract
Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). However, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO) are the key enzymes in the conversion of arachidonic acid to prostaglandins (PG) and leukotrienes (LT) and are implicated in a wide variety of inflammatory disorders, including atherosclerosis. In fact, PGE2 activates Matrix Metallo-proteinases whereas LTB4 is a chemoactractant for monocytes and activates gene expression in inflammatory cells. We have tested the hypothesis that anti-inflammatory variants of these genes confer genetic resistance to MI and conversely favour longevity. So, we analyzed MI patients, age-related controls and centenarians. The pro-inflammatory alleles of COX-2 and 5-LO were overrepresented in MI and under-represented in centenarians whereas age-related controls displayed intermediate values. MI is a multifactorial disease, hence MI might be the result of a cumulative effect which contributes with different timing to achieve a threshold where the chance to develop the diseases is very high. In particular, differences in inflammatory status can contribute to the chance of developing a risk phenotype. However, these studies might contribute to the determination of a risk profile which may allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug.
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- 2008
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32. Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging.
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Balistreri CR, Candore G, Listì F, Fazio T, Gangi S, Incalcaterra E, Caruso M, Vecchi ML, Lio D, and Caruso C
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- Adult, Blood Cells metabolism, Cells, Cultured, Dinoprostone biosynthesis, Escherichia coli, Escherichia coli Infections genetics, Escherichia coli Infections metabolism, Female, Genotype, Humans, Immunity, Innate genetics, Inflammation genetics, Inflammation metabolism, Leukotriene B4 biosynthesis, Lipopolysaccharides pharmacology, Male, Middle Aged, Time Factors, Aging genetics, Aging metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Myocardial Infarction genetics, Myocardial Infarction metabolism, Polymorphism, Single Nucleotide, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism
- Abstract
The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the present report, to validate this hypothesis, the levels of the eicosanoids, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), known to be involved as mediators in age-related diseases, were determined by an enzyme-linked immunosorbent assay in supernatants from a whole blood assay, after stimulation with subliminal doses of LPS from Escherichia coli. The samples, genotyped for the +896A/G SNP, were challenged with LPS for 4, 24, and 48 h. Both LTB4 and PGE2 values were significantly lower in carriers bearing the TLR4 mutation. Therefore, the pathogen burden, by interacting with the host genotype, determines the type and intensity of the inflammatory responses accountable for proinflammatory status, CVD, AD, and unsuccessful aging (i.e., age-related inflammatory diseases).
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- 2007
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33. Zinc and inflammatory/immune response in aging.
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Vasto S, Mocchegiani E, Malavolta M, Cuppari I, Listì F, Nuzzo D, Ditta V, Candore G, and Caruso C
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- Animals, Antioxidants pharmacology, Atherosclerosis metabolism, Diabetes Mellitus, Type 2 metabolism, Humans, Interleukin-6 metabolism, Metallothionein chemistry, Models, Biological, Models, Genetic, NF-kappa B metabolism, Tumor Necrosis Factor-alpha metabolism, Zinc chemistry, Zinc metabolism, Aging, Immune System, Inflammation, Zinc pharmacology
- Abstract
Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of refined wheat products that lack zinc and other critical nutrients as a consequence of the refining process. On the other hand, plasma zinc concentration is influenced by proinflammatory cytokines (IL-6 and TNF-alpha) and by metallothioneins (MT) homeostasis, which is in turn affected by proinflammatory cytokines. MT increase in aging and chronic inflammation allowing a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon leads to an impaired inflammatory/immune response in the elderly. A major target of zinc is NF-kappaB, a transcription factor critical for the expression of proinflammatory cytokines whose production is regulated by extra- and intracellular activating and inhibiting factors interacting with the regulatory elements on cytokine genes. Effects of zinc on translocation of NF-kappaB have been attributed to the suppression of phosphorylation and degradation of the inhibitory proteins (A20) that normally sequester it in the cytoplasm. Moreover, this factor and A20 are regulated by specific genes involved in inflammation and by intracellular zinc ion availability. So, it is not so surprising that zinc deficiency is constantly observed in chronic inflammation, such as in old individuals. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms are associated with atherosclerosis and diabetes type 2. Therefore, zinc turnover, via MT homeostasis, in individuals genetically predisposed to a dysregulation of the inflammatory/immune response may play a crucial role in causing possible adverse events with the appearance of age-related diseases.
- Published
- 2007
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34. PECAM-1/CD31 in infarction and longevity.
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Listì F, Caruso C, Balistreri CR, Grimaldi MP, Caruso M, Caimi G, Hoffmann E, Lio D, and Candore G
- Subjects
- Aged, 80 and over, Case-Control Studies, Cell Adhesion, Coronary Disease metabolism, Genetic Predisposition to Disease, Genotype, Humans, Inflammation, Italy, Male, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Sex Factors, Longevity, Myocardial Infarction genetics, Myocardial Infarction metabolism, Platelet Endothelial Cell Adhesion Molecule-1 physiology
- Abstract
Inflammation has recently proven to be associated with the pathogenesis of atherosclerosis and inflammatory genes are good candidates for the risk of developing atherosclerosis. The early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration. This process is mainly mediated by cellular adhesion molecules, which are expressed by the vascular endothelium and by circulating leukocytes in response to several inflammatory stimuli. Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leukocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule-1 (PECAM-1/CD31), involved in this migration, has been associated with the developmental course of atherosclerosis. Studies have investigated an association between coronary heart disease (CHD) and single nucleotide polymorphisms (SNP) located in functionally important domains of the PECAM-1/CD31 gene, with contrasting results. In particular, we previously analyzed for the following PECAM-1/CD31 SNP: Val125Leu, Asn563Ser, and Gly670Arg. The frequency of the Gly670Arg polymorphism was significantly higher in patients with myocardial infarction (MI), whereas the frequencies of the other two SNP (Leu125Val and Ser563Asn) were not significantly different between patients and controls. To check the validity of our results, we have analyzed the distribution of these SNP in centenarian men (age >99) from our homogeneous Sicilian population, since our previous studies have demonstrated that alleles associated with MI susceptibility are not included in the genetic background favoring longevity. We showed, as regard to polymorphisms of PECAM-1/CD31, that there were no significant differences between male patients affected by MI, male controls, and male centenarians. According to our hypothesis present results seemingly do not support a role for these SNP in conferring the susceptibility to MI at least in this Italian population.
- Published
- 2007
- Full Text
- View/download PDF
35. Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity.
- Author
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Listì F, Candore G, Grimaldi MP, Lio D, Colonna-Romano G, Orlando V, Caruso M, Hoffmann E, Paolisso G, Franceschi C, and Caruso C
- Subjects
- Adult, Aged, 80 and over, Case-Control Studies, Cohort Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Middle Aged, Risk Assessment, Risk Factors, Sicily, Aging genetics, Heterozygote, Longevity genetics, Myocardial Infarction genetics, alpha 1-Antitrypsin genetics
- Abstract
Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha1-antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AMI patients (1.2%) (P = 0.0000001). The heterozygous MZ genotype was significantly over represented in centenarians (38/143) and under represented in AMI patients (3/127) with intermediate values in young controls (16/255) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a positive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.
- Published
- 2007
- Full Text
- View/download PDF
36. CCR5 receptor: biologic and genetic implications in age-related diseases.
- Author
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Balistreri CR, Caruso C, Grimaldi MP, Listì F, Vasto S, Orlando V, Campagna AM, Lio D, and Candore G
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Atherosclerosis genetics, Cardiovascular Diseases metabolism, Dendritic Cells cytology, Gene Deletion, Genome, Humans, Inflammation, Killer Cells, Natural metabolism, Ligands, Macrophages metabolism, Microglia pathology, Models, Biological, Aging, Cardiovascular Diseases genetics, Receptors, CCR5 genetics, Receptors, CCR5 physiology
- Abstract
The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age-related diseases, atherosclerosis and Alzheimer's disease, suggesting a possible role of chemokine system on these diseases' pathophysiology. Finally, we review the data on the probable association between CCR5Delta32 deletion and cardiovascular diseases and Alzheimer's disease.
- Published
- 2007
- Full Text
- View/download PDF
37. Connexin37 1019 gene polymorphism in myocardial infarction patients and centenarians.
- Author
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Listì F, Candore G, Balistreri CR, Caruso M, Incalcaterra E, Hoffmann E, Lio D, and Caruso C
- Subjects
- Aged, 80 and over, Cytosine, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Risk Assessment, Risk Factors, Sicily, Thymine, Gap Junction alpha-4 Protein, Alleles, Connexins genetics, Longevity genetics, Myocardial Infarction genetics, Polymorphism, Single Nucleotide
- Published
- 2007
- Full Text
- View/download PDF
38. Polymorphisms of pro-inflammatory genes and Alzheimer's disease risk: a pharmacogenomic approach.
- Author
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Candore G, Balistreri CR, Grimaldi MP, Listì F, Vasto S, Chiappelli M, Licastro F, Colonna-Romano G, Lio D, and Caruso C
- Subjects
- Alzheimer Disease pathology, Animals, Humans, Risk, Alzheimer Disease genetics, Genome, Inflammation Mediators physiology, Pharmacogenetics, Polymorphism, Genetic
- Abstract
Clinically and pathologically Alzheimer's disease (AD) represents a sequential progressive neurodegenerative disorder. AD is etiologically heterogeneous and accounts for a majority of dementia in western societies. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has lead to the identification of numerous gene polymorphisms that might act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators, although not all the studies were replied. Here, we review several data suggesting that inflammatory genetic variation may contribute to AD susceptibility. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenomic driving of drug responsiveness.
- Published
- 2007
- Full Text
- View/download PDF
39. Pharmacogenomics: a tool to prevent and cure coronary heart disease.
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Candore G, Balistreri CR, Caruso M, Grimaldi MP, Incalcaterra E, Listì F, Vasto S, and Caruso C
- Subjects
- Atherosclerosis complications, Atherosclerosis therapy, Case-Control Studies, Chemokines genetics, Coronary Disease prevention & control, Cytokines genetics, Genetic Predisposition to Disease, Humans, Inflammation complications, Inflammation therapy, Lipopolysaccharide Receptors genetics, Lipoxygenase genetics, Myocardial Infarction genetics, Myocardial Infarction therapy, Prostaglandin-Endoperoxide Synthases genetics, Receptors, Chemokine genetics, Risk Assessment, Risk Factors, Toll-Like Receptor 4 genetics, Treatment Outcome, Atherosclerosis genetics, Coronary Disease genetics, Coronary Disease therapy, Inflammation genetics, Patient Selection, Pharmacogenetics, Polymorphism, Genetic
- Abstract
Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). This is supported by epidemiological studies which have thoroughly investigated the association between CHD and gene polymorphisms of the inflammatory molecules. Moreover, efforts to find elective therapy have not been rewarding and, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. A critical search of published literature has suggested few inflammatory genes directly involved in the risk to develop CHD and MI. The selected genes are, the pro- and anti-inflammatory cytokines, Toll-like receptor 4 (TLR4), CD14, CCR5, cyclooxygenases (COXs) and lipoxygenases (LOXs). The associations between candidate gene polymorphisms and CHD/MI are difficult and complex as a consequence of pleiotropy, variations with age, selection due to the lethality of the disease, and interactions with other genes and environmental factors. However, current data indicate that screening for interleukin (IL)-6, IL-10, TLR4, CCR5, COX and LOX polymorphisms are likely to be a useful tool for CHD and MI risk assessment. What we believe is that dissecting out the influence of genetics polymorphism within the complex pathophysiology of CHD and MI will help to provide a more complete risk assessment and complement known classical cardiological risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug of lifestyle modification.
- Published
- 2007
- Full Text
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40. A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence.
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Listì F, Candore G, Modica MA, Russo M, Di Lorenzo G, Esposito-Pellitteri M, Colonna-Romano G, Aquino A, Bulati M, Lio D, Franceschi C, and Caruso C
- Subjects
- Aged, Aged, 80 and over, Biomarkers blood, Female, Humans, Immunologic Memory, Male, B-Lymphocytes immunology, Immunoglobulins blood, Longevity immunology
- Abstract
The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, we investigated the serum immunoglobulin levels in a cohort of 166 subjects (20-106 years). Serum IgG (and IgG subclasses) were quantified by the nephelometric technique, IgE by CAP system fluorescence enzyme immunoassay, and IgD by radial immunodiffusion (RID). There was an age-related increase of IgG and IgA; the IgG age-related increase was significant only in men, but IgG1 levels showed an age-related increase both in men and women, whereas IgG3 showed an age-related increase only in men. IgE levels remain unchanged, whereas IgD and IgM serum levels decreased with age; the IgM age-related decrease was significant only in women, likely due to the relatively small sample of aged men. Thus, in the elderly the B cell repertoire available to respond to new antigenic challenge is decreased. A lot of memory IgD- B cells are filling immunological space and the amount of naïve IgD+ B cells is dramatically decreased. This shift away from a population of predominantly naïve B cells obviously reflects the influences of cumulative exposure to foreign pathogens over time. These age-dependent B cell changes indicate that advanced age is a condition characterized by lack of clonotypic immune response to new extracellular pathogens. In any event, the increase of memory B cells and the loss of naïve B cells, as measured by serum IgD levels, could represent hallmarks of immunosenescence and could provide useful biomarkers possibly related to the life span of humans.
- Published
- 2006
- Full Text
- View/download PDF
41. Role of proinflammatory alleles in longevity and atherosclerosis: results of studies performed on -1562C/T MMP-9 in centenarians and myocardial infarction patients from Sicily.
- Author
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Nuzzo D, Vasto S, Balistreri CR, Di-Carlo D, Listì F, Caimi G, Caruso M, Hoffmann E, Incalcaterra E, Lio D, Caruso C, and Candore G
- Subjects
- Adult, Aged, 80 and over, Alleles, Cohort Studies, Coronary Artery Disease complications, Coronary Artery Disease enzymology, Female, Gene Frequency, Humans, Inflammation genetics, Male, Middle Aged, Myocardial Infarction enzymology, Myocardial Infarction etiology, Sicily, Coronary Artery Disease genetics, Longevity genetics, Matrix Metalloproteinase 9 genetics, Myocardial Infarction genetics, Polymorphism, Single Nucleotide
- Abstract
Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic background favoring longevity. Hence, genotypes of natural immunity should play an opposite role in atherosclerosis and longevity. Metalloproteinase (MMPs) are involved in tissue remodeling and therefore play a remarkable role in inflammation-based disease. MMPs are a family of Zn(2+)-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans, and elastin, which appear to play important roles in the development and progression of the atherosclerotic lesion. There is evidence indicating a role played by the MMPs in the weakening of atherosclerotic plaque which predisposes to lesion disruption. In this study we performed a genetic study on -1562C/T MMP-9 single nucleotide polymorphism (SNP) in order to discern a possible role in AMI. We analyzed the distribution of this SNP in 115 AMI patients, 123 controls, and 34 centenarians from Sicily. We found no significant differences in the genetic distribution and allelic frequency of -1562C/T MMP-9 SNP between the studied groups. The present results are not in agreement with our previous findings, strengthening our hypothesis that genetic background protection against cardiovascular disease is a relevant component of the longevity trait, at least in the generation of Italian male centenarians under study. However, present results do not exclude that differential expression of MMP-9 playing an opposite role in AMI and longevity because other kinds of regulation might be more relevant than those linked to the SNP under study.
- Published
- 2006
- Full Text
- View/download PDF
42. Age-related inflammatory diseases: role of genetics and gender in the pathophysiology of Alzheimer's disease.
- Author
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Candore G, Balistreri CR, Grimaldi MP, Vasto S, Listì F, Chiappelli M, Licastro F, Lio D, and Caruso C
- Subjects
- Age Factors, Aged, Female, Humans, Male, Polymorphism, Genetic, Alzheimer Disease etiology, Alzheimer Disease genetics, Estrogens physiology, Inflammation genetics, Sex Ratio
- Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxidative stress, inflammation, and the cerebral vasculature might also be expected to increase AD risk. During the Women's Health Initiative Memory Study--a randomized, placebo-controlled trial of women 65-79 years of age--oral estrogen plus progestin was seen to double the rate of developing dementia, with risk appearing soon after the treatment was initiated. On the basis of current evidence, hormone therapy (HT) is thus not indicated for the prevention of AD. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has led to the identification of numerous gene polymorphisms that act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators. Here we review several data suggesting that inflammatory genetic variation may contribute to higher AD susceptibility in women too. All together this information may represent the basis both for future recognition of individuals at risk as well as for a pharmacogenomic approach in achieving drug responsiveness.
- Published
- 2006
- Full Text
- View/download PDF
43. Immunogenetics, gender, and longevity.
- Author
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Candore G, Balistreri CR, Listì F, Grimaldi MP, Vasto S, Colonna-Romano G, Franceschi C, Lio D, Caselli G, and Caruso C
- Subjects
- Aging genetics, Aging immunology, Female, HLA Antigens genetics, Humans, Immunogenetics, Inflammation genetics, Inflammation immunology, Male, HLA Antigens physiology, Longevity genetics, Longevity immunology, Sex Ratio
- Abstract
In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In Italy this female/male ratio is relatively lower (about 5/1; F/M ratios are usually 5-6:1 in other developed countries), but significant differences have been observed between Italian regions in the distribution of centenarians by gender--from two women per man in the South to more than eight in certain regions in the North. Thus, a complex interaction of environmental, historical, and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. This can be due to gender-specific cultural and anthropological characteristics of Italian society in the last 100 years. Age-related immunoinflammatory factors increase during proinflammatory status, and the frequency of pro/anti-inflammatory gene variants also show gender differences. There is some suggestion that people genetically predisposed to weak inflammatory activity may be at reduced chance of developing coronary heart disease (CHD) and, therefore, may achieve longer lifespan if they avoid serious life-threatening infectious disease thoroughout life. Thus, the pathogen burden, by interacting with host genotype, could determine the type and intensity of the immune-inflammatory response responsible for both proinflammatory status and CHD. These findings point to a strong relationship between the genetics of inflammation, successful aging, and the control of cardiovascular disease, but seem to suggest that the evidence for men is much stronger. The importance of these studies lies in the fact that half of the population (males) lives approximately 10% shorter lives than the other half (females). Understanding the different strategies that men and women seem to follow to achieve longevity may help us to comprehend better the basic phenomenon of aging and allow us to search for safe ways to increase male lifespan.
- Published
- 2006
- Full Text
- View/download PDF
44. Inflammation, genes and zinc in ageing and age-related diseases.
- Author
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Vasto S, Mocchegiani E, Candore G, Listì F, Colonna-Romano G, Lio D, Malavolta M, Giacconi R, Cipriano C, and Caruso C
- Subjects
- Aging genetics, Aging immunology, Animals, Atherosclerosis genetics, Atherosclerosis metabolism, Cellular Senescence genetics, Cytokines genetics, Humans, Immunity, Innate genetics, Inflammation genetics, Inflammation immunology, Interleukin-6 metabolism, Metallothionein metabolism, Polymorphism, Genetic, Tumor Necrosis Factor-alpha metabolism, Zinc deficiency, Aging metabolism, Cytokines metabolism, Gene Expression, Inflammation metabolism, Longevity genetics, Zinc metabolism
- Abstract
Lifelong antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and pro-inflammatory cytokine production. A large number of studies have documented changes in Zn metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory diseases. In particular, modification of zinc plasma concentration as well as intracellular disturbance of antioxidant intracellular pathways have been found associated to age-related inflammatory diseases, like atherosclerosis. Zinc deficiency is extremely diffused in aged people that are educated to avoid meat and other high Zn-content foods due to fear of cholesterol. Rather, they increase consumption of refined wheat products that lack of Zn, magnesium and other critical nutrients in consequence of refining process. On the other hand, plasma concentration of metallic ions like Zn is influenced by pro-inflammatory cytokines production. A major target of Zn may be NF-kB, a transcription factor critical for the expression of many pro-inflammatory cytokines whose production is finely regulated by extra- and intracellular activating and inhibiting factors interacting with regulatory elements on cytokine genes. Moreover, this factor is regulated by the expression of specific cellular genes involved in inflammation. So it is not surprising that Zn deficiency is constantly observed in aged patients affected by infectious diseases. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms have been found associated to age-related diseases as atherosclerosis. Therefore, Zn deficiency in individuals genetically predisposed to a dis-regulation of inflammation response, may play a crucial role, in causing adverse events and in reducing the probability of a successful aging.
- Published
- 2006
- Full Text
- View/download PDF
45. Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study.
- Author
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Balistreri CR, Vasto S, Listì F, Grimaldi MP, Lio D, Colonna-Romano G, Caruso M, Caimi G, Hoffmann E, Caruso C, and Candore G
- Subjects
- Acute Disease epidemiology, Adult, Case-Control Studies, Cohort Studies, Gene Frequency, Humans, Immunogenetics, Inflammation blood, Inflammation epidemiology, Inflammation genetics, Male, Middle Aged, Myocardial Infarction blood, Myocardial Infarction epidemiology, Odds Ratio, Pilot Projects, Polymorphism, Single Nucleotide, Sicily epidemiology, C-Reactive Protein genetics, Myocardial Infarction genetics, Polymorphism, Genetic
- Abstract
Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute-phase reactant, C-reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age-related male controls from Sicily for +1059G/C CRP single-nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P = 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather than in C- subjects (P = 0.0075). The results of the present pilot case-control study performed in a homogeneous caucasoid population suggest that +1059C CRP gene SNP is associated with AMI. In any case, the results of the present study should add to the growing body of evidence on the role of pro-inflammatory genotypes in unsuccessful aging, determining susceptibility to immune-inflammatory diseases such as coronary heart disease.
- Published
- 2006
- Full Text
- View/download PDF
46. Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4.
- Author
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Candore G, Aquino A, Balistreri CR, Bulati M, Di Carlo D, Grimaldi MP, Listì F, Orlando V, Vasto S, Caruso M, Colonna-Romano G, Lio D, and Caruso C
- Subjects
- Acute Disease, Adult, Enzyme-Linked Immunosorbent Assay, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Inflammation immunology, Interleukin-6 genetics, Interleukin-6 immunology, Lipopolysaccharides pharmacology, Longevity immunology, Male, Middle Aged, Mutation, Polymorphism, Genetic immunology, Time Factors, Inflammation genetics, Longevity genetics, Myocardial Infarction genetics, Polymorphism, Genetic genetics, Toll-Like Receptor 4 genetics
- Abstract
The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzyme-linked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6 levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well.
- Published
- 2006
- Full Text
- View/download PDF
47. Opposite role of pro-inflammatory alleles in acute myocardial infarction and longevity: results of studies performed in a Sicilian population.
- Author
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Candore G, Balistreri CR, Grimaldi MP, Listì F, Vasto S, Caruso M, Caimi G, Hoffmann E, Colonna-Romano G, Lio D, Paolisso G, Franceschi C, and Caruso C
- Subjects
- Acute Disease epidemiology, Aged, 80 and over, Cytoskeletal Proteins genetics, Humans, Inflammation genetics, Inflammation immunology, Inflammation physiopathology, Myocardial Infarction epidemiology, Myocardial Infarction immunology, Pyrin, Receptors, CCR5 genetics, Sicily epidemiology, Alleles, Genetic Predisposition to Disease genetics, Longevity genetics, Myocardial Infarction genetics
- Abstract
The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.
- Published
- 2006
- Full Text
- View/download PDF
48. Systemic inflammatory response in erderly patients following hernioplastical operation.
- Author
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Di Vita G, Balistreri CR, Arcoleo F, Buscemi S, Cillari E, Donati M, Garofalo M, Listì F, Grimaldi MP, Patti R, and Candore G
- Abstract
The number of old and oldest old patients undergoing surgery of varying severity is increasing. Ageing is a process that changes the performances of most physiological systems and increases susceptibility to diseases and death; accordingly, host responses to surgical stress are altered with ageing and the occurrence of age-related increase in susceptibility to post-operative complications has been claimed. Twenty-four male patients undergoing Lichtenstein (LH) hernioplasty for unilateral inguinal hernia were included in this study and divided in two groups (Young and Old respectively), according to their age. As expression of the acute phase response, we measured changes in concentration of pro-inflammatory cytokines Tumor necrosis factor-alpha and Interleukin-1beta, leukocytes, acute phase proteins C-reactive protein and alpha 1-antitrypsin. Elderly humans showed prolonged and strong inflammatory activity compared to younger subjects in response to surgical stress, indicating that the acute-phase response to surgical stress of elderly humans varies from that of the young, showing initial hyperactivity and a delayed termination of the response. Thus, the acute phase response to surgical stress is higher in old subjects, but the clinical significance of this remains unclear. It is not known whether a causal relationship exists between this stronger acute phase response and the increases in susceptibility to post-operative complications observed in aged patients.
- Published
- 2006
- Full Text
- View/download PDF
49. Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily.
- Author
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Listì F, Candore G, Lio D, Russo M, Colonna-Romano G, Caruso M, Hoffmann E, and Caruso C
- Subjects
- Adult, Connexins blood, Gene Frequency, Genetic Markers, Genotype, Humans, Incidence, Male, Middle Aged, Myocardial Infarction blood, Myocardial Infarction epidemiology, Odds Ratio, Phenotype, Polymerase Chain Reaction, Retrospective Studies, Risk Factors, Sicily epidemiology, Gap Junction alpha-4 Protein, Connexins genetics, DNA genetics, Myocardial Infarction genetics, Polymorphism, Single Nucleotide
- Abstract
During atherogenesis, a critical role is played by intercellular communication via gap junctions, cell membrane channels linking the cytoplasmic compartments of adjacent cells. The component protein subunits of these channels, called connexin (Cx), belong to a multigene family. Cx37 is involved in growth, regeneration after injury and ageing of the endothelial cells, suggesting its role in atherosclerosis. The C1019 single nucleotide polymorphism (SNP) of Cx37 gene was associated with thickening of the carotid intima in Swedish men and was also associated with coronary artery disease in a Taiwanese population. On the other hand, in two more recent studies performed in male Japanese population, T1019 Cx37 SNP has shown to be a risk factor for acute myocardial infarction (AMI). In the light of these discrepant results, we have studied the frequency of this SNP in a very homogeneous cohort of young male people affected by AMI. We analysed 97 male Sicilian patients (mean age 40, age range 20-46) and 196 healthy male controls (mean age 39, age range 20-55) for C1019T of the Cx37. The 1019T SNP was significantly increased in the patients compared to the controls (43.8% vs. 34.4%; p=0.03 by chi2 test with Yates' correction; odds ratio (OR) 1.5, (1.0-2.1) 95% confidence interval (CI)). The present case control study performed in a homogeneous Caucasoid population confirms the Japanese results that T SNP of Cx37 gene is involved in AMI phenotype, demonstrating the consistency of the association across past studies and across different populations. The differences between patients and controls are significant but relatively small with an odd ratio risk of 1.5. However, as AMI is a multifactorial disease, any single mutation will only provide a small or modest contribution to risk, also depending on interaction with other genes and/or a particular environment.
- Published
- 2005
- Full Text
- View/download PDF
50. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.
- Author
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Candore G, Modica MA, Lio D, Colonna-Romano G, Listì F, Grimaldi MP, Russo M, Triolo G, Accardo-Palumbo A, Cuccia MC, and Caruso C
- Subjects
- Adult, Alleles, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Enzyme-Linked Immunosorbent Assay, Female, Gene Frequency genetics, HLA-B8 Antigen genetics, HLA-DR3 Antigen genetics, Haplotypes immunology, Humans, Male, Middle Aged, Autoimmune Diseases etiology, Complement C4 genetics, HLA Antigens genetics, Haplotypes genetics
- Abstract
Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-alpha may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.
- Published
- 2003
- Full Text
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