@article {10419, title = {Genetic profile of patients with early onset inflammatory bowel disease.}, journal = {Gene}, volume = {645}, year = {2018}, month = {2018 Mar 01}, pages = {18-29}, abstract = {

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

}, keywords = {Age of Onset, Autophagy-Related Proteins, Child, Child, Preschool, Computer Simulation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Inflammatory Bowel Diseases, Interleukin-10, Male, Nod2 Signaling Adaptor Protein, Polymorphism, Single Nucleotide, Receptors, Interleukin, Receptors, Interleukin-10, Sequence Analysis, DNA, X-Linked Inhibitor of Apoptosis Protein}, issn = {1879-0038}, doi = {10.1016/j.gene.2017.12.029}, author = {Girardelli, Martina and Basaldella, Federica and Paolera, Sara Della and Vuch, Josef and Tommasini, Alberto and Martelossi, Stefano and Crovella, Sergio and Bianco, Anna Monica} } @article {8323, title = {Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology.}, journal = {Int J Mol Sci}, volume = {17}, year = {2016}, month = {2016}, pages = {365}, abstract = {

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

}, issn = {1422-0067}, doi = {10.3390/ijms17030365}, author = {Marcuzzi, Annalisa and Piscianz, Elisa and Zweyer, Marina and Bortul, Roberta and Loganes, Claudia and Girardelli, Martina and Baj, Gabriele and Monasta, Lorenzo and Celeghini, Claudio} } @article {8306, title = {Protective Role of BST2 Polymorphisms in Mother-to-Child Transmission of HIV-1 and Adult AIDS Progression.}, journal = {J Acquir Immune Defic Syndr}, volume = {72}, year = {2016}, month = {2016 Jul 1}, pages = {237-41}, abstract = {

Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.

}, issn = {1944-7884}, doi = {10.1097/QAI.0000000000000949}, author = {Kamada, Anselmo J and Bianco, Anna M and Zupin, Luisa and Girardelli, Martina and Matte, Maria C C and Medeiros, R{\'u}bia Mar{\'\i}lia de and Almeida, Sabrina Esteves de Matos and Rocha, Marineide M and Segat, Ludovica and Chies, Jos{\'e} A B and Kuhn, Louise and Crovella, Sergio} } @article {8315, title = {Putative modifier genes in mevalonate kinase deficiency.}, journal = {Mol Med Rep}, volume = {13}, year = {2016}, month = {2016 Apr}, pages = {3181-9}, abstract = {

Mevalonate kinase deficiency (MKD) is an autosomal recessive auto-inflammatory disease, caused by impairment of the mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non-homogeneous genotype-phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit {\textquoteright}extreme{\textquoteright} clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.

}, issn = {1791-3004}, doi = {10.3892/mmr.2016.4918}, author = {Marcuzzi, Annalisa and Vozzi, Diego and Girardelli, Martina and Tricarico, Paola Maura and Knowles, Alessandra and Crovella, Sergio and Vuch, Josef and Tommasini, Alberto and Piscianz, Elisa and Bianco, Anna Monica} } @article {7694, title = {Alendronate, a double-edged sword acting in the mevalonate pathway.}, journal = {Mol Med Rep}, volume = {12}, year = {2015}, month = {2015 Sep}, pages = {4238-42}, abstract = {

Aminobisphosphonate aledronate is a compound commonly used clinically for the treatment of osteoporosis and other bone diseases, as a result of it preventing bone resorption. However, in previous years it has also been used to obtain cellular and animal models of a rare genetic disorder termed Mevalonate Kinase Deficiency (MKD). MKD is caused by mutations affecting the mevalonate kinase enzyme, in the cholesterol pathway and alendronate can be used to biochemically mimic the genetic defect as it inhibits farnesyl pyrophosphate synthase in the same pathway. Despite evidence in favor of the inhibition exerted on the mevalonate pathway, there is at least one clinical case of MKD in which alendronate improved not only skeletal and bone fractures, as expected, but also MKD clinical features. Based on this finding, the present study assessed the anti-inflammatory properties of this aminobisphosphonate in vitro. No anti-inflammatory effects of alendronate were observed in the in vitro experiments. Since MKD lacks specific treatments, these results may assist scientists and physicians in making the decision as to the most suitable choice of therapeutic compounds for this neglected disease.

}, issn = {1791-3004}, doi = {10.3892/mmr.2015.3957}, author = {Tricarico, Paola Maura and Girardelli, Martina and Kleiner, Giulio and Knowles, Alessandra and Valencic, Erica and Crovella, Sergio and Marcuzzi, Annalisa} } @article {7787, title = {Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype.}, journal = {Clin Immunol}, volume = {159}, year = {2015}, month = {2015 Jul}, pages = {33-6}, keywords = {B-Lymphocytes, Child, Preschool, Female, Germinal Center, Humans, Hyper-IgM Immunodeficiency Syndrome, Infant, Male, Mutation, Phenotype, Phosphatidylinositol 3-Kinases, RNA Splice Sites, Sequence Analysis, DNA}, issn = {1521-7035}, doi = {10.1016/j.clim.2015.04.014}, author = {Lougaris, Vassilios and Faletra, Flavio and Lanzi, Gaetana and Vozzi, Diego and Marcuzzi, Annalisa and Valencic, Erica and Piscianz, Elisa and Bianco, AnnaMonica and Girardelli, Martina and Baronio, Manuela and Loganes, Claudia and Fasth, Anders and Salvini, Filippo and Trizzino, Antonino and Moratto, Daniele and Facchetti, Fabio and Giliani, Silvia and Plebani, Alessandro and Tommasini, Alberto} } @article {8088, title = {The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency.}, journal = {BMC Pediatr}, volume = {15}, year = {2015}, month = {2015}, pages = {208}, abstract = {

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

}, issn = {1471-2431}, doi = {10.1186/s12887-015-0522-5}, author = {Girardelli, Martina and Arrigo, Serena and Barabino, Arrigo and Loganes, Claudia and Morreale, Giuseppe and Crovella, Sergio and Tommasini, Alberto and Bianco, Anna Monica} } @article {8083, title = {Genetics of inflammatory bowel disease from multifactorial to monogenic forms.}, journal = {World J Gastroenterol}, volume = {21}, year = {2015}, month = {2015 Nov 21}, pages = {12296-310}, abstract = {

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn{\textquoteright}s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

}, issn = {2219-2840}, doi = {10.3748/wjg.v21.i43.12296}, author = {Bianco, Anna Monica and Girardelli, Martina and Tommasini, Alberto} } @article {8028, title = {Two-gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results.}, journal = {Mol Med Rep}, volume = {12}, year = {2015}, month = {2015 Oct}, pages = {6128-32}, abstract = {

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X-chromosome inactivation (XCI) studies on the patient{\textquoteright}s mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 {\textmu}g/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient{\textquoteright}s mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X-linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

}, issn = {1791-3004}, doi = {10.3892/mmr.2015.4215}, author = {Bianco, Anna Monica and Faletra, Flavio and Vozzi, Diego and Girardelli, Martina and Knowles, Alessandra and Tommasini, Alberto and Zauli, Giorgio and Marcuzzi, Annalisa} } @article {3518, title = {Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds.}, journal = {Int J Mol Sci}, volume = {15}, year = {2014}, month = {2014}, pages = {6843-56}, abstract = {

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines{\textquoteright} release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

}, keywords = {Animals, Apoptosis, Carotenoids, Carrier Proteins, Cell Line, Cytokines, Diterpenes, Humans, Mevalonate Kinase Deficiency, Mevalonic Acid, Mice, Mitochondria, Nitric Oxide, Phytol, Terpenes}, issn = {1422-0067}, doi = {10.3390/ijms15046843}, author = {Tricarico, Paola Maura and Kleiner, Giulio and Valencic, Erica and Campisciano, Giuseppina and Girardelli, Martina and Crovella, Sergio and Knowles, Alessandra and Marcuzzi, Annalisa} } @article {3627, title = {Curcumin and inflammatory bowel disease: potential and limits of innovative treatments.}, journal = {Molecules}, volume = {19}, year = {2014}, month = {2014}, pages = {21127-53}, abstract = {

Curcumin belongs to the family of natural compounds collectively called curcuminoids and it possesses remarkable beneficial anti-oxidant, anti-inflammatory, anti-cancer, and neuroprotective properties. Moreover it is commonly assumed that curcumin has also been suggested as a remedy for digestive diseases such as inflammatory bowel diseases (IBD), a chronic immune disorder affecting the gastrointestinal tract and that can be divided in two major subgroups: Crohn{\textquoteright}s disease (CD) and Ulcerative Colitis (UC), depending mainly on the intestine tract affected by the inflammatory events. The chronic and intermittent nature of IBD imposes, where applicable, long-term treatments conducted in most of the cases combining different types of drugs. In more severe cases and where there has been no good response to the drugs, a surgery therapy is carried out. Currently, IBD-pharmacological treatments are generally not curative and often present serious side effects; for this reason, being known the relationship between nutrition and IBD, it is worthy of interesting the study and the development of new dietary strategy. The curcumin principal mechanism is the suppression of IBD inflammatory compounds (NF-κB) modulating immune response. This review summarizes literature data of curcumin as anti-inflammatory and anti-oxidant in IBD, trying to understand the different effects in CD e UC.

}, keywords = {Animals, Anti-Inflammatory Agents, Non-Steroidal, Chemistry, Pharmaceutical, Clinical Trials as Topic, Curcumin, Humans, Inflammatory Bowel Diseases, Molecular Targeted Therapy, Nanotechnology, Treatment Outcome}, issn = {1420-3049}, doi = {10.3390/molecules191221127}, author = {Vecchi Brumatti, Liza and Marcuzzi, Annalisa and Tricarico, Paola Maura and Zanin, Valentina and Girardelli, Martina and Bianco, Anna Monica} } @article {3505, title = {Mevalonate kinase deficiency and IBD: shared genetic background.}, journal = {Gut}, volume = {63}, year = {2014}, month = {2014 Aug}, pages = {1367-8}, keywords = {Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases}, issn = {1468-3288}, doi = {10.1136/gutjnl-2013-306555}, author = {Bianco, Anna Monica and Girardelli, Martina and Vozzi, Diego and Crovella, Sergio and Kleiner, Giulio and Marcuzzi, Annalisa} } @article {3502, title = {Novel missense mutation in the NOD2 gene in a patient with early onset ulcerative colitis: causal or chance association?}, journal = {Int J Mol Sci}, volume = {15}, year = {2014}, month = {2014}, pages = {3834-41}, abstract = {

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn{\textquoteright}s disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease.

}, keywords = {Age of Onset, Amino Acid Sequence, Base Sequence, Child, Colitis, Ulcerative, Crohn Disease, DNA Mutational Analysis, Genetic Predisposition to Disease, Genotype, Humans, Interleukin-10 Receptor alpha Subunit, Interleukin-10 Receptor beta Subunit, Molecular Sequence Data, Mutation, Missense, Nod2 Signaling Adaptor Protein, Polymorphism, Single Nucleotide, Risk Factors, Sequence Homology, Amino Acid}, issn = {1422-0067}, doi = {10.3390/ijms15033834}, author = {Girardelli, Martina and Vuch, Josef and Tommasini, Alberto and Crovella, Sergio and Bianco, Anna Monica} } @article {1864, title = {A common genetic background could explain early-onset Crohn{\textquoteright}s disease.}, journal = {Med Hypotheses}, volume = {78}, year = {2012}, month = {2012 Apr}, pages = {520-2}, abstract = {

Crohn{\textquoteright}s disease (CD) is a multifactorial disease, in which environmental, microbial and genetic factors play important roles. CD is characterized by a chronic granulomatous inflammation by necrotic scarring with aspects of full-thickness wall. In spite of affecting mainly young adults, sometimes, CD can be present in the first year of life (early onset Crohn disease, EOCD) showing an unpredictable course and being often more severe than at older ages. In this paper we propose the hypothesis that EOCD patients should be analyzed using a Mendelian approach with family studies aimed to identify new loci directly involved in the early onset Crohn{\textquoteright}s disease. So we will leave the classic association study approach used until now for the identification of genes responsible for susceptibility to CD and propose linkage family analysis as alternative and powerful tool for the identification of new genetic variants associated with familiar cases of EOCD.

}, keywords = {Crohn Disease, Genetic Linkage, Genetic Predisposition to Disease, Humans, Models, Biological}, issn = {1532-2777}, doi = {10.1016/j.mehy.2012.01.023}, author = {Bianco, Anna Monica and Zanin, Valentina and Girardelli, Martina and Magnolato, Andrea and Martelossi, Stefano and Martellossi, Stefano and Tommasini, Alberto and Marcuzzi, Annalisa and Crovella, Sergio} } @article {1844, title = {Inflammation profile of four early onset Crohn patients.}, journal = {Gene}, volume = {493}, year = {2012}, month = {2012 Feb 10}, pages = {282-5}, abstract = {

Crohn disease (CD) is a multifactorial disorder affecting mainly young adults. Sometimes, however, it can present in the first year of life (Early onset Crohn disease (EOCD)) showing an unpredictable course and can often be more severe than at older ages. Some cases have been associated to an underlying primary immunodeficiency such as IL10R deficiency. We studied the functional response to IL-10 and the genotype of IL-10 receptor in four patients with early onset crohn-like colitis. We found an IL10R variant, which may be associated with a decreased response to the cytokine in one patient. Further studies to determine its pathogenic effect should be performed. In addition IL-10 mediated inhibition of LPS-induced TNFα expression was measured in patient{\textquoteright}s monocytes.

}, keywords = {Crohn Disease, Cytokines, Humans, Inflammation, Monocytes, Nod2 Signaling Adaptor Protein, Polymorphism, Genetic, Receptors, Interleukin-10, Tumor Necrosis Factor-alpha}, issn = {1879-0038}, doi = {10.1016/j.gene.2011.11.043}, author = {Marcuzzi, Annalisa and Girardelli, Martina and Bianco, Anna Monica and Martelossi, Stefano and Magnolato, Andrea and Tommasini, Alberto and Crovella, Sergio} } @article {1943, title = {Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line.}, journal = {Int J Dev Neurosci}, volume = {30}, year = {2012}, month = {2012 Oct}, pages = {451-6}, abstract = {

Mevalonic aciduria (MA), the most severe form of mevalonate kinase deficiency (MKD), is still an orphan drug disease and the pathogenetic mechanisms underlying neuronal dysfunction is still poorly understood. In our study we have investigated the apoptotic mechanism mediated by the exposure of the cultured neuroblastoma cell line, SH-SY5Y, to lovastatin in absence or in presence of the isoprenoid, geranylgeraniol, with the aim of unraveling the pathogenesis of MA. Lovastatin, blocks the mevalonate pathway inhibiting the 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR), an enzyme of the mevalonate pathway upstream the mevalonate kinase enzyme, reproducing biochemical features similar to those found in MKD. We demonstrate that apoptosis in neuronal lovastatin treated-cells is induced by the mitochondrial pathway, with caspase-9 as the initiator and caspase-3 as the effector caspase. The presence of geranylgeraniol modulates both the caspase-9 and caspase-3 activity in a dose-dependent way, confirming that this isoprenoid enters the mevalonate pathway, is metabolized and finally is able to by-pass the statin biochemical block reconstituting the mevalonate pathway. According to our findings, it should not be the time course adopted that modulates the apoptotic response but rather the isoprenoid itself. Being aware that our results have been obtained using a biochemical model of MKD, and not cells from patients with the disease, we believe our findings increase the knowledge of MA pathogenesis, and may possibly contribute to the development of novel therapeutic strategies.

}, keywords = {Analysis of Variance, Apoptosis, Caspases, Cell Line, Tumor, Diterpenes, Dose-Response Relationship, Drug, Drug Interactions, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lovastatin, Neuroblastoma, Time Factors}, issn = {1873-474X}, doi = {10.1016/j.ijdevneu.2012.06.002}, author = {Marcuzzi, Annalisa and Zanin, Valentina and Piscianz, Elisa and Tricarico, Paola Maura and Vuch, Josef and Girardelli, Martina and Monasta, Lorenzo and Bianco, Anna Monica and Crovella, Sergio} } @article {1971, title = {NLRP1 polymorphisms in patients with asbestos-associated mesothelioma.}, journal = {Infect Agent Cancer}, volume = {7}, year = {2012}, month = {2012}, pages = {25}, abstract = {

UNLABELLED:

BACKGROUND: An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22\% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta ({\ss}) activated within the inflammasome complex.NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1{\ss} secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM.

METHODS: 134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms.

RESULTS: While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma. This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52).

CONCLUSION: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesothelioma.

}, issn = {1750-9378}, doi = {10.1186/1750-9378-7-25}, author = {Girardelli, Martina and Maestri, Iva and Rinaldi, Rosa R and Tognon, Mauro and Boldorini, Renzo and Bovenzi, Massimo and Crovella, Sergio and Comar, Manola} } @article {1871, title = {Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus.}, journal = {Autoimmunity}, volume = {45}, year = {2012}, month = {2012 Jun}, pages = {271-8}, abstract = {

Recent findings provide evidence of inflammasome critical role in the predisposition to autoimmune disorders. The involvement of inflammasome in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesized even if no significant association within inflammasome genes mutations or polymorphisms and lupus has been reported yet. We analyzed 14 single nucleotide polymorphisms (SNPs) within 7 inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1, IL1B) in 144 patients affected by systemic lupus erythematosus and in 158 healthy controls from Southern Brazilian (state of S{\~a}o Paulo) with the aim of disclosing the possible role of inflammasome genes in the susceptibility of SLE. Our results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with SLE in our study population, and in particular with the development of nephritis, rash and arthritis. These findings are concordant with previously reported association of NLRP1 with vitiligo and type-1 diabetes underlining once more the involvement of NALP1 inflammasome in the pathogenesis of autoimmune disorders.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Alleles, Apoptosis Regulatory Proteins, Brazil, Female, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Inflammasomes, Lupus Erythematosus, Systemic, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1607-842X}, doi = {10.3109/08916934.2011.637532}, author = {Pontillo, Alessandra and Girardelli, Martina and Kamada, Anselmo J and Pancotto, Joao A T and Donadi, Eduardo A and Crovella, Sergio and Sandrin-Garcia, Paula} } @article {1905, title = {Polymorphisms in inflammasome{\textquoteright} genes and susceptibility to HIV-1 infection.}, journal = {J Acquir Immune Defic Syndr}, volume = {59}, year = {2012}, month = {2012 Feb 1}, pages = {121-5}, abstract = {

The involvement of inflammasome genes in the susceptibility to HIV-1 infection was investigated. Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects and 158 healthy controls. The 2 polymorphisms rs10754558 in NLRP3 and rs1143634 in IL1B were significantly associated to the HIV-1 infection. These findings supported the previously hypothesized involvement of NALP3-inflammasome in HIV-1 pathogenesis, underlining once more the key role of inflammation and innate immunity in the susceptibility to HIV-1 infection.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Apoptosis Regulatory Proteins, Brazil, Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Carrier Proteins, Caspase 1, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, HIV Infections, HIV-1, Humans, Inflammasomes, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Neoplasm Proteins, Polymorphism, Single Nucleotide}, issn = {1944-7884}, doi = {10.1097/QAI.0b013e3182392ebe}, author = {Pontillo, Alessandra and Oshiro, Telma M and Girardelli, Martina and Kamada, Anselmo J and Crovella, Sergio and Duarte, Alberto J S} }