@article {3491, title = {Exome analysis of HIV patients submitted to dendritic cells therapeutic vaccine reveals an association of CNOT1 gene with response to the treatment.}, journal = {J Int AIDS Soc}, volume = {17}, year = {2014}, month = {2014}, pages = {18938}, abstract = {

INTRODUCTION: With the aim of searching genetic factors associated with the response to an immune treatment based on autologous monocyte-derived dendritic cells pulsed with autologous inactivated HIV, we performed exome analysis by screening more than 240,000 putative functional exonic variants in 18 HIV-positive Brazilian patients that underwent the immune treatment.

METHODS: Exome analysis has been performed using the ILLUMINA Infinium HumanExome BeadChip. zCall algorithm allowed us to recall rare variants. Quality control and SNP-centred analysis were done with GenABEL R package. An in-house implementation of the Wang method permitted gene-centred analysis.

RESULTS: CCR4-NOT transcription complex, subunit 1 (CNOT1) gene (16q21), showed the strongest association with the modification of the response to the therapeutic vaccine (p=0.00075). CNOT1 SNP rs7188697 A/G was significantly associated with DC treatment response. The presence of a G allele indicated poor response to the therapeutic vaccine (p=0.0031; OR=33.00; CI=1.74-624.66), and the SNP behaved in a dominant model (A/A vs. A/G+G/G p=0.0009; OR=107.66; 95\% CI=3.85-3013.31), being the A/G genotype present only in weak/transient responders, conferring susceptibility to poor response to the immune treatment.

DISCUSSION: CNOT1 is known to be involved in the control of mRNA deadenylation and mRNA decay. Moreover, CNOT1 has been recently described as being involved in the regulation of inflammatory processes mediated by tristetraprolin (TTP). The TTP-CCR4-NOT complex (CNOT1 in the CCR4-NOT complex is the binding site for TTP) has been reported as interfering with HIV replication, through post-transcriptional control. Therefore, we can hypothesize that genetic variation occurring in the CNOT1 gene could impair the TTP-CCR4-NOT complex, thus interfering with HIV replication and/or host immune response.

CONCLUSIONS: Being aware that our findings are exclusive to the 18 patients studied with a need for replication, and that the genetic variant of CNOT1 gene, localized at intron 3, has no known functional effect, we propose a novel potential candidate locus for the modulation of the response to the immune treatment, and open a discussion on the necessity to consider the host genome as another potential variant to be evaluated when designing an immune therapy study.

}, keywords = {AIDS Vaccines, Dendritic Cells, Exome, HIV Infections, Humans, Immunity, Humoral, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Transcription Factors, Treatment Outcome}, issn = {1758-2652}, doi = {10.7448/IAS.17.1.18938}, author = {Moura, Ronald and Pontillo, Alessandra and d{\textquoteright}Adamo, Pio and Pirastu, Nicola and Campos Coelho, Antonio and Crovella, Sergio} } @article {3624, title = {NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection.}, journal = {Mem Inst Oswaldo Cruz}, volume = {109}, year = {2014}, month = {2014 Nov}, pages = {960-3}, abstract = {

Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

}, keywords = {Adult, Brazil, Carrier Proteins, Female, Genetic Predisposition to Disease, HTLV-I Infections, Human T-lymphotropic virus 1, Humans, Inflammasomes, Interleukin-1, Male, Middle Aged, Polymorphism, Single Nucleotide, Protective Factors}, issn = {1678-8060}, author = {Kamada, Anselmo Jiro and Pontillo, Alessandra and Guimar{\~a}es, Rafael Lima and Loureiro, Paula and Crovella, Sergio and Brand{\~a}o, Lucas Andr{\'e} Cavalcanti} } @article {1825, title = {HIV-1 induces NALP3-inflammasome expression and interleukin-1β secretion in dendritic cells from healthy individuals but not from HIV-positive patients.}, journal = {AIDS}, volume = {26}, year = {2012}, month = {2012 Jan 2}, pages = {11-8}, abstract = {

OBJECTIVE: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals.

DESIGN AND METHODS: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion.

RESULTS: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients{\textquoteright} immune cells.

CONCLUSION: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines.

}, keywords = {Acquired Immunodeficiency Syndrome, Adult, Brazil, Carrier Proteins, Caspase 1, Cells, Cultured, Dendritic Cells, DNA, Viral, Female, HIV-1, Humans, Immunity, Innate, Inflammasomes, Interleukin-1beta, Male, Tumor Necrosis Factor-alpha}, issn = {1473-5571}, doi = {10.1097/QAD.0b013e32834d697f}, author = {Pontillo, Alessandra and Silva, Lais T and Oshiro, Telma M and Finazzo, Claudia and Crovella, Sergio and Duarte, Alberto J S} } @article {1731, title = {NALP1/NLRP1 genetic variants are associated with Alzheimer disease.}, journal = {Alzheimer Dis Assoc Disord}, volume = {26}, year = {2012}, month = {2012 Jul-Sep}, pages = {277-81}, abstract = {

Alzheimer disease (AD) is a complex neurodegenerative disease. Genetic and molecular studies have confirmed that in the human brain, amyloid-β fibrils can induce, through the activation of NALP1 inflammosome, inflammatory and apoptotic responses involved in the pathogenesis of AD. Considering that AD pathogenesis is multifactorial, we hypothesized that NALP1/NLRP1 could be a susceptibility gene involved in the devolvement of the disease. The possible association between 9 selected polymorphisms in the NALP1/NLRP1 gene and AD was evaluated by comparing their frequency distribution in an Italian cohort of AD patients (AD, n = 276) and in a group of Italian sex-matched and age-matched healthy controls without dementia (HC, n = 266). Our study, evidences the association of 4 nonsynonymous polymorphisms in the NLRP1 gene (rs2137722, rs34733791, rs11657747, rs11651595) with AD. The major alleles of all 4 single nucleotide polymorphisms and the corresponding homozygote genotypes were more frequent in AD patients than in healthy controls, suggesting an association of these variants in the predisposition versus the development of the disease. These findings seem to support the previously reported role of NALP1 in neuronal damage, and provide evidence of an association between single nucleotide variations in the NLRP1 gene and AD.

}, keywords = {Adaptor Proteins, Signal Transducing, Aged, 80 and over, Alzheimer Disease, Apoptosis Regulatory Proteins, Female, Genetic Predisposition to Disease, Genotype, Humans, Italy, Male, Polymerase Chain Reaction, Polymorphism, Single Nucleotide}, issn = {1546-4156}, doi = {10.1097/WAD.0b013e318231a8ac}, author = {Pontillo, Alessandra and Catamo, Eulalia and Arosio, Beatrice and Mari, Daniela and Crovella, Sergio} } @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} } @article {1797, title = {Anti-α-enolase Antibodies in Serum from Pediatric Patients Affected by Inflammatory Diseases: Diagnostic and Pathogenetic Insights.}, journal = {Int J Rheumatol}, volume = {2011}, year = {2011}, month = {2011}, pages = {870214}, abstract = {

Human glycolytic enzyme α-enolase was associated with human diseases and with inflammation. An ELISA test was developed to measure anti-α-enolase AAE IgG and AAE IgA in the serum from patients affected by inflammatory diseases with the purpose to evaluate it as a novel diagnostic marker. 80 healthy blood donors and 194 paediatric patients affected by Juvenile idiopathic arthritis (JIA), celiac disease (CD), Crohn{\textquoteright}s Disease (CrD), hereditary periodic fever (HPF), and PFAPA syndrome were included in the study. HPF patients showed high levels of AAE antibodies, whereas JIA, CD, and CrD presented only partial results. Benign fevers such as PFAPA were almost negative for AAE Abs. These findings suggested that the genetic dysfunction of inflammasome associated with HPF could lead to the formation of AAE Abs that could be used for an early and easy diagnosis.

}, issn = {1687-9279}, doi = {10.1155/2011/870214}, author = {Pontillo, Alessandra and Di Toro, Nicola and Edomi, Paolo and Shadlow, A and Ammadeo, A and Gattorno, M and Not, T and Lepore, L and Crovella, S} } @article {1600, title = {Comments on {\textquoteright}{\textquoteright}Geranylgeraniol--a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw" by Ziebart T et al. (2011).}, journal = {Oral Oncol}, volume = {47}, year = {2011}, month = {2011 May}, pages = {436-7; author reply 438}, keywords = {Bone Density Conservation Agents, Diphosphonates, Diterpenes, Humans, Jaw Diseases, Osteonecrosis}, issn = {1879-0593}, doi = {10.1016/j.oraloncology.2011.02.017}, author = {Marcuzzi, Annalisa and Zanin, Valentina and Crovella, Sergio and Pontillo, Alessandra} } @article {1725, title = {The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency.}, journal = {Pediatr Res}, volume = {70}, year = {2011}, month = {2011 Jul}, pages = {78-82}, abstract = {

The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients{\textquoteright} monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.

}, keywords = {Alendronate, Animals, Anti-Inflammatory Agents, Cell Line, Child, Child, Preschool, Cholesterol, Cytokines, Dose-Response Relationship, Drug, Enzyme Inhibitors, Farnesyltranstransferase, Humans, Inflammation Mediators, Lovastatin, Male, Mevalonate Kinase Deficiency, Mice, Monocytes, Phosphotransferases (Alcohol Group Acceptor), Piperidines, Polyenes, Polyisoprenyl Phosphates, Polyunsaturated Alkamides, Pyridines, Quinolones, Terpenes}, issn = {1530-0447}, doi = {10.1038/pr.2011.303}, author = {Marcuzzi, Annalisa and De Leo, Luigina and Decorti, Giuliana and Crovella, Sergio and Tommasini, Alberto and Pontillo, Alessandra} } @article {1652, title = {Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.}, journal = {J Clin Gastroenterol}, volume = {45}, year = {2011}, month = {2011 Jan}, pages = {e1-7}, abstract = {

BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.

AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.

METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.

RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.

CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.

}, keywords = {Adolescent, Child, Drug Resistance, Female, Follow-Up Studies, Genotype, Glucocorticoids, Humans, Inflammatory Bowel Diseases, Male, Multivariate Analysis, Polymorphism, Genetic, Receptors, Glucocorticoid, Regression Analysis, Retrospective Studies, Sex Factors, Treatment Outcome}, issn = {1539-2031}, doi = {10.1097/MCG.0b013e3181e8ae93}, author = {De Iudicibus, Sara and Stocco, Gabriele and Martelossi, Stefano and Londero, Margherita and Ebner, Egle and Pontillo, Alessandra and Lionetti, Paolo and Barabino, Arrigo and Bartoli, Fiora and Ventura, Alessandro and Decorti, Giuliana} } @article {1672, title = {Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency.}, journal = {In Vivo}, volume = {25}, year = {2011}, month = {2011 Jan-Feb}, pages = {87-92}, abstract = {

BACKGROUND/AIM: The inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1β release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate.

MATERIALS AND METHODS: The effect of natural isoprenoid geraniol on bacterial induced-inflammation was evaluated in a monocytic cell line (Raw 264.7) and in Balb/c mice treated with pamidronate.

RESULTS: Geraniol diminished the levels of inflammatory markers induced by pamidronate stimuli in vitro and in vivo.

CONCLUSION: Geraniol may be proposed as a novel therapeutic approach for the orphan disease MKD, and may also be considered for the evaluation of possible inflammatory side-effects of aminobisphosphonates.

}, keywords = {Animals, Anti-Inflammatory Agents, Cell Line, Diphosphonates, Disease Models, Animal, Inflammation, Lipopolysaccharides, Mevalonate Kinase Deficiency, Mice, Mice, Inbred BALB C, Monocytes, Nitric Oxide, Terpenes}, issn = {1791-7549}, author = {Marcuzzi, Annalisa and Crovella, Sergio and Pontillo, Alessandra} } @article {1824, title = {High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Nov}, pages = {3625-32}, abstract = {

OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in \~{}40\% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.

METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.

RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2\%). Estimates of the level of mosaicism ranged from 4.2\% to 35.8\% (mean {\textpm} SD 12.1 {\textpm} 7.9\%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.

CONCLUSION: Somatic NLRP3 mutations were identified in 69.2\% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

}, keywords = {Adolescent, Adult, Carrier Proteins, Case-Control Studies, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Female, Genetic Association Studies, Humans, Infant, Male, Mosaicism}, issn = {1529-0131}, doi = {10.1002/art.30512}, author = {Tanaka, Naoko and Izawa, Kazushi and Saito, Megumu K and Sakuma, Mio and Oshima, Koichi and Ohara, Osamu and Nishikomori, Ryuta and Morimoto, Takeshi and Kambe, Naotomo and Goldbach-Mansky, Raphaela and Aksentijevich, Ivona and de Saint Basile, Genevi{\`e}ve and Neven, B{\'e}n{\'e}dicte and van Gijn, Mari{\"e}lle and Frenkel, Joost and Ar{\'o}stegui, Juan I and Yag{\"u}e, Jordi and Merino, Rosa and Iba{\~n}ez, Mercedes and Pontillo, Alessandra and Takada, Hidetoshi and Imagawa, Tomoyuki and Kawai, Tomoki and Yasumi, Takahiro and Nakahata, Tatsutoshi and Heike, Toshio} } @article {1761, title = {Letter to the editor: acute effects of intravenous administration of pamidronate in patients with osteoporosis.}, journal = {J Korean Med Sci}, volume = {26}, year = {2011}, month = {2011 Jun}, pages = {848-9; author reply 850}, keywords = {Anti-Inflammatory Agents, Cytokines, Diphosphonates, Humans, Injections, Intravenous, Osteoporosis}, issn = {1598-6357}, doi = {10.3346/jkms.2011.26.6.848}, author = {Marcuzzi, Annalisa and Zanin, Valentina and Vuch, Josef and Pontillo, Alessandra and Crovella, Sergio} } @article {1690, title = {The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease.}, journal = {Am J Gastroenterol}, volume = {106}, year = {2011}, month = {2011 Mar}, pages = {539-44}, abstract = {

OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD.

METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls.

RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42).

CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Apoptosis Regulatory Proteins, Carrier Proteins, Celiac Disease, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genotype, Glutamine, Haplotypes, Humans, Inflammasomes, Italy, Lysine, Male, Mutation, Missense, Polymorphism, Single Nucleotide}, issn = {1572-0241}, doi = {10.1038/ajg.2010.474}, author = {Pontillo, Alessandra and Vendramin, Anna and Catamo, Eulalia and Fabris, Annalisa and Crovella, Sergio} } @article {1689, title = {A 3{\textquoteright}UTR SNP in NLRP3 gene is associated with susceptibility to HIV-1 infection.}, journal = {J Acquir Immune Defic Syndr}, volume = {54}, year = {2010}, month = {2010 Jul}, pages = {236-40}, abstract = {

OBJECTIVES: Innate immunity genes polymorphisms are known to be involved in the multifactorial susceptibility to HIV-1 infection. Recently it has been hypothesized that inflammasomes could play an important role in the host response to viruses. The aim of our study is to verify if single-nucleotide polymorphisms (SNPs) in genes encoding for NALPs-innate immune receptors that form molecular complexes leading to the production of IL-1beta and the activation of immune response-could influence the individual susceptibility to HIV-1.

DESIGN: We performed an association study analyzing 2 NLRP1 and NLRP3 SNPs in HIV-1 vertically infected Brazilian children (n = 135), HIV-1-infected Brazilain adults (n = 192) and HIV-1-positive Italian seropositive subjects (n = 192).

RESULTS: The 3{\textquoteright}UTR NLRP3 rs10754558 SNP was associated with HIV-1 infection in all the studied groups. The frequency of rs10754558 G allele was differently distributed within seropositive subjects (HIV+) and controls, and in particular the GG genotype was less frequent in HIV+.

CONCLUSIONS: susceptibility to HIV-1 infection is associated with a 3{\textquoteright}UTR NLRP3 polymorphism. This is the first report linking SNPs in the NALPs with HIV-1 infection, and further epidemiologic and functional studies are needed to deeper investigate the role of inflammasome in the susceptibility to HIV-1 infection.

}, keywords = {Adult, Brazil, Carrier Proteins, Case-Control Studies, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genotype, HIV Infections, HIV-1, Humans, Infant, Infectious Disease Transmission, Vertical, Male, Middle Aged, Polymorphism, Single Nucleotide, Pregnancy, Young Adult}, issn = {1944-7884}, doi = {10.1097/QAI.0b013e3181dd17d4}, author = {Pontillo, Alessandra and Brand{\~a}o, Lucas A and Guimar{\~a}es, Rafael L and Segat, Ludovica and Athanasakis, Emmanouil and Crovella, Sergio} } @article {1673, title = {Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency.}, journal = {Inflamm Res}, volume = {59}, year = {2010}, month = {2010 May}, pages = {335-8}, abstract = {

OBJECTIVE: The aim of this study was to evaluate, in a mouse model of mevalonate kinase deficiency (MKD), the possible link between inflammatory symptoms and serum cholesterol levels.

MATERIALS AND METHODS: Balb/c mice were treated with alendronate and bacterial muramyl dipeptide. Body temperature, interleukin-1 beta (IL-1 beta) secretion and serum cholesterol levels were measured.

RESULTS: An increased production of the pro-inflammatory cytokine IL-1 beta (p < 0.05) and a rise in body temperature (p < 0.05) was observed, while, in parallel, serum cholesterol concentration significantly decreased (p < 0.05). These effects were completely reversed when animals were treated with exogenous isoprenoids.

CONCLUSIONS: In the mouse model of MKD, the inflammatory response is associated with a reduction in cholesterol levels, and hence this parameter could be used as an indicator of isoprenoid consumption. In addition, plant derived isoprenoids could represent candidate treatments for this disease.

}, keywords = {Animals, Anti-Inflammatory Agents, Cholesterol, Disease Models, Animal, Inflammation, Interleukin-1beta, Male, Mevalonate Kinase Deficiency, Mice, Mice, Inbred BALB C, Random Allocation, Terpenes}, issn = {1420-908X}, doi = {10.1007/s00011-010-0168-6}, author = {Marcuzzi, Annalisa and Decorti, Giuliana and Pontillo, Alessandra and Ventura, Alessandro and Tommasini, Alberto} } @article {1683, title = {Histatins in non-human primates: gene variations and functional effects.}, journal = {Protein Pept Lett}, volume = {17}, year = {2010}, month = {2010 Jul}, pages = {909-18}, abstract = {

Human histatins are histidine-rich, low molecular weight salivary proteins that contribute to the immune system of the oral cavity. In this work, nucleotide sequences of the HIS1 (coding for histatin 1) and HIS2 (coding for histatin 3) genes, homologous to the human ones, have been sequenced and analysed in five primates species including Great Ape, Hylobatidae and Cercopithecidae. In HIS1, the region corresponding to the putative mature peptide shows a premature stop codon in Macaca and Cercopithecus, while HIS2 a six codon insertion in the Cercopithecidae. Histatin 5, a 24-residue peptide derived from histatin 3, is the most antimicrobially active among human histatins, thus macaque and nomascus orthologues of histatin 5 were selected for chemical synthesis and functional characterization, in comparison to the human peptide. All synthesized histatins are predicted to be poorly amphipathic, depending on the charged state of His residues and assume partially a-helical conformations only in lipophilic conditions. Antimicrobial assays against Candida and Criptococcus spp. indicate somewhat different spectra of in vitro activity against the tested fungi. We have described HIS1 and HIS2 gene variations in primates and have analysed their functional effects on selected Hst5 orthologues. The human antimicrobial peptide has been proposed to represent an important lead for new generation of antimicrobial compounds for the treatment of oral mycoses, thus the information from the non-human primates histatins studied may aid strategies for drugs design.

}, keywords = {Amino Acid Sequence, Animals, Anti-Infective Agents, Base Sequence, Candida, Catarrhini, Cell Proliferation, Computational Biology, Cryptococcus, Genetic Variation, Histatins, Humans, Molecular Sequence Data, Phylogeny, Sequence Alignment, Sequence Analysis, DNA}, issn = {1875-5305}, author = {Padovan, Lara and Segat, Ludovica and Pontillo, Alessandra and Antcheva, Nikolinka and Tossi, Alessandro and Crovella, Sergio} } @article {1674, title = {Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes.}, journal = {Int Immunopharmacol}, volume = {10}, year = {2010}, month = {2010 Jun}, pages = {639-42}, abstract = {

The inhibition of mevalonate pathway through genetic defects (mevalonate kinase deficiency, MKD) or pharmacologic drugs (aminobisphosphonates) causes a shortage of intermediate compounds and, in particular, of geranylgeranyl-pyrophosphate (GGPP) associated to the activation of caspase-1 and IL-1beta release. Geraniol (GOH), farnesol (FOH), geranylgeraniol (GGOH) and menthol (MOH), due to their isoprenoid structure, are supposed to enter the mevalonate pathway and to by-pass the biochemical block, reconstituting the pathway. Considering the already known side effects of aminobisphosphonates, and the lack of a specific treatment for MKD, we evaluated the impact of these natural isoprenoids compounds in a RAW cell lines chemically treated with the aminobisphosphonate alendronate, and in monocytes isolated from 2 patients affected by MKD. GOH, FOH, GGOH and MOH were all capable to diminish inflammatory marker levels induced by LPS. These natural isoprenoids could be proposed as novel therapeutic approach for the still orphan drug MKD, but also considered for the evaluation of possible inflammatory side effects of aminobisphosphonates.

}, keywords = {Animals, Cell Line, Cells, Cultured, Child, Child, Preschool, Cytokines, Diphosphonates, Humans, Inflammation, Interleukin-1beta, Lipopolysaccharides, Male, Mevalonate Kinase Deficiency, Mice, Monocytes, Nitric Oxide, Terpenes}, issn = {1878-1705}, doi = {10.1016/j.intimp.2010.03.008}, author = {Marcuzzi, Annalisa and Tommasini, Alberto and Crovella, Sergio and Pontillo, Alessandra} } @article {1654, title = {Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches.}, journal = {Pharmacol Res}, volume = {61}, year = {2010}, month = {2010 Jun}, pages = {506-10}, abstract = {

Mevalonate kinase deficiency (MKD) is a rare inborn auto-inflammatory disease due to the impairment of the pathway for the biosynthesis of cholesterol and non-sterol isoprenoids. The shortage of isoprenoids compounds and in particular of geranylgeranylpyrophosphate (GGPP) was recently associated to the MKD characteristic inflammatory attacks. The aim of this study is to demonstrate that the normalization of the mevalonate pathway intermediates levels and in particular of GGPP, through the specific inhibition of farnesyl-transferase (FT) with Manumycin A could ameliorate the inflammatory phenotype of MKD patients. The effect of Manumycin A was first evaluated in MKD mouse and cellular models, chemically obtained using the aminobisphosphonate alendronate (ALD), and then in monocytes isolated from 2 MKD patients. Our findings were compared to those obtained by using natural exogenous isoprenoids (NEIs). Manumycin A was able to significantly reduce the inflammatory marker serum amyloid A in ALD-treated Balb/c mice, as well as IL-1 beta secretion in ALD-monocytes and in MKD patients. These results clearly showed that, through the inhibition of FT, an increased number of mevalonate pathway intermediates could be redirected towards the synthesis of GGPP diminishing the inflammatory response. The importance in limiting the shortage of GGPP was emphasized by the anti-inflammatory effect of NEIs that, due to their biochemical structure, can enter the MKD pathway. In conclusion, manumycin A, as well as NEIs, showed anti-inflammatory effect in MKD models and especially in MKD-monocytes, suggesting novel approaches in the treatment of MKD, an orphan disease without any efficacious treatment currently available.

}, keywords = {Adult, Animals, Anti-Inflammatory Agents, Cells, Cultured, Child, Preschool, Enzyme Inhibitors, Farnesyltranstransferase, Female, Humans, Male, Mevalonate Kinase Deficiency, Mevalonic Acid, Mice, Mice, Inbred BALB C, Monocytes, Polyenes, Polyisoprenyl Phosphates, Polyunsaturated Alkamides, Young Adult}, issn = {1096-1186}, doi = {10.1016/j.phrs.2010.02.012}, author = {De Leo, Luigina and Marcuzzi, Annalisa and Decorti, Giuliana and Tommasini, Alberto and Crovella, Sergio and Pontillo, Alessandra} }