@article {10764, title = {Changing Epidemiology of Liver Involvement in Children With Celiac Disease.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {68}, year = {2019}, month = {2019 Apr}, pages = {547-551}, abstract = {

OBJECTIVES: Available data indicate that liver involvement is present in a significant proportion of children with celiac disease (CD) at the diagnosis (elevated transaminases 15\%-57\%, autoimmune liver disease 1\%-2\%). We sought to evaluate prevalence, clinical course, and risk factors for liver involvement in a large cohort of children with CD.

METHODS: Children (age 0-18 years) diagnosed with CD from March 2010 to April 2016 were enrolled. Liver involvement was considered to be present when alanine transaminase (ALT) levels were >40 U/L (hypertransaminasemia [HTS]). Patients with HTS were re-evaluated after at least 12 months of a gluten-free diet.

RESULTS: CD was diagnosed in 806 patients during the study period; of these, ALT levels were available for 700 patients (86.9\%), and were elevated in 27 (3.9\%, HTS group); median ALT and aspartate transaminase levels in the HTS group were 57 U/L (interquartile range 49-80 U/L) and 67 U/L (interquartile range 53-85 U/L), respectively. Younger age, malabsorption symptoms, and low hemoglobin or ferritin were significantly more common in the HTS group at univariate analysis. At multivariate analysis, only age <=4.27 years correlated with risk of liver involvement (odds ratio 3.73; 95\% confidence interval: 1.61-8.66). When retested on a gluten-free diet, all but 3 patients normalized ALT levels; of these, 1 was diagnosed with sclerosing cholangitis.

CONCLUSIONS: Liver involvement in celiac children is now less frequent than previously reported, possibly due to changing CD epidemiology. Younger age is the only risk factor. Associated autoimmune liver disease is rare.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000002209}, author = {Benelli, Elisa and Naviglio, Samuele and De Leo, Luigina and Stera, Giacomo and Giangreco, Manuela and Ronfani, Luca and Villanacci, Vincenzo and Martelossi, Stefano and Ventura, Alessandro and Not, Tarcisio} } @article {10416, title = {Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {66}, year = {2018}, month = {2018 Jan}, pages = {64-68}, abstract = {

OBJECTIVES: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic gluten intolerance, and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders.

METHODS: Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children experiencing gastrointestinal disorders. CD patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD).

RESULTS: We analyzed the sera of 274 CD children and of 121 controls. Anti-TG6 were detected in 68/274 (25\%) CD patients and in 19/121 (16\%) controls, with significant difference between the 2 groups (P = 0.04). None of the CD patients and of the controls testing positive for anti-TG6 were experiencing neurological disorders. Eleven of 18 (61\%) CD patients with other autoimmune diseases were positive for anti-TG6. In CD patients, a significant correlation between the gluten exposure before the CD diagnosis and anti-TG6 concentration was found (P = 0.006 for IgA; P < 0.0001 for IgG). After GFD anti-TG6 concentrations were significantly reduced (P < 0.001). No significant correlation was observed between anti-TG6 and anti-TG2 serum concentrations.

CONCLUSIONS: Anti-TG6 are more prevalent in children with untreated CD in the absence of overt neurological disorders. The synthesis of the anti-TG6 is related to a longer exposure to gluten before the CD diagnosis, and the autoimmunity against TG6 is gluten dependent and disappeared during GFD.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001642}, author = {De Leo, Luigina and Aeschlimann, Daniel and Hadjivassiliou, Marios and Aeschlimann, Pascale and Salce, Nicola and Vatta, Serena and Ziberna, Fabiana and Cozzi, Giorgio and Martelossi, Stefano and Ventura, Alessandro and Not, Tarcisio} } @article {10443, title = {Immunohistologic analysis of the duodenal bulb: a new method for celiac disease diagnosis in children.}, journal = {Gastrointest Endosc}, volume = {88}, year = {2018}, month = {2018 Sep}, pages = {521-526}, abstract = {

BACKGROUND AND AIMS: Anti-tissue transglutaminase antibodies (anti-tTG) have simplified celiac disease (CD) diagnosis. However, in atypical forms of CD, intestinal biopsy sampling is still required. This prospective study investigates whether histologic analysis of the duodenal bulb combined with intestinal IgA anti-tTG deposit immunoassay makes CD diagnosis possible in at-risk children with low concentrations of serum anti-tTG.

METHODS: Histologic and intestinal IgA anti-tTG deposit immunoassays were used.

RESULTS: Two hundred forty-five symptomatic children positive for serum anti-tTG (>7 U/mL) were enrolled and~divided into 3 groups: extensive duodenal atrophy (n~= 209), with IgA anti-tTG deposits throughout the duodenum and high serum anti-tTG concentrations (157 {\textpm} 178 U/mL); bulb duodenal atrophy (n~= 22), with widespread IgA anti-tTG deposits in 9 and in the bulb alone in 13 and low serum anti-tTG concentrations (13.9~{\textpm} 8.7 U/mL); and normal duodenum (n~= 14), with widespread IgA anti-tTG deposits in 8 and in the bulb alone in 6 and low serum anti-tTG concentrations (10.6 {\textpm} 6.2 U/mL). All patients in the first 2 groups were diagnosed with CD and 8 from the third group. All improved after 1 year of gluten-free diet. Bulb duodenal analysis led to a 12\% (30/245) increase in CD diagnosis. No CD-related lesions were observed in the 30 control subjects.

CONCLUSIONS: In children at risk for CD, bulb duodenum biopsy sampling is essential to identify villous atrophy and detect IgA anti-tTG deposits even in absence of intestinal lesions. These mucosal autoantibodies could well represent a new standard for diagnosing CD.

}, keywords = {Adolescent, Autoantibodies, Celiac Disease, Child, Child, Preschool, Duodenum, Female, Humans, Immunoglobulin A, Immunohistochemistry, Infant, Male, Prospective Studies, Transglutaminases}, issn = {1097-6779}, doi = {10.1016/j.gie.2018.05.014}, author = {De Leo, Luigina and Villanacci, Vincenzo and Ziberna, Fabiana and Vatta, Serena and Martelossi, Stefano and Di Leo, Grazia and Zanchi, Chiara and Bramuzzo, Matteo and Giudici, Fabiola and Ventura, Alessandro and Not, Tarcisio} } @article {10834, title = {Potential use of MCR-ALS for the identification of coeliac-related biochemical changes in hyperspectral Raman maps from pediatric intestinal biopsies.}, journal = {Integr Biol (Camb)}, volume = {10}, year = {2018}, month = {2018 06 18}, pages = {356-363}, abstract = {

Raman hyperspectral imaging is an emerging practice in biological and biomedical research for label free analysis of tissues and cells. Using this method, both spatial distribution and spectral information of analyzed samples can be obtained. The current study reports the first Raman microspectroscopic characterisation of colon tissues from patients with Coeliac Disease (CD). The aim was to assess if Raman imaging coupled with hyperspectral multivariate image analysis is capable of detecting the alterations in the biochemical composition of intestinal tissues associated with CD. The analytical approach was based on a multi-step methodology: duodenal biopsies from healthy and coeliac patients were measured and processed with Multivariate Curve Resolution Alternating Least Squares (MCR-ALS). Based on the distribution maps and the pure spectra of the image constituents obtained from MCR-ALS, interesting biochemical differences between healthy and coeliac patients has been derived. Noticeably, a reduced distribution of complex lipids in the pericryptic space, and a different distribution and abundance of proteins rich in beta-sheet structures was found in CD patients. The output of the MCR-ALS analysis was then used as a starting point for two clustering algorithms (k-means clustering and hierarchical clustering methods). Both methods converged with similar results providing precise segmentation over multiple Raman images of studied tissues.

}, issn = {1757-9708}, doi = {10.1039/c8ib00028j}, author = {Fornasaro, Stefano and Vicario, Annalisa and De Leo, Luigina and Bonifacio, Alois and Not, Tarcisio and Sergo, Valter} } @article {8505, title = {Cross-sectional study of coeliac autoimmunity in a population of Vietnamese children.}, journal = {BMJ Open}, volume = {6}, year = {2016}, month = {2016}, pages = {e011173}, abstract = {

OBJECTIVE: The prevalence of coeliac disease (CD) in Vietnam is unknown. To fill this void, we assessed the prevalence of serological markers of CD autoimmunity in a population of children in Hanoi.

SETTING: The outpatient blood drawing laboratory of the largest paediatric hospital in North Vietnam was used for the study, which was part of an international project of collaboration between Italy and Vietnam.

PARTICIPANTS: Children having blood drawn for any reason were included. Exclusion criteria were age younger than 2 years, acquired or congenital immune deficiency and inadequate sample. A total of 1961 children (96\%) were enrolled (838 females, 1123 males, median age 5.3 years).

OUTCOMES: Primary outcome was the prevalence of positive autoimmunity to both IgA antitransglutaminase antibodies (anti-tTG) assessed with an ELISA test and antiendomysial antibodies (EMA). Secondary outcome was the prevalence of CD predisposing human leucocyte antigens (HLA) (HLA DQ2/8) in the positive children and in a random group of samples negative for IgA anti-tTG.

RESULTS: The IgA anti-tTG test was positive in 21/1961 (1\%; 95\% CI 0.61\% to 1.53\%); however, EMA antibodies were negative in all. HLA DQ2/8 was present in 7/21 (33\%; 95\% CI 14.5\% to 56.9\%) of the anti-tTG-positive children and in 72/275 (26\%; 95\% CI 21\% to 32\%) of those who were negative.

CONCLUSIONS: Coeliac autoimmunity is rare in Vietnam, although prevalence of HLA DQ2/8 is similar to that of other countries. We hypothesise that the scarce exposure to gluten could be responsible for these findings.

}, issn = {2044-6055}, doi = {10.1136/bmjopen-2016-011173}, author = {Zanella, Sara and De Leo, Luigina and Nguyen-Ngoc-Quynh, Le and Nguyen-Duy, Bo and Not, Tarcisio and Tran-Thi-Chi, Mai and Phung-Duc, Son and Le-Thanh, Hai and Malaventura, Cristina and Vatta, Serena and Ziberna, Fabiana and Mazzocco, Martina and Volpato, Stefano and Phung-Tuyet, Lan and Le-Thi-Minh, Huong and Borgna-Pignatti, Caterina} } @article {8346, title = {Innate and adaptive immunity in self-reported nonceliac gluten sensitivity versus celiac disease.}, journal = {Dig Liver Dis}, volume = {48}, year = {2016}, month = {2016 Jul}, pages = {745-52}, abstract = {

BACKGROUND: Immune mechanisms have been implicated in nonceliac gluten sensitivity (NCGS), a condition characterized by intestinal and/or extraintestinal symptoms caused by the ingestion of gluten in non-celiac/non-wheat allergic individuals.

AIMS: We investigated innate and adaptive immunity in self-reported NCGS versus celiac disease (CD).

METHODS: In the supernatants of ex vivo-cultured duodenal biopsies from 14 self-reported NCGS patients, 9 untreated and 10 treated CD patients, and 12 controls we detected innate cytokines - interleukin (IL)-15, tumor necrosis factor-α, IL-1β, IL-6, IL-12p70, IL-23, IL-27, IL-32α, thymic stromal lymphopoietin (TSLP), IFN-α-, adaptive cytokines - interferon (IFN)-γ, IL-17A, IL-4, IL-5, IL-10, IL-13-, chemokines - IL-8, CCL1, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL10-, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF).

RESULTS: Mucosal innate and adaptive cytokines, chemokines and growth factors did not differ between self-reported NCGS, treated CD and controls. On the contrary, IL-6, IL-15, IL-27, IFN-α, IFN-γ, IL-17A, IL-23, G-CSF, GM-CSF, IL-8, CCL1 and CCL4 were significantly higher in untreated CD than in self-reported NCGS, treated CD and controls, while TSLP was significantly lower in untreated CD than in self-reported NCGS, treated CD and controls.

CONCLUSION: In our hands, patients with self-reported NCGS showed no abnormalities of the mucosal immune response.

}, issn = {1878-3562}, doi = {10.1016/j.dld.2016.03.024}, author = {Di Sabatino, Antonio and Giuffrida, Paolo and Fornasa, Giulia and Salvatore, Chiara and Vanoli, Alessandro and Naviglio, Samuele and De Leo, Luigina and Pasini, Alessandra and De Amici, Mara and Alvisi, Costanza and Not, Tarcisio and Rescigno, Maria and Corazza, Gino Roberto} } @article {8524, title = {Lack of Evidence of Rotavirus-Dependent Molecular Mimicry as a Trigger of Celiac Disease.}, journal = {Clin Exp Immunol}, year = {2016}, month = {2016 Aug 22}, abstract = {

New data suggest the involvement of Rotavirus (RV) in triggering autoimmunity in celiac disease (CD) by molecular mimicry between the human-transglutaminase protein and the dodecapeptide (260-271 aa) of the RV protein VP7 (pVP7). To assess the role of RV in the onset of CD, we measured the anti-pVP7 antibodies in the sera of children with CD and of control groups. We analysed serum samples of 118 biopsy proven CD patients and 46 patients with potential-CD; 32 children with other gastrointestinal diseases; 107 no-CD children and 107 blood donors. By ELISA assay, we measured IgA-IgG antibodies against the synthetic peptides pVP7, the human transglutaminase-derived peptide (476-487 aa) which shows an homology with VP7 protein and a control peptide. The triple-layered RV particles (TLPs), containing the VP7 protein, and the double-layered RV-particles (DLPs), lacking the VP7 protein were also used as antigens in ELISA assay. Antibody reactivity to the RV-TLPs was positive in 22/118 (18\%) CD patients and in both paediatric (17/107, 16\%) and adult (29/107, 27\%) control groups, without showing a statistically significant difference among them (p=0.6, p=0.1). Biopsy-proven CD patients as well as the adult control group demonstrated a high positive antibody reactivity against both pVP7 (34/118, 29\% CD patients; 66/107, 62\% adult controls) and control synthetic peptides (35/118, 30\% CD patients; 56/107, 52\% adult controls) suggesting a non-specific response against RV pVP7. We show that children with CD do not have higher immune reactivity to RV, thus questioning the molecular mimicry mechanism as a triggering factor of CD. This article is protected by copyright. All rights reserved.

}, issn = {1365-2249}, doi = {10.1111/cei.12855}, author = {Ziberna, Fabiana and De Lorenzo, Giuditta and Schiavon, Valentina and Arnoldi, Francesca and Quaglia, Sara and De Leo, Luigina and Vatta, Serena and Martelossi, Stefano and Burrone, Oscar R and Ventura, Alessandro and Not, Tarcisio} } @article {8073, title = {A Sensitive Electrochemiluminescence Immunosensor for Celiac Disease Diagnosis Based on Nanoelectrode Ensembles.}, journal = {Anal Chem}, volume = {87}, year = {2015}, month = {2015 Dec 15}, pages = {12080-7}, issn = {1520-6882}, doi = {10.1021/acs.analchem.5b02801}, author = {Habtamu, Henok B and Sentic, Milica and Silvestrini, Morena and De Leo, Luigina and Not, Tarcisio and Arbault, Stephane and Manojlovic, Dragan and Sojic, Neso and Ugo, Paolo} } @article {7759, title = {Serum anti-tissue transglutaminase antibodies detected during febrile illness may not be produced by the intestinal mucosa.}, journal = {J Pediatr}, volume = {166}, year = {2015}, month = {2015 Mar}, pages = {761-3}, abstract = {

Anti-transglutaminase antibodies are the diagnostic marker of celiac disease, and are considered to be synthesized only by intestinal B-lymphocytes. During an infectious disease, these antibodies are transiently detected in serum. We show that these infection-triggered antibodies may not originate in the intestinal mucosa and are not an indication of celiac disease.

}, keywords = {Autoantibodies, Celiac Disease, Child, Preschool, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, GTP-Binding Proteins, Humans, Intestinal Mucosa, Male, Transglutaminases}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.12.005}, author = {De Leo, Luigina and Quaglia, Sara and Ziberna, Fabiana and Vatta, Serena and Martelossi, Stefano and Maschio, Massimo and Not, Tarcisio} } @article {3521, title = {Intestinal-mucosa anti-transglutaminase antibody assays to test for genetic gluten intolerance.}, journal = {Cell Mol Immunol}, volume = {11}, year = {2014}, month = {2014 Nov}, pages = {617-20}, keywords = {Celiac Disease, Cell Surface Display Techniques, Child, Diet, Gluten-Free, Disease Progression, Early Diagnosis, Female, Follow-Up Studies, HLA-DQ Antigens, Humans, Immunoassay, Immunoglobulin A, Intestinal Mucosa, Male, Prospective Studies, Transglutaminases}, issn = {2042-0226}, doi = {10.1038/cmi.2014.32}, author = {Quaglia, Sara and De Leo, Luigina and Ziberna, Fabiana and Vatta, Serena and Villanacci, Vincenzo and Granzotto, Marilena and Petix, Vincenzo and Martelossi, Stefano and Di Leo, Grazia and Torelli, Lucio and Not, Tarcisio} } @article {1931, title = {Gluten-dependent intestinal autoimmune response.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5753-8}, abstract = {

Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten-dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti-transglutaminase antibodies are found deposited in intestinal and extra-intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease.

}, keywords = {Animals, Autoantibodies, Celiac Disease, Genetic Predisposition to Disease, Gliadin, Glutens, Humans, Intestinal Mucosa, T-Lymphocytes, Transglutaminases}, issn = {1873-4286}, author = {Korponay-Szab{\'o}, Ilma Rita and Simon-Vecsei, Zsafia and De Leo, Luigina and Not, Tarcisio} } @article {1602, title = {The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation.}, journal = {FASEB J}, volume = {25}, year = {2011}, month = {2011 Jan}, pages = {144-58}, abstract = {

Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure-function analysis has mapped this activity to aa 288-293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did Zot and its processed mature form, ΔG. AT1002 increased in vivo permeability to sugar tracers, whereas scrambled control peptides did not. Binding and barrier assays in proteinase activated receptor (PAR)(2)-expressing and PAR(2)-null cells established AT1002 activity to be PAR(2) dependent. Coincident with the increased intestinal permeability, confocal microscopy of AT1002-exposed rat intestinal IEC6 cells revealed displacement of ZO-1 and occludin from intercellular boundaries. In coimmunoprecipitation assays, AT1002 decreased ZO-1-occludin and ZO-1-claudin 1 interactions coincident with PKCα-dependent ZO-1 serine/threonine phosphorylation. Further, AT1002 increased serine phosphorylation of myosin 1C and, at the same time, transiently diminished its association with ZO-1. The COOH-terminal domain of ZO-1 was required for its association with myosin 1C. These data indicate that the NH(2)-terminal portion of active Zot contains a PAR(2)-activating motif, FCIGRL, that increases PKCα-dependent ZO-1 and myosin 1C serine/threonine phosphorylation. These modifications provoke selective disengagement of ZO-1 from its binding partners, occludin, claudin 1, and myosin 1C, coincident with opening of tjs.

}, keywords = {Amino Acid Sequence, Animals, Caco-2 Cells, Cell Line, Cells, Cultured, Cholera Toxin, Epithelial Cells, Humans, Immunoblotting, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Myosins, Oligopeptides, Phosphoproteins, Phosphorylation, Protein Binding, Protein Kinase C-alpha, Rats, Rats, Wistar, Receptor, PAR-2, RNA Interference, Serine, Threonine, Tight Junctions, Zonula Occludens-1 Protein}, issn = {1530-6860}, doi = {10.1096/fj.10-158972}, author = {Goldblum, Simeon E and Rai, Usha and Tripathi, Amit and Thakar, Manjusha and De Leo, Luigina and Di Toro, Nicola and Not, Tarcisio and Ramachandran, Rithwik and Puche, Adam C and Hollenberg, Morley D and Fasano, Alessio} } @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 {1653, title = {Fasting increases tobramycin oral absorption in mice.}, journal = {Antimicrob Agents Chemother}, volume = {54}, year = {2010}, month = {2010 Apr}, pages = {1644-6}, abstract = {

The pharmacokinetics of the aminoglycoside tobramycin was evaluated after oral administration to fed or fasting (15 h) mice. As expected, under normal feeding conditions, oral absorption was negligible; however, fasting induced a dramatic increase in tobramycin bioavailability. The dual-sugar test with lactulose and l-rhamnose confirmed increased small bowel permeability via the paracellular route in fasting animals. When experiments aimed at increasing the oral bioavailability of hydrophilic compounds are performed, timing of fasting should be extremely accurate.

}, keywords = {Administration, Oral, Animals, Anti-Bacterial Agents, Biological Availability, Fasting, Injections, Intramuscular, Injections, Intravenous, Intestinal Absorption, Lactulose, Male, Mice, Mice, Inbred BALB C, Rhamnose, Tobramycin}, issn = {1098-6596}, doi = {10.1128/AAC.01172-09}, author = {De Leo, Luigina and Di Toro, Nicola and Decorti, Giuliana and Malus{\`a}, Noelia and Ventura, Alessandro and Not, Tarcisio} } @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} }