Liliana Mannucci - Academia.edu (original) (raw)

Papers by Liliana Mannucci

Acta Diabetologica, Nov 6, 2010

Plant sterols lower serum cholesterol concentration. Available data have confirmed the lipid-lowe... more Plant sterols lower serum cholesterol concentration. Available data have confirmed the lipid-lowering efficacy in adults, while there is a relative dearth of data in children and almost exclusively restricted to subjects with familial hypercholesterolemia (FH). Aim of the present study was to evaluate the efficacy, tolerability and safety of plant sterol supplementation in children with different forms of primary hyperlipidemias. The effect of plant sterol consumption on plasma lipids was evaluated in 32 children with heterozygous FH, 13 children with Familial Combined Hyperlipidemia (FCH) and 13 children with Undefined Hypercholesterolemia (UH) in a 12-week open-label intervention study using plant sterol-enriched yoghurt. Plasma lipids and apolipoproteins were measured by routine methods. Markers of cholesterol synthesis (lathosterol) and absorption (campesterol and sitosterol) were measured by GC-MS. Tolerability and adherence to recommended regimen was very high. A significant reduction was observed in LDL-cholesterol in the three groups (10.7, 14.2 and 16.0% in FH, FCH and UH, respectively). Lathosterol concentrations were unchanged, reflecting a lack of increased synthesis of cholesterol. Of the two absorption markers, only sitosterol showed a slight but significant increase. Daily consumption of plant sterol dairy products favorably changes lipid profile by reducing LDL-cholesterol. To our knowledge, this is the first report of the use of plant sterols-enriched foods in treating children with primary hyperlipidemia such as FCH and UH, likely to be the most frequent form also in the young age in the western populations.

International Journal of Immunopathology and Pharmacology, 2019

Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and... more Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and death. Recently, many data have sustained the biological link between microvascular dysfunction, oxidative stress, vascular inflammation, and metabolic diseases. The determination of new and specific blood biomarkers of vascular inflammation associated with obesity-related metabolic syndrome (MetS) and diabetes such as lipoprotein-associated phospholipase A 2 (Lp-PLA 2) could be useful to identify subject with high risk of cardiovascular events. Lp-PLA 2 participates by a crucial role in microvascular dysfunction and oxidative stress showing positive association with metabolic disorders. In this review, we will argue the evolving role of Lp-PLA 2 in predicting cardiovascular events in metabolic disease patients.

American Journal of Physiology-renal Physiology, May 1, 2008

Pediatric Research, Feb 1, 2006

Cystinotic patients have been shown to excrete in their urine high levels of pyroglutamate, an in... more Cystinotic patients have been shown to excrete in their urine high levels of pyroglutamate, an intermediate metabolite of the adenosine triphosphate (ATP)-dependent ␥-glutamyl cycle, which is responsible for glutathione (GSH) synthesis. Human fibroblasts were used to study the mechanisms leading to pyroglutamate accumulation in nephropathic cystinosis (NC). We show that inhibition of ATP synthesis caused a marked intracellular accumulation of pyroglutamate, reflecting decreased GSH synthesis. Despite similar degrees of ATP depletion, pyroglutamate increased more in cystinotic fibroblasts than in controls, while GSH decreased to lower levels. In addition, cystinotic cells exposed to oxidative stress (hydrogen peroxide) were unable to increase their GSH concentration above baseline. These results could not be attributed to differences in mitochondrial oxidative activity or to increased apoptotic cell death. Together, these results support the hypothesis that cysteine derived from lysosomal cystine efflux limits the activity of the ␥-glutamyl cycle and GSH synthesis.

Annals of Human Genetics, Jun 2, 2020

The complexity in the molecular diagnosis of Cystic Fibrosis (CF) also depends on the variable pr... more The complexity in the molecular diagnosis of Cystic Fibrosis (CF) also depends on the variable prevalence/incidence of the disease associated with the wide CFTR allelic heterogeneity among different populations. In fact, CF incidence in Asian and African countries is underestimated and the few patients reported so far have rare or unique CFTR pathogenic variants. To obtain insights into CF variants profile and frequency, we used the large population sequencing data in the Genome Aggregation Database (gnomAD). We selected 207 CF‐causing/varying clinical consequence variants from CFTR2 database and additional 15 variants submitted to the ClinVar database. Only 14 of these variants were found in the East‐Asian population, while for South‐Asian and African populations we identified 43 and 52 variants, respectively, confirming the peculiarity of the CFTR allelic spectrum with only few population‐specific variants. These data could be used to optimize CFTR carrier screening in non‐Caucasian subjects, choosing between the full gene sequencing and cost and time‐effective targeted panels.

Clinical Chemistry and Laboratory Medicine, May 27, 2010

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths. However... more Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths. However, prevention is possible by early detection. In the present work, we have demonstrated and validated a novel quantitative method based on a DNA integrity assay and mutation in faeces of CRC patients using denaturing high performance liquid chromatography (dHPLC). Methods: Faecal DNA (fDNA) was isolated from 28 CRC, 96 healthy and 61 patients with adenomas. Adenomatosis polyposis coli (APC)-Long-DNA and its mutations were analysed using dHPLC and the Sanger sequencing method. The diagnostic performance was assessed using receiver operating characteristic curve analysis. Results: We detected APC-Long-DNA in 21/28 CRC subjects with a sensitivity of 75% and specificity of 91.7%. A cut-off ratio of 0.2317 was used for APC/β-actin. The Q-dHPLC detection limit was 0.02 ng/injection. The average initial fDNA presence based on a single gene of β-actin was 26.12±13.39 ng/mL for healthy, and 49.61±46.28 ng/mL for CRC subjects, with a sensitivity of 71.4% and a specificity of 84.4% at a cut-off value >29 ng/mL. We also detected a novel mutation at codon 1576 Lys/Glu using dHPLC. Conclusions: This study highlights a novel application of Q-dHPLC in the DNA integrity assay, which demonstrates high performance, good reproducibility, and low cost for the CRC detection using faeces. Further studies in a larger population are needed to confirm these results. Clin Chem Lab Med 2010;48:1303–11.

Biochemia Medica, Aug 28, 2017

Introduction: Lipoprotein-associated phospholipase A2 (Lp-PLA 2) is a marker of vascular inflamma... more Introduction: Lipoprotein-associated phospholipase A2 (Lp-PLA 2) is a marker of vascular inflammation associated with coronary heart disease and stroke. We evaluated analytical performance of the PLAC® Activity Test on Siemens Dimension Vista® 1500 analyzer and measured Lp-PLA 2 activity in Italian adults to establish reference intervals (RIs) and evaluate correlation with circulating lipids and age. Materials and methods: The evaluation protocol consisted of precision, linearity, sensitivity, method comparison, substrate depletion ("hook") effect and interference assessment. Inhibitor (Darapladib) effect was also evaluated. Lp-PLA 2 activity was measured in 250 healthy donors (123 males, 127 females, aged 18-70 years). Central 95% RIs were established using nonparametric statistics. Results: Intra-assay and inter-assay precision showed CVs of 0.6%-1.4% and 0.9%-2.0%, respectively. Linearity replicates showed R 2 > 0.98. Limit of quantitation was 5.8 U/L (CV = 9.4%). Bland Altman plot showed bias-0.9, 95% limits of agreement-6.5-4.72. Passing-Bablok regression showed excellent correlation (Slope = 1.02, 95% CI: 1.01 to 1.03; Intercept =-1.86, 95% CI:-3.08 to-1.26; R 2 = 0.999). No "hook effect" was observed at Lp-PLA 2 activities ≤ 1000 U/L. Average Lp-PLA 2 activity in 250 healthy donors was 182 ± 44 U/L (mean ± SD). Males showed statistically significant higher activities than females (P < 0.001). RIs were 107-265 U/L for males and 84-225 U/L for females. Moderate significant correlation (r = 0.29, P < 0.001) was found between Lp-PLA 2 activity and total cholesterol. Conclusions: The PLAC® Activity Test shows very good performance characteristics on Dimension Vista® 1500.

Movement Disorders, Jan 9, 2019

A BS TRACT: Background: Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by... more A BS TRACT: Background: Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. Objectives: With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Methods: Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a highthroughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Results: Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Conclusions: Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.

Journal of Chromatography B, Sep 1, 2002

A simple, accurate and sensitive high-performance liquid chromatographic method with UV detection... more A simple, accurate and sensitive high-performance liquid chromatographic method with UV detection was carried out to measure plasma concentrations of mycophenolic acid. Following a simplified acid hydrolysis of the sample, the separation   was carried out in 4 min using a Zorbax Eclipse C reversed-phase column with a flow-rate of 1.5 ml / min, and 8 monitoring the absorbance at 250 nm. Throughput was up to 100 samples in 24 h. Within the investigated concentration ranges of mycophenolic acid (0-100 mg / l), good linearity (r.0.99) was obtained. The method is sensitive (the limit of detection was about 20 mg / l) and precise (for 0.49 mg / l added to plasma, within-run C. V. was 2% and between-run was 4.2%; for 2.88 mg / l, within-run C. V. was 0.35% and between-run C. V. was 0.69%; for 24.38 mg / l, within-run C. V. was 0.77% and between-run C. V. was 3.1%). Analytical recoveries were 96% for 0.5 mg / l mycophenolic acid added to plasma, 100% for 12 mg / l and 102.5% for 24 mg / l.

Analytical Biochemistry, 2003

Since glutathionyl-hemoglobin has been suggested to be a clinical marker of oxidative stress in h... more Since glutathionyl-hemoglobin has been suggested to be a clinical marker of oxidative stress in human blood and given the growing biological relevance of oxidative stress as a pathogenic factor in several diseases, we describe a method to measure glutathionyl-hemoglobin concentration in erythrocytes, by using cation-exchange high-pressure liquid chromatography with UV detection. The glutathionyl-hemoglobin peak has been identified on the basis of the following findings: (a) the peak increased when the sample was incubated with oxidized glutathione; (b) the peak disappeared when the sample was reduced with dithiothreitol, with the simultaneous increase of that corresponding to hemoglobin A 0 ; (c) the peak could be detected by incubating hemoglobin A 0 with reduced glutathione; (e) deconvoluted mass spectrum of the glutathionyl-hemoglobin peak showed a 16172.0-Da molecular mass, corresponding to hemoglobin b bound to glutathione. Glutathionyl-hemoglobin concentration has been determined in erythrocytes of 40 healthy subjects, with a mean value of 2.58 AE 0.7%, calculated as the percentage of its peak area ratio to that of total hemoglobin (HbA 0 þ HbA 2 þ HbA 1C + glutathionyl-hemoglobin). The availability of a simple and reproducible method to detect glutathionyl-hemoglobin concentration in blood could be useful in monitoring oxidative stress, and for investigating the efficacy of antioxidant therapies in clinical trials.

The Journal of Neuroscience, May 15, 2000

C.B. was supported in part by fellowships from the Deutsche Forschungsgemeinshaft and the Europea... more C.B. was supported in part by fellowships from the Deutsche Forschungsgemeinshaft and the European Science Foundation. We thank Michael Kiebler for helpful and stimulating discussions, Meltsie de Hoop for advice, and Iain Mattaj and Kai Simons for critical reading of this manuscript. We are also grateful to David Bredt and Mauro Piacentini for providing PSD-95 and TGase antibodies and Marcello Giorgi for technical assistance.

Atherosclerosis Supplements, 2006

European Journal of Clinical Investigation, Dec 1, 2007

Background Sitosterolaemia is a rare autosomal recessive disorder characterised by elevated plasm... more Background Sitosterolaemia is a rare autosomal recessive disorder characterised by elevated plasma levels of plant sterols and cholesterol. Sitosterolaemia is caused by gene mutations in either of two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8. The plasma sterol profile and genetic analysis of a 10-year-old girl who had tuberous xanthomas is the subject of this report. Materials and methods Genomic DNA was isolated from white blood cells from the proband, her family and a control group of healthy people. All exons of ABCG5 and ABCG8 were sequenced. Plasma cholesterol and triglycerides were measured by routine methods. All other plasma sterols were measured by Gas Chromatography coupled to Mass Spectrometry. Results The proband was found to be homozygous for a single nucleotide mutation in exon 10 of the ABCG5 gene, consisting of a C to T transition at nucleotide 1336 of the coding sequence, which results in the premature termination of the ABCG5 protein at amino acid 446 (Arg446X). Her mother and brother were also homozygous for the same mutation and all had elevated plasma beta-sitosterol levels. The father was heterozygous and showed normal beta-sitosterol levels. This mutation was not found in healthy normolipidaemic subjects. Conclusions We describe a novel nonsense mutation in exon 10 of the ABCG5 gene in a 10-year-old girl showing clinical and biochemical features of sitosterolaemia. This family study broadens the spectrum of the ABCG5/ABCG8 mutations causing sitosterolaemia and helps highlight the correlations between such gene mutations, biochemical phenotype and the development of cardiovascular disease.

Journal of Inherited Metabolic Disease, Jul 15, 2004

Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mu... more Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mutation of the SLC7A7 gene characterized by renal failure, pulmonary alveolar proteinosis, lupus-like autoimmune symptoms and usually increased plasma citrulline. In order to better understand the underlying mechanism, we studied the plasma and urinary nitrite/nitrate (NO2-/NO3-) concentrations in three LPI patients and the in vitro NO2- production in cultured fibroblasts. Our data show that NO3- levels are increased in the plasma of patients with LPI. Similarly, NO2- release in the medium of cultured fibroblasts was increased. On this basis, we hypothesize that some of the poorly understood clinical signs of LPI could be related to the activation of the NO-citrulline pathway.

Annals of Human Genetics, 2020

Clinica Chimica Acta, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Movement Disorders, 2019

The Journal of Neuroscience, 2000

In Vitro Cellular & Developmental Biology - Animal, 1998