Campagna F

References (7)

Title : Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity - Pisani_2017_Eur.J.Pharm.Sci_109_381
Author(s) : Pisani L , De Palma A , Giangregorio N , Miniero DV , Pesce P , Nicolotti O , Campagna F , Altomare CD , Catto M
Ref : Eur J Pharm Sci , 109 :381 , 2017
Abstract : Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Abeta) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Abeta fibrillization, 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Abeta aggregation and cholinesterases with IC50s in the low muM range. With the aim of increasing aqueous solubility, a Mannich-base functionalization led to the synthesis of N-methylpiperazine derivative 2. At acidic pH, an outstanding solubility increase of 2 over the parent compound 1 was proved through a turbidimetric method. HPLC analysis revealed an improved stability of the Mannich base 2 at pH2 along with a rapid release of 1 in human serum as well as an outstanding hydrolytic stability of the parent hydrazone. Coincubation of Abeta1-42 with 2 resulted in the accumulation of low MW oligomers, as detected with PICUP assay. Cell assays on SH-SY5Y cells revealed that 2 exerts strong cytoprotective effects in both cell viability and radical quenching assays, mainly related to its active metabolite 1. These findings show that 2 drives the formation of non-toxic, off-pathway Abeta oligomers unable to trigger the amyloid cascade and toxicity.
ESTHER : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedSearch : Pisani_2017_Eur.J.Pharm.Sci_109_381
PubMedID: 28801274

Title : Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl\/butyryl cholinesterase - Catto_2012_Eur.J.Med.Chem_58C_84
Author(s) : Catto M , Berezin AA , Lo Re D , Loizou G , Demetriades M , De Stradis A , Campagna F , Koutentis PA , Carotti A
Ref : Eur Journal of Medicinal Chemistry , 58C :84 , 2012
Abstract : Alzheimer's disease AD onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target Two new chemical entities the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one benzotriazinone I and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one triazafluoranthenone II were explored for their multitarget-directed inhibition of beta-amyloid Abeta fibrillization and acetyl AChE and/or butyryl BChE cholinesterase three valuable targets for AD therapy Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II respectively allowed the preparation of a series of compounds that were tested as Abeta(1-40 aggregation and cholinesterase inhibitors Potent inhibitors of Abeta self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50 equal to 0.37 muM Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors In particular benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity the former displaying IC(50 values of 1.4 1.5 and 1.9 muM on Abeta aggregation and AChE and BChE inhibition respectively and the latter showing IC(50 values of 1.4 and an outstanding 0.025 muM in the Abeta aggregation and BChE inhibition respectively Benzotriazinone 24 and triazafluoranthenone 29 selected owing to their suitable aqueous solubility and Abeta aggregation inhibition were submitted to a time course kinetic assay followed with thioflavin T ThT spectrofluorimetry circular dichroism CD and transmission electron microscopy TEM Experimental data indicated that 24 acted at a low concentration ratio 10 muM 24vs 50 muM Abeta stabilizing the unstructured Abeta peptide and inhibiting fibrillogenesis and that 29 also acted as fibrillization inhibitor but likely enhancing and stabilizing the beta-sheet arrangement of Abeta to yield protofibrillar species as detected by TEM.
ESTHER : Catto_2012_Eur.J.Med.Chem_58C_84
PubMedSearch : Catto_2012_Eur.J.Med.Chem_58C_84
PubMedID: 23108363

Title : Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases - Pisani_2011_Curr.Med.Chem_18_4568
Author(s) : Pisani L , Catto M , Leonetti F , Nicolotti O , Stefanachi A , Campagna F , Carotti A
Ref : Curr Med Chem , 18 :4568 , 2011
Abstract : The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.
ESTHER : Pisani_2011_Curr.Med.Chem_18_4568
PubMedSearch : Pisani_2011_Curr.Med.Chem_18_4568
PubMedID: 21864289

Title : Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia - Nanni_2010_Atherosclerosis_213_206
Author(s) : Nanni L , Quagliarini F , Megiorni F , Montali A , Minicocci I , Campagna F , Pizzuti A , Arca M
Ref : Atherosclerosis , 213 :206 , 2010
Abstract : OBJECTIVE: Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits. METHODS: Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed. RESULTS: No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 +/- 66.8 vs. 197.1 +/- 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 +/- 15.8 vs. 51.0 +/- 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 +/- 0.11 vs. 0.46 +/- 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR). CONCLUSION: These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoproteins.
ESTHER : Nanni_2010_Atherosclerosis_213_206
PubMedSearch : Nanni_2010_Atherosclerosis_213_206
PubMedID: 20832801

Title : Novel mutations in the adipose triglyceride lipase gene causing neutral lipid storage disease with myopathy - Campagna_2008_Biochem.Biophys.Res.Commun_377_843
Author(s) : Campagna F , Nanni L , Quagliarini F , Pennisi E , Michailidis C , Pierelli F , Bruno C , Casali C , Dimauro S , Arca M
Ref : Biochemical & Biophysical Research Communications , 377 :843 , 2008
Abstract : A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan's anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron-exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.I212X, respectively). These mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous.
ESTHER : Campagna_2008_Biochem.Biophys.Res.Commun_377_843
PubMedSearch : Campagna_2008_Biochem.Biophys.Res.Commun_377_843
PubMedID: 18952067

Title : Common variants in the lipoprotein lipase gene, but not those in the insulin receptor substrate-1, the beta3-adrenergic receptor, and the intestinal fatty acid binding protein-2 genes, influence the lipid phenotypic expression in familial combined hyperlipidemia - Campagna_2002_Metabolism_51_1298
Author(s) : Campagna F , Montali A , Baroni MG , Maria AT , Ricci G , Antonini R , Verna R , Arca M
Ref : Metabolism , 51 :1298 , 2002
Abstract : Familial combined hyperlipidemia (FCHL) is a common, atherogenic lipid disorder characterized by a variable phenotypic expression of hyperlipidemia. Variations in genes regulating fatty acid metabolism must be considered in the search for factors affecting the lipid phenotypic expression of FCHL. Therefore, we have evaluated the association of the common variants in the lipoprotein lipase (LPL) (D9N, N291S, and S447X), insulin receptor substrate-1 (IRS-1) (G972R), fatty acid binding protein-2 (FABP-2) (A54T), and beta3-adrenergic receptor (beta3-AR) (W64R) genes with lipid and lipoprotein levels in 30 Italian FCHL families (195 individuals). The transmission disequilibriun test (TDT) was used to evaluate the association between these variants and the FCHL trait. No significant differences were observed in the frequencies of the common LPL variants between affected and nonaffected FCHL family members. A significantly lower frequency of the LPL447X allele was noted only when members of the FCHL families were compared with normolipemic controls (.06 v.142, respectively; P <.01) suggesting a reduced representation of this LPL variant in FCHL families. The frequencies of variants in the IRS-1, FABP-2, and beta3-AR genes were not significantly different between affected and nonaffected FCHL family members and normolipemic controls. The TDT did not demonstrate any significant association of these gene variants with the FCHL trait. FCHL individuals carrying the LPL N291S gene showed higher plasma lipids and apolipoprotein B (apoB) levels compared with affected noncarriers. Only a marginal effect of the LPL D9N and S447X variants on lipid levels in FCHL individuals was observed. Conversely, the variants in the IRS-1, FABP2, and beta3-AR genes did not show any major influence on lipid and lipoprotein levels in FCHL family members. In conclusion, these results confirmed that none of the investigated genes were major loci for FCHL. Nevertheless, variations in genes affecting the removal rate of triglycerides (TG) from plasma, such as the LPL gene, significantly influence the lipid phenotypic expression of FCHL. Conversely, genetic variants in the IRS-1, FABP-2, and the beta3-AR gene appear not to have a major role as modifier genes in FCHL.
ESTHER : Campagna_2002_Metabolism_51_1298
PubMedSearch : Campagna_2002_Metabolism_51_1298
PubMedID: 12370850

Title : The common mutations in the lipoprotein lipase gene in Italy: effects on plasma lipids and angiographically assessed coronary atherosclerosis - Arca_2000_Clin.Genet_58_369
Author(s) : Arca M , Campagna F , Montali A , Barilla F , Mangieri E , Tanzilli G , Seccareccia F , Campa PP , Ricci G , Pannitteri G
Ref : Clin Genet , 58 :369 , 2000
Abstract : The present study evaluated the role of the common lipoprotein lipase (LPL) mutations on the risk of dyslipidemia and coronary atherosclerosis in an Italian population. Cohorts of 632 patients undergoing coronary angiography, as well as 191 healthy controls, were screened by a combination of PCR and restriction enzyme digestion. In the pooled population, the frequencies of LPL D9N and N291S were 4.1%, with no homozygous carriers, whereas that of LPL S447X was 21% with 19.6% heterozygous and 1.4% homozygous carriers. Compared to non-carriers, LPL N291S carriers showed higher plasma triglycerides (TG) (p < 0.03) and increased risk of high TG phenotype (odds ratio [OR] 2.49, 95% Cl 1.06-5.81; p < 0.03). When this LPL mutation was associated with high body mass index (BMI) ( > 25 Kg/m2) or fasting, plasma insulin (> 10.6 mU ml(-1)) significantly reduced HDL-C levels were also observed. Carriers of the S447X mutation presented with higher HDL-C concentrations (p < 0.05) as compared to non-carriers; they also showed a significantly reduced risk of high TG/low HDL-C dyslipidemia (OR 0.34, 95%, Cl 0.12-0.99; p < 0.05). The favourable effect of the LPL S447X variant was even more pronounced in lean subjects and in those with low insulin levels. No significant influence on plasma lipids by the LPL D9N was observed. None of LPL variants was a significant predictor of angiographically assessed coronary atherosclerosis. At most, the risk was borderline, increased in N291S carriers and possibly decreased in S447X carriers.
ESTHER : Arca_2000_Clin.Genet_58_369
PubMedSearch : Arca_2000_Clin.Genet_58_369
PubMedID: 11140837