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The Island of Giglio consists of the lower Pliocene monzogranite intrusion (91.5% of the territory) and Mesozoic–lower Miocene metamorphic and sedimentary tectonic units (8.5% of the territory) of the Ligurian-Piemontese and Tuscan domains in the Franco Promontory. Climatic data recorded from 1993 to 2015 highlight that the average annual temperature and rainfall have increased overall. The main morphological characteristics of the island are: (1) the landslides that affect either the geological formations, above all along the coastal belt, in particular in the Franco Promontory, or the widespread eluvium–colluvium deposits and numerous piles of rock blocks originating from the monzogranite intrusion; (2) the several torrents that cut across the monzogranite intrusion with high gradients resulting in considerable erosion. The island, which includes some very small perennial springs, is covered mainly by short brush and garrigue and subordinately by forests. Six environmental issues have been detected: the high geomorphological and hydraulic risk, respectively, along the coastline, and in the urban areas of Cala delle Cannelle, Giglio Campese, and Giglio Porto; the abandoned quarries showing unstable fronts; the landfill of municipal solid waste, lacking remediation aimed at its safety; the protection and set up of the perennial springs; the safety of paths; and the mining of pyrite started in 1875 until the closure of works in 1962. Suitable suggestions to solve the environmental issues are provided.

Dose-dependent side effects related to myo-inositol (MI) oral administration represent a significant shortcoming for its clinical use. Aiming to search for a pharmaceutical form able to be better absorbed, the pharmacokinetic (PK) profile of the new manufactured MI soft gelatin capsule form was evaluated and compared with the commercially available MI powder.A single-dose relative trial, consisting of four phases, was performed on 20 healthy volunteers who received different doses of MI powder and MI soft gelatin capsules. PK profiles related to the two pharmaceutical forms were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared.The administration of MI powder and MI soft gelatin capsules resulted in a different bioavailability. MI soft gelatin capsule form showed similar PK parameters compared with three times higher doses of MI in powder form.MI soft gelatin capsules displayed an improved bioavailability, allowing to substantially reduce the administered dose and to minimize the dose-dependent side effects. Considering the number of conditions in which MI supplementation is recommended, this evidence could support a broader use of MI in clinical practice.

A series of N-substituted-3-[(2′-hydroxy-4′-prenyloxy)-phenyl]-5-phenyl-4,5-dihydro-(1H)-pyrazolines were synthesized and tested on human monoamine oxidase-A and -B isoforms. Structure–activity relationships and molecular modelling showed that some substitutions, such as benzyloxy or chlorine atom, improve the best interaction with active site of hMAO-B.

This report describes novel pyrazoline derivatives investigated for their ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase. These new synthetic compounds proved to be reversible, potent, and selective inhibitors of monoamine oxidase-A rather than of monoamine oxidase-B, and are promising candidates to further advance drug discovery efforts. The most active compounds show inhibitory activity on monoamine oxidase-A in the 1.0x10(-8)-8.6x10(-9) M range. Moreover, it should be pointed out that for some compounds a high IC50>or=10(-9) M value is associated with a high A-selectivity (Selectivity Index monoamine oxidase-B/monoamine oxidase-A in the 10,000-12,500 range). Further insight to understand enzyme-inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms.

A novel series of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesised and investigated for the ability to inhibit selectively monoamine oxidases, swine kidney oxidase, and bovine serum amine oxidase. The newly synthesised compounds 1 – 6 proved to be reversible and non-competitive inhibitors of all types of the assayed amine oxidases. Compounds inhibit monoamine oxidases potently, displaying low I 50 values of particular interest. In particular 1-acetyl-3-(2,4-dihydroxyphenyl)-5-(3-methylphenyl)-4,5-dihydro-(1H)-pyrazole 6 showed to be a potent monoamine oxidase inhibitor with a K i of about 10 −8 M. Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidase B have been developed through a computational approach.

Background The ingestion of nickel (Ni)-rich foods may result in allergic contact mucositis (ACM), a not yet well defined condition identifiable by oral mucosa patch test (omPT). Our aim was to characterize immunologically the ACM taking advantage from the allergen exposure that occurs during the omPT for Ni. Methods Thirty-seven symptomatic patients underwent to omPT for Ni. Before and after omPT, serum and urine Ni concentrations were determined by mass spectrometry, the white blood cells were counted by hemochromocytometric assay, the peripheral lymphocyte typing was carried out by flow cytometry, total IgE and cytokine serum concentrations were measured by immunoenzymatic assays. The local lymphocyte typing was performed by immunohistochemistry only after omPT. Results According to the omPT outcomes, 25 patients were defined as Ni-sensitive and the remaining 12 as controls. After omPT, serum and urine Ni concentrations increased significantly in all patients, while a significant increment of circulating lymphocytes and neutrophils was highlighted, respectively, in Ni-sensitive and control patients. Consistently, the Th and Tc circulating lymphocytes, as well as the Th/Tc ratio increased significantly in Ni-sensitive patients after omPT. No noteworthy increment in serum concentrations of total IgE and selected cytokines was observed in any patient after omPT. The presence of CD3+, CD4+, and CD8+ cells was highlighted on the oral mucosa biopsy samples taken from Ni-sensitive patients after omPT. Conclusions In patients with ACM, a local adaptive response with increased lymphocyte trafficking appears to be the most likely mechanism of reaction to Ni administered with the omPT.

The aim of this research is to verify the quality and quantity of heavy metals (HM) of dental origin in TMD patients. A population of 100 subject was studied and divided in two homogeneous groups: Study Group (SG) and Control Group (CG). Organism heavy metals were tested by a spot sampling method in which the first urine of the day, through Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), were analyzed. The results obtained were compared with reference values (RV) of Italian people. Descriptive statistical analysis and student's t-test has been applied (statistical significance for p > 0.05). The SG presented the absolute highest levels of HM compared to the CG (p=0.787). As regards the relation between pain and HM, the subjects that refer “severe/very severe” values of pain present the highest levels of HM in urines. The obtained results seem to highlight a possible direct proportionality between the level of pain the increase of the concentration of heavy metals in all the examined groups and subgroups.

The influenza virus neuraminidase (NA) is essential for viral infection and offers a potential target for antiviral drug development. We prepared a carbocyclic sialic acid analogue, potentially able to inhibit NA. Its structure is an analogue of the transition-state of the reaction catalysed by NA. As starting material, quinic acid was selected owing to its ready availability and its stereochemical feature suitable for the target structure. The quinic acid was first converted in the shikimic acid; then two of the three hydroxyl functions of this product were selectively functionalised to obtain the target molecule (3R,4S,5R)-4-acetamido-3-guanidino-5-hydroxycyclohex-1-ene-1-carboxylic acid.

4,6-diaryl and 4,6-aryl-indolyl substituted 3-cyano-2-aminopyridines were synthesized and submitted to evaluation for their anti-inflammatory, analgesic and antipyretic activity. The electronegativity of the substituents and their displacement on the 4- or 6-aryl ring of the 4,6-diaryl-3-cyano-2-aminopyridine nucleus ( 3a – q ) influenced the anti-inflammatory activity which was higher in the presence of electron-realising groups. The introduction of the indol-3-yl substituent in the 4-position of the 3-cyano-2-aminopyridine nucleus ( 6a – x ) increased the anti-inflammatory and analgesic power, but there was no evidence of the relationship among the electronic characteristic of the substituents, their displacement on the 6-phenyl ring and the activity. Conversely, the displacement of the 2-hydroxyphenyl group in the 4-position ( 4a – e ) and of the indol-3-yl group in the 6-position ( 8h – w ) decreased the anti-inflammatory activity. All derivatives did not show any significative antipyretic activity.

Some coumarin 7-substituted cephalosporins and related sulfones were prepared and an antimicrobial assay was performed. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) carried out on cephalosporins showed a potential activity of some of the synthesized compounds against Gram-positive microorganisms. The tests performed on the corresponding sulfones showed no significant activity, neither as antimicrobial agents nor as inhibitors of β-lactamase. An association of sulfone 6a with ampicillin was observed to inhibit Gram-positive microorganisms with a lower MIC than for ampicillin alone.

A new series of 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives was synthesized to ascertain the contribution of substituted phenyl rings present on the 4,5-dihydro-(1H)-pyrazole nucleus to the monoamine oxidases inhibition and bovine serum amine oxidase inhibition. All compounds were tested on bovine brain mitochondria preparation containing flavin-monoamine oxidases and on purified bovine serum amine oxidases, taken as a model of trihydroxy-phenylalanine quinone-copper-containing amine oxidases.The 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives showed a good inhibitory activity and belonged to the third generation of monoamine oxidase inhibitors and bovine serum amine oxidase inhibitors which have the advantage of acting through a reversible mode. Furthermore, their activity showed a good degree of selectivity towards the bovine serum amine oxidase inhibition dependent on the substituents present on the phenyl ring at position 5 of the 4,5-dihydro-(1H)-pyrazole.

The Tyrrhenian resort of S. Marinella (central Italy) is subjected to significant anthropogenic pressures during the summer vacation period, a common situation all along the Italian coast. Located 65 km NW of Rome on the southern slopes of the Tolfa Mountains, S. Marinella is built on a gently sloping, E–W trending belt which is cut by 14 N–S oriented ephemeral streams that discharge into the Tyrrhenian Sea. The low to medium permeability turbiditic sandstones which outcrop along this belt belong to the Late Cretaceous Pietraforte unit. Three environmental problems are addressed in this study. The first problem is related to the high water supply demand during the summer months which has forced local residents to dig a large number of wells. Extensive pumping from these wells has caused salt-water intrusion into the Pietraforte, thus compromising the domestic use of the groundwater. The second problem consists of the illegal dumping of urban solid waste, material that represents a hazard during significant rain events as well as a possible cause of groundwater contamination. The final issue addressed concerns the flooding potential of the 14 ephemeral streams that cross the inhabited area of S. Marinella, a risk which is highlighted by the disastrous flood which occurred on 2 October 1981 and during the period of the Roman Emperor Settimio Severo (205 A.D.). Some suggestions are proposed to mitigate and contain the effects of these problems.

Some coumarin 7-substituted cephalosporins and related sulfones were prepared and an antimicrobial assay was performed. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) carried out on cephalosporins showed a potential activity of some of the synthesized compounds against Gram-positive microorganisms. The tests performed on the corresponding sulfones showed no significant activity, neither as antimicrobial agents nor as inhibitors of β-lactamase. An association of sulfone 6a with ampicillin was observed to inhibit Gram-positive microorganisms with a lower MIC than for ampicillin alone.

The preparation of 3-cyano-4,6-diaryl-pyridin-2(1H)-ones 4a – h , calcium entry blockers related to diltiazem, is described starting from 1,3-diaryl-2-propen-1-ones 5 . On preliminary pharmacological tests all compounds are active and some of them show calcium antagonistic activity superior or comparable to diltiazem.

The influenza virus neuraminidase (NA) is essential for viral infection and offers a potential target for antiviral drug development. We prepared a carbocyclic sialic acid analogue, potentially able to inhibit NA. Its structure is an analogue of the transition-state of the reaction catalysed by NA. As starting material, quinic acid was selected owing to its ready availability and its stereochemical feature suitable for the target structure. The quinic acid was first converted in the shikimic acid; then two of the three hydroxyl functions of this product were selectively functionalised to obtain the target molecule (3R,4S,5R)-4-acetamido-3-guanidino-5-hydroxycyclohex-1-ene-1-carboxylic acid.

1-Acetyl-3-(2-hydroxyphenyl)-5-(R,R′-aryl)-4,5-dihydro-(1H)pyrazoles (2a–o) were synthesized and showed anti-inflammatory and analgesic activity. The substituents on the 5-aryl group were necessary for biological activity. R-R′-aryl-2-dihydro-1,2(4H)thieno(2,3-c)benzo(e)pyranone-4 derivatives (3a–f) also showed analgesic and anti-inflammatory activity. The position and the number of the substituents caused a modulation of analgesic or anti-inflammatory activity of the N-acetyl-Δ2-pyrazoline2 and dihydrothienocoumarines 3. All compounds showed low antipyretic activity.

3-Cyano-4-(R,R′-aryl)-6(2-hydroxyphenyl)-2-(1H)pyridones 2a–o and 3-cyano-4-(R-R′-aryl)-6-(2-hydroxyphenyl)-2-aminopyridines were synthesized which showed anti-inflammatory and analgesic activity. Electron withdrawing substituents in 2′ or 4′ position on 4-aryl group of compounds 2 increased the anti-inflammatory activity, while their displacement in the 3′ position produced an increase of analgesic activity and the appearance of an edematous reaction. All compounds showed low antipyretic and antimicrobial activity. The compounds 2b, 2d, 2i, 2m and 2o did not show any interesting activity in the β-adrenolytic, antihypertensive and heart frequency tests.

Selective quantitative determination of barium by commercially available Sulphonazo III was studied in complex matrices. The application of two more promising methods was tried, but interferences derived from cations and anions present in natural waters and waste waters made them unuseful.

A series of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and assayed as inhibitors of MAO-A and MAO-B isoforms. Most of the tested compounds showed inhibitory activity with micromolar values and MAO-A selectivity. In addition a computational work was carried out on the most selective compound 3b to highlight the most relevant interactions in the mechanism of recognition within both the MAO-A and the MAO-B enzyme active sites.

A series of 3,5-diaryl pyrazoles were prepared and assayed for their ability to inhibit reversibly monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds show inhibitory activity with concentration values in the nanomolar range. A computational work was carried out on the two most selective inhibitors that have tautomeric pyrazole forms. The binding free energies of these compounds for each MAO isoform were influenced by the tautomeric equilibria.

The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10(-8) - 9.0 x 10(-9)M range. Moreover, it should be pointed out that for most of them a high IC(50) > or = 10(-9)M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.

The preparation of 3-cyano-4,6-diaryl-pyridin-2(1H)-ones 4a – h , calcium entry blockers related to diltiazem, is described starting from 1,3-diaryl-2-propen-1-ones 5 . On preliminary pharmacological tests all compounds are active and some of them show calcium antagonistic activity superior or comparable to diltiazem.

Hyaluronic acid (HA) derivatives have been developed to try to enhance rheological properties of this molecule to make it suitable for various medical applications. The main dermatological application of HA derivatives is the augmentation of soft tissues, via injection into the dermis. HA derivatives are indicated for the correction of cutaneous contour deficiencies of the skin, particularly in cases of ageing or degenerative lesions or to increase lips. Two HA derivatives have been evaluated: Hylaform Viscoelastic Gel (Hylan B), derived from rooster combs and subjected to cross-linking, and Restylane, produced through bacterial fermentation (streptococci) and stabilized, as declared by the producer. In both cases the purpose is to improve HA theological characteristics and slow down its degradation once it is in contact with biological structures. Distribution of particle dimensions, pH, protein concentration and rheological properties have been investigated in order to evaluate their reliability as fillers for soft tissue augmentation. The results of the analyses showed that there are differences between Restylane and Hylaform. Especially as far as rheological characteristics are concerned, the results outline different structures of the products: Hylaform behaves as a strong hydrogel, Restylane as a weak hydrogel; rheologically Hylaform is clearly superior to Restylane. Hylaform contains a definitely minor quantity (about a quarter) of cross-linked hyaluronic acid than Restylane. Furthermore, although not declared by the manufacturer, Restylane contains protein, resulting from bacterial fermentation or added to enable cross-linking reaction; the quantity of proteins contained by Restylane can be as much as four times the quantity contained by Hylaform, for the same volume (1 ml). It is evident that Hylaform offers higher safety margin than Restylane. Furthermore, wide literature and 20 years of clinical experience on hyaluronan derived from rooster combs confirm the reliability of this derivative while we did not find evidence regarding about the safety of HA obtained from streptococcus.

ABSTRAC~ Copper is both an essential nutrient required for the activity of several enzymes and a toxic element able to catalyze free radical formation. Trichloroethylene (TCE) is a xenobiotic that generates epoxidic intermediates by bioactivation through the cytochrome P450 system. In this study, the influence of a dietary copper imbalance on the TCE-induced lung damage was investigated. Weaning mice were fed copper-deficient, copper-sufficient. and copper-excessive diets. After 4 wk, mice were exposed for 30 min to 6,500 ppm of TCE and euthanatized 48 hr later. Lung damage in the TCE-treated mice consisted of vacuolations of Clara cells and was quantitatively evaluated by counting the vacuolated cells per micrometer of basal lamina. At the ultrastructural level, vacuolations appeared as the result of hydropic swelling of the endoplasmic reticulum cisternae. The copper-deficient mice presented the highest number of vacuolated Clara cells. These mice also showed alteration of the capillary endothelium and interstitium and decreased pulmonary copper-zinc-superoxide dismutase activity. Occurrence of oxidative stress in lungs of both copper-sufficient and coppcrdeficient mice following TCE treatment was indicated by a decrease in reduced glutathione and an increase in its oxidized form. Pulmonary toxicity; dietary copper; Clara cells; electron microscopy; antioxidant defense system A'ejwmfs.

3-Hydroxypyridine N-oxide reacts readily in acetic anhydride with ethyl cyanoacetate, cyanoacetone and malononitrile. The three reaction products (2-substituted-3-acetoxypyridines) show different equilibria between tautomeric structures; in strong acids they undergo cyclization to 3-substituted 2-aminofuro[3,2-b]pyridines.

The rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium iodide in basic solution was studied. The reaction product is 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine which was obtained also by alkylation with ethyl iodide and sodium hydride in dimethylformamide of 2-oxo-3-cyano-3H-furo[3,2-b]-pyridine or of p-nitrophenyl-3-acetoxypyridine-2-cyanacetate.

Ethyl 2-aminofuro[3,2-b]pyridine-3-carboxylate rearranges with sodium ethoxide in ethanol to 2-oxo-3-cyano-2,3-dihydro[3,2-b]furopyridine; the corresponding p-nitrophenyl ester undergoes the same rearrangement by dilute aqueous sodium hydroxide. In the first case it was possible to isolate the labile intermediate, which was shown to be the hemiacetal of the above mentioned cyanolactone.

The rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium iodide in basic solution was studied. The reaction product is 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine which was obtained also by alkylation with ethyl iodide and sodium hydride in dimethylformamide of 2-oxo-3-cyano-3H-furo[3,2-b]-pyridine or of p-nitrophenyl-3-acetoxypyridine-2-cyanacetate.

Some 2-substituted 3-pyridinolethers were synthesized, with one side chain bearing a carboxylic function; among these there are products having structure analogies with the prostaglandins. The results of hypolipidemic and hypocholesterolemic tests on experimental hyperdyslipidemic animals, as well as those on the inhibition of platelets aggregation and on fibrinolytic activity are reported.