Publications by authors named "Enrico Boldrini"

8 Publications

  • Page 1 of 1

Interaction of arabinogalactan with mucins.

Int J Biol Macromol 2014 Jun 12;67:446-51. Epub 2014 Apr 12.

Department of Biology, University of Pisa, via S. Zeno, 51, Pisa 56127, Italy. Electronic address:

Arabinogalactan is a naturally-occurring, densely branched, polysaccharide mainly made-up of galactose and arabinose with variable amounts of uronic acids, which received attention for several industrial and biomedical applications. The ability of Western Larch arabinogalactan to interact with mucins was assessed by both classical gel filtration chromatography and frontal chromatography on Sephacryl S300 resin. The shift of arabinogalactan elution volume in classical gel filtration chromatography induced by both bovine submaxillary mucin and porcine gastric mucin resulted useful for revealing the occurrence of an interaction between arabinogalactan and mucins. A frontal gel chromatography, in which arabinogalactan is used as eluent, enabled a dissociation constant of 5×10(-6)M to be measured for the arabinogalactan-bovine submaxillary mucin complex, with approximately 50 equivalents of arabinogalactan bound per mucin mole. The mucoadhesivity of arabinogalactan may be a relevant feature for its biomedical and industrial applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2014.04.001DOI Listing
June 2014

Arabinogalactan as active compound in the management of corneal wounds: in vitro toxicity and in vivo investigations on rabbits.

Curr Eye Res 2011 Jan;36(1):21-8

Department of Pharmaceutical Sciences, University of Pisa, Via Bonanno 33, Pisa, Italy.

Purpose: Aims of the present investigation were to prove that natural polysaccharide arabinogalactan (AG) is well tolerated after ocular administration and exerts a high restoring effect on corneal epithelium abrasions.

Materials And Methods: AG interactions with corneal cells, as well as its effect on their proliferation, were evaluated employing rabbit corneal epithelial cell cultures. The effects due to the presence of benzalkonium chloride (BAK) were also studied on cell cultures, ex vivo on rabbit isolated corneas, evaluating the hydration level, and on the healing rate of experimental corneal wounds in rabbits. Furthermore, the healing process of corneal lesions treated with an experimental 5.0% AG solution was studied and compared with those obtained applying solutions of hyaluronic acid and tamarind seed polysaccharide, both chosen as a reference by virtue of their well-known adjuvant properties on corneal trophism; the study was carried out by light and transmission electron microscopy.

Results: BAK showed toxic effects on corneal epithelium in all experiments. AG proved to stimulate the growth of the corneal epithelial cells by interacting at the level of the cell plasma membrane. The microscopy observations of the epithelial surface of AG-treated damaged corneas revealed a well-restored and histologically organized ultrastructure characterized by fully formed microvilli and glycocalyx; the healing process resulted faster with respect to spontaneously recovered untreated corneas.

Conclusion: Our results suggest that AG can interact with corneal epithelial cells without any toxic side effect; moreover, it proved to stimulate cell proliferation, thus promoting tissue re-epithelialization and reorganization just 48 hr post-wounding.
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http://dx.doi.org/10.3109/02713683.2010.523193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154582PMC
January 2011

Larch arabinogalactan for dry eye protection and treatment of corneal lesions: investigations in rabbits.

J Ocul Pharmacol Ther 2007 Dec;23(6):541-50

Department of Bioorganic Chemistry and Biopharmaceutics, University of Pisa, Pisa, Italy.

Purpose: The aim of the present study was to investigate the corneal protective and healing properties of arabinogalactan (AG), a natural polysaccharide present in conifers of the genus Larix (Larch). AG was tested in comparison with other two polysaccharides possessing well-established properties in the treatment of dry eye: tamarind seed polysaccharide and hyaluronic acid.

Methods: The AG formulation was subjected to the following investigations: rheologic measurements; evaluation of mucoadhesive properties by rheologic interaction with mucin; ferning test; and in vivo evaluation on rabbits, including treatment of an experimental dry eye; evaluation of the preocular retention; and evaluation of healing rate of experimental corneal wound.

Results: AG dispersions showed a newtonian nonviscous behavior, eta = 1.6 mPa . s for 10% w/w solution; it possessed good mucoadhesive properties useful for retention on the eye surface. In fact, a prolonged time of residence in rabbit eyes was ascertained using fluorescein-labeled AG. Five percent (5.0%) w/w AG exerted a good protective effect against the appearance of corneal dry spots. It also reduced significantly the healing time of an experimental corneal lesion since 27 h after the first treatment.

Conclusions: These findings suggest that AG may be a potential therapeutic product for dry eye protection and for the treatment of corneal wounds.
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http://dx.doi.org/10.1089/jop.2007.0048DOI Listing
December 2007

Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors.

J Med Chem 2005 Nov;48(22):6897-907

Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.

Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.
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http://dx.doi.org/10.1021/jm050382pDOI Listing
November 2005

Pirenoxine prevents oxidative effects of argon fluoride excimer laser irradiation in rabbit corneas: biochemical, histological and cytofluorimetric evaluations.

J Photochem Photobiol B 2005 Jan;78(1):35-42

Department of Preclinical and Clinical Pharmacology, University of Florence, V.le Pierraccini, 6, Florence, Italy.

The production of reactive oxygen species (ROS) associated with excimer laser irradiation is recognized as a possible cause of corneal haze following photorefractive keratectomy (PRK). Our work was aimed at investigating in vitro the oxidative effects induced by subablative laser fluences and at demonstrating the protective effectiveness of pirenoxine. Comparative trials of subablative fluence on rabbit eyes with or without 10(-5) M pirenoxine were carried out. Superoxide anion (O(2)(-)), conjugated diene (CD), and thiobarbituric acid reagent substance (TBARS) formation were analyzed. Cellular death was evaluated by flow cytometry. Histological examinations were also performed. No appraisable differences in O(2)(-),CD,andTBARS formation were detected soon after irradiation, whereas they all increased following incubation. Pirenoxine inhibited such increases. Cytofluorimetric and histological observations gave coherent results. The experimental data indicate that oxidative and toxic effects are ascribable to ROS avalanches triggered by laser irradiation-induced photodissociation and are inhibited by pirenoxine.
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http://dx.doi.org/10.1016/j.jphotobiol.2004.09.005DOI Listing
January 2005

Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.

Bioorg Med Chem 2005 Jan;13(2):491-9

Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.

The 2,3-dihydrospiro[4H-thiopyrano[2,3-b]pyridin-4,4'-imidazolidine]-2',5'-dione 3 and its 7-methyl analogue 4 were synthesized and tested for their ability to inhibit aldose reductase (ALR2). To expand the structure-activity relationships, the sulfone 5 and the acetic acid derivative 7 were also prepared and tested. Compounds 3 and 4 proved to be potent ALR2 inhibitors, with IC50 values in the submicromolar range (0.96 and 0.94 microM, respectively) similar to that of sorbinil (0.65 microM). Moreover, compound 3 was found to be highly potent in preventing cataract development in severely galactosemic rats, like tolrestat, when administered as an eyedrop solution. Docking simulations of both R- and S-isomers of 3 into the ALR2 crystal structure were carried out to guide, prospectively, the design of new analogues.
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http://dx.doi.org/10.1016/j.bmc.2004.10.019DOI Listing
January 2005

A mucoadhesive polymer extracted from tamarind seed improves the intraocular penetration and efficacy of rufloxacin in topical treatment of experimental bacterial keratitis.

Antimicrob Agents Chemother 2004 Sep;48(9):3396-401

Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Università di Pisa, Via S. Zeno 37, 56127 Pisa, Italy.

Bacterial keratitis is a serious infectious ocular disease requiring prompt treatment to prevent frequent and severe visual disabilities. Standard treatment of bacterial keratitis includes topical administration of concentrated antibiotic solutions repeated at frequent intervals in order to reach sufficiently high drug levels in the corneal tissue to inhibit bacterial growth. However, this regimen has been associated with toxicity to the corneal epithelium and requires patient hospitalization. In the present study, a mucoadhesive polymer extracted from tamarind seeds was used for ocular delivery of 0.3% rufloxacin in the treatment of experimental Pseudomonas aeruginosa and Staphylococcus aureus keratitis in rabbits. The polysaccharide significantly increased the intra-aqueous penetration of rufloxacin in both infected and uninfected eyes. Rufloxacin delivered by the polysaccharide reduced P. aeruginosa and S. aureus in the cornea at a higher rate than that obtained by rufloxacin alone. In particular, use of the polysaccharide allowed a substantial reduction of S. aureus in the cornea to be achieved even when the time interval between drug administrations was extended. These results suggest that the tamarind seed polysaccharide prolongs the precorneal residence times of antibiotics and enhances drug accumulation in the cornea, probably by reducing the washout of topically administered drugs. The tamarind seed polysaccharide appears to be a promising candidate as a vehicle for the topical treatment of bacterial keratitis.
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http://dx.doi.org/10.1128/AAC.48.9.3396-3401.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514778PMC
September 2004

Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.

J Med Chem 2003 Apr;46(8):1419-28

Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, Italy.

Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.
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http://dx.doi.org/10.1021/jm030762fDOI Listing
April 2003