Development of novel galactosylated PLGA nanoparticles for hepatocyte targeting using molecular modelling

FCT/MEC (UID/QUI/50006/2019). ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007265).Doxorubicin-loaded PLGA nanoparticles conjugated with a new galactose-based ligand for the specific recognition by human hepatoma cellular carcinoma cells (Hep G2) were successfully produced. The new targeting compound was selected using molecular docking combined with quantum chemical calculations for modelling and comparing molecular interactions among the H1 subunit of the asialoglycoprotein receptor containing the carbohydrate recognition domain and the ligand. The ligand, bis(1-O-ethyl-β-D-galactopyranosyl)amine, was synthetized, characterized, and subsequently linked to PLGA. Unloaded (PLGA-di-GAL NP) and doxorubicin-loaded (DOX-PLGA-di-GAL NP) nanoparticles were prepared using an emulsion method and characterized. The produced DOX-PLGA-di-GAL NP are spherical in shape with a size of 258 ± 47 nm, a zeta potential of-62.3 mV, and a drug encapsulation efficiency of 83%. The in vitro drug release results obtained show a three-phase release profile. In vitro cell studies confirmed the interaction between Hep G2 cells and PLGA-di-GAL NP. Cell cytotoxicity tests showed that unloaded NP are nontoxic and that DOX-PLGA-di-GAL NP caused a decrease of around 80% in cellular viability. The strategy used in this work to design new targeting compounds represents a promising tool to develop eective hepatocyte targeting drug delivery systems and can be applied to other tissues/organs.publishersversionpublishe

Antimicrobial and cytotoxic activities of short carbon chain unsaturated sucrose esters

A library of C3–C5 unsaturated 6-O-sucrose esters have been investigated for their antibacterial, antifungal, and cytotoxic activities. Most of the target compounds showed good inhibitory activity against a variety of clinically and food contaminant important microbial pathogens. In particular, 6-O-methacryloyl sucrose 2 and 1′,2,3,3′,4,4′,6′-hepta-O-acetyl-6-O-methacryloyl sucrose 9 were the most active bactericides against all the tested bacteria with minimal inhibitory concentrations (MICs) ranging between 0.24 and 1.40 μM. The compound 9 showed also the highest antifungal activity with MICs from 0.28 to 1.10 μM. The synthesized compounds possessed low cytotoxicity against human breast, lung, cervical, and hepatocellular carcinoma cell lines without showing toxicity for non-tumor liver cells. Thus, this library of short carbon chain unsaturated sucrose esters represent promising leads for the development of new generation of sucrose-based antimicrobial agents.This work has been supported by Fundação para a Ciência e a Tecnologia through grant nos. PEst-C/EQB/ LA0006/2013 and PEst-OE/AGR/UI0690/2014. The authors thank Serbian Ministry of Education, Science, and Technological Development for financial support (grant number 173032).info:eu-repo/semantics/publishedVersio

Synthesis, characterization, antimicrobial and antitumor activities of sucrose Octa(N-ethyl)carbamate

Sucrose octa(N-ethyl)carbamate was synthesized directly from sucrose and ethyl isocyanate, and its structure was confirmed by various analytical methods, such as 1H and 13C NMR, FTIR, m.p., MS, and optical rotation. Its antibacterial, antifungal and cytotoxic activities were investigated. It exhibited strong inhibition against all bacteria tested, namely S. aureus (MIC 0.18±0.006), B. cereus (MIC 0.094±0.000), M. flavus (MIC 0.28±0.01), L. monocytogenes (MIC 0.18±0.006), P. aeruginosa (MIC 0.094±0.002), S. typhimurium (MIC 0.094±0.002), E. coli (MIC 0.18±0.006) and E. cloacae (MIC 0.18±0.006) and strong antifungal activity towards T. viride (MIC 0.09 ± 0.006), A. versicolor (MIC 0.18 ± 0.01), A. ochraceus (MIC 0.375 ± 0.01) and P. ochrochloron (MIC 0.375 ± 0.04). Furthermore, it showed moderate antitumor potential against human breast (GI50357.20±14.12), colon (GI50 332.43±11.19) and cervical (GI50 282.67±3.97) cell lines and, more important, without hepatotoxicity.This work has been supported by Fundação para a Ciência e a Tecnologia through grants No. PEst- C/EQB/LA0006/2013 and PEst-OE/AGR/UI0690/2011. The authors thank to Serbian Ministry of Education and Science for financial support (grant No. 173032). The NMR spectrometers are part of The National NMR Facility, supported by Fundação para a Ciência e a Tecnologia (RECI/BBBBQB/ 0230/2012).info:eu-repo/semantics/publishedVersio

Challenges in matrix metalloproteinases inhibition

SAICT-POL/24288/2016 UIDB/50006/2020 UID/Multi/04378/2019Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.publishersversionpublishe

Polymerizable matrix metalloproteinases’ inhibitors with potential application for dental restorations

Funding Information: This research was funded by A Molecular View of Dental Restoration, grant number PTDC/SAU-BMA/122444/2010 and by Molecular Design for Dental Restauration, grant number SAICT-POL/24288/2016. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Collagen cleavage by matrix metalloproteinase (MMP) is considered a major cause of dental resins long term failure. Most MMP inhibitors display significant toxicity and are unsuitable for dental resins’ applications. Here we report a study of a new class of inhibitors that display the unique property of being co-polymerizable with other vinyl compounds present in commercial dental resins, limiting their release and potential toxicity. Computational affinity towards the active site of different MMP-1;-2;-8;-9 and-13 of several compounds showed interesting properties and were synthesized. These free compounds were tested concerning their toxicity upon contact with two different cell types, with no substantial decrease in cell viability at high concentrations. Even so, compound’s safety can be further improved upon copolymerization with commercial dental resins, limiting their release.publishersversionpublishe

Antimicrobial and cytotoxic activities of 1,2,3-triazole-sucrose derivatives

A library of 1-(1′,2,3,3′,4,4′,6-hepta-O-acetyl-6′-deoxy-sucros-6′-yl)-1,2,3-triazoles have been investigated for their antibacterial, antifungal and cytotoxic activities. Most of the target compounds showed good inhibitory activity against a variety of clinically and food contaminant important microbial pathogens. In particular, 1-(1′,2,3,3′,4,4′,6-hepta-O-acetyl-6′-deoxy-sucros-6′-yl)-4-(4-pentylphenyl)-1,2,3- triazole (5) was highly active against all the tested bacteria with minimal inhibitory concentrations (MICs) ranging between 1.1 and 4.4 μM and bactericidal concentrations (MBCs) from 2.2 and 8.4 μM. The compound 1-(1′,2,3,3′,4,4′,6-hepta-O-acetyl-6′-deoxy-sucros-6′-yl)-4-(4-bromophenyl)-1,2,3-triazole (3) showed antifungal activity with MICs from 0.6 to 4.8 μM and minimal fungicidal concentrations (MFCs) ranging between 1.2 and 8.9 μM. Furthermore, some of the compounds possessed moderate cytotoxicity against human breast, lung, cervical and hepatocellular carcinoma cell lines, without showing toxicity for nontumor liver cells. The above mentioned derivatives represent promising leads for the development of new generation of sugar-triazole anti fungal agents.This work has been supported by Fundação para a Ciência e a Tecnologia through grant Nos. PEst-C/EQB/LA0006/2013 and PEst-OE/AGR/UI0690/2014. T.M. Potewar and R.C. Calhelha are grateful to Fundação para a Ciência e a Tecnologia for their pos-doctoral Grant Nos. SFRH/ BPD/65173/2009 and SFRH/BPD/68344/2010, respectively. The authors thank to Serbian Ministry of Education, Science and Technological Development for financial support (grant number 173032). The NMR spectrometers are part of The National NMR Facility, supported by Fundação para a Ciência e a Tecnologia (RECI/BBB-BQB/0230/2012)

Synthesis of Hydrophilic and Amphiphilic Acryl Sucrose Monomers and Their Copolymerisation with Styrene, Methylmethacrylate and α- and β-Pinenes

Herein, we report the synthesis of monomethacryloyl sucrose esters, and their successful free radical homo- and co-polymerisation with styrene, methylmethacrylate, α-and β-pinene. The chemical, physical, structural and surface chemical properties of these polymers, containing a hydrophobic olefin backbone and hydrophilic sugar moieties as side chains, have been investigated. Biodegradation tests of the copolymer samples by a microbial fungal culture (Aspergillus niger) method showed good biodegradability. The chemical structure and surface chemistry of the synthesized homo- and co-polymers demonstrate their potential technological relevance as amphiphilic and biodegradable polymers

Dietary amino acids and risk of stroke subtypes: a prospective analysis of 356,000 participants in seven European countries

Purpose: Previously reported associations of protein-rich foods with stroke subtypes have prompted interest in the assessment of individual amino acids. We examined the associations of dietary amino acids with risks of ischaemic and haemorrhagic stroke in the EPIC study. Methods: We analysed data from 356,142 participants from seven European countries. Dietary intakes of 19 individual amino acids were assessed using validated country-specific dietary questionnaires, calibrated using additional 24-h dietary recalls. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of ischaemic and haemorrhagic stroke in relation to the intake of each amino acid. The role of blood pressure as a potential mechanism was assessed in 267,642 (75%) participants. Results: After a median follow-up of 12.9 years, 4295 participants had an ischaemic stroke and 1375 participants had a haemorrhagic stroke. After correction for multiple testing, a higher intake of proline (as a percent of total protein) was associated with a 12% lower risk of ischaemic stroke (HR per 1 SD higher intake 0.88; 95% CI 0.82, 0.94). The association persisted after mutual adjustment for all other amino acids, systolic and diastolic blood pressure. The inverse associations of isoleucine, leucine, valine, phenylalanine, threonine, tryptophan, glutamic acid, serine and tyrosine with ischaemic stroke were each attenuated with adjustment for proline intake. For haemorrhagic stroke, no statistically significant associations were observed in the continuous analyses after correcting for multiple testing. Conclusion: Higher proline intake may be associated with a lower risk of ischaemic stroke, independent of other dietary amino acids and blood pressure