Fisetin derivatives exhibit enhanced anti-inflammatory activity and modulation of endoplasmic reticulum stress

Fisetin (FST) is a dietary flavonol that is known to possess multiple relevant bioactivities, raising the question of its potential health benefits and even its use in novel pharmacological approaches. To attain this prospect, some limitations to this molecule, namely its poor bioavailability and solubility, must be addressed. Inflammation and endoplasmic reticulum (ER) stress are often hand in hand in the context of chronic disease. Both are activated upon perceived disturbances in homeostasis but can be deleterious when intensely or chronically activated. We have synthesized a set of FST derivatives trying to improve the biological properties of the parent molecule. These new molecules were tested along with the original compound for their ability to mitigate the activation of these signaling pathways. FST has proven to be effective against the onset of inflammation, reducing NF-κB activation, cytokine release, inflammasome activation and ROS generation, as well as decreasing the activation of the unfolded protein response (UPR). Some of the tested derivatives are also described as new caspase-1 inhibitors, being also capable of reducing pro-inflammatory cytokines and ER stress markers.(undefined

Prospection and Evaluation of (Hemi) Cellulolytic Enzymes Using Untreated and Pretreated Biomasses in Two Argentinean Native Termites

Saccharum officinarum bagasse (common name: sugarcane bagasse) and Pennisetum purpureum (also known as Napier grass) are among the most promising feedstocks for bioethanol production in Argentina and Brazil. In this study, both biomasses were assessed before and after acid pretreatment and following hydrolysis with Nasutitermes aquilinus andCortaritermes fulviceps termite gut digestome. The chemical composition analysis of the biomasses after diluted acid pretreatment showed that the hemicellulose fraction was partially removed. The (hemi) cellulolytic activities were evaluated in bacterial culture supernatantsof termite gut homogenates grown in treated and untreated biomasses. In all cases, we detected significantly higher endoglucanase and xylanase activities using pretreated biomasses compared to untreated biomasses, carboxymethylcellulose and xylan. Several protein bands with (hemi) cellulolytic activity were detected in zymograms and two-dimensionalgel electrophoresis. Some proteins of these bands or spots were identified as xylanolytic peptides by mass spectrometry. Finally, the diversity of cultured cellulolytic bacterial endosymbionts associated to both Argentinean native termite species was analyzed. This study describes, for the first time, bacterial endosymbionts and endogenous (hemi) cellulases of two Argentinean native termites as well as their potential application in degradation of lignocellulosic biomass for bioethanol production.Fil: Ben Guerrero, Emiliano. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Arneodo Larochette, Joel Demián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Microbiología y Zoología Agrícola; ArgentinaFil: Bombarda Campanha, Raquel. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: Oliveira, Patrícia Abrão de. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: Labate, Mônica T. Veneziano. Universidade de Sao Paulo; BrasilFil: Cataldi, Thaís Regiani. Universidade de Sao Paulo; BrasilFil: Campos, Eleonora. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cataldi, Ángel Adrián. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Labate, Carlos A.. Universidade de Sao Paulo; BrasilFil: Rodrigues, Clenilson Martins. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: Talia, Paola Monica. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Biological evaluation of naproxen–dehydrodipeptide conjugates with self-hydrogelation capacity as dual LOX/COX inhibitors

The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen–dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.This work is funded by National Funds through FCT-Portuguese Foundation for Science and Technology under the Project cand CQ/UM UID/QUI/00686/2013 and UID/QUI/0686/2016. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).This work is funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT-Portuguese Foundation for Science and Technology under the Project UID/CTM/50025/2013 and UIDB/50006/2020. We thank Vera Alexandra de Macedo Ribeiro for isolation of the 26S proteasome subunit. We acknowledge the precious advice of Tarsila Castro on the docking studies. For computing resources:”Search-ON2: Revitalization of HPC infrastructure of UMinho, (NORTE-07-0162-FEDER-000086), co-funded by the North Portugal Regional Operational Programme (ON.2-O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF)

Magnetic dehydrodipeptide-based self-assembled hydrogels for theragnostic applications

Self-assembled peptide hydrogels have emerged in recent years as the new paradigm in biomaterials research. We have contributed to this field the development of hydrogels based on dehydrodipeptides N-capped with naproxen. The dehydrodipeptide hydrogels can be loaded with drugs, thus being potential nanocarriers for drug delivery. In this work novel dehydrodipeptides containing tyrosine and aspartic acid amino acid residues N-capped with naproxen and C-terminal dehydrophenylalanine were prepared and characterized. Superparamagnetic iron oxide nanoparticles (SPIONs) were incorporated into the dehydrodipeptide-based hydrogels and their effect on the self-assembly, structure and rheological and magnetic properties of the hydrogels was studied. Magnetic hydrogels, with incorporated SPIONs, displayed concentration-dependent T2-MRI contrast enhancement. Moreover, upon magnetic excitation (alternating magnetic field –AMF–) the SPIONs were able to generate a significant amount of heat. Hence, magnetic hyperthermia can be used as a remote trigger for release of drug cargos and SPIONs incorporated into the self-assembled dehydrodipeptide hydrogels.This work is funded by National Funds through FCT - Portuguese Foundation for Science and Technology under the Project PTDC/QUI-QOR/29015/2017 and CQ/UM UID/QUI/00686/2013 and UID/QUI/0686/2016. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).info:eu-repo/semantics/publishedVersio

Superpulsed low-level laser therapy protects skeletal muscle of mdx mice against damage, inflammation and morphological changes delaying dystrophy progression.

Aim: To evaluate the effects of preventive treatment with low-level laser therapy (LLLT) on progression of dystrophy in mdx mice. Methods: Ten animals were randomly divided into 2 experimental groups treated with superpulsed LLLT (904 nm, 15 mW, 700 Hz, 1 J) or placebo-LLLT at one point overlying the tibialis anterior muscle (bilaterally) 5 times per week for 14 weeks (from 6th to 20th week of age). Morphological changes, creatine kinase (CK) activity and mRNA gene expression were assessed in animals at 20th week of age. Results: Animals treated with LLLT showed very few morphological changes in skeletal muscle, with less atrophy and fibrosis than animals treated with placebo-LLLT. CK was significantly lower (p = 0.0203) in animals treated with LLLT (864.70 U.l−1, SEM 226.10) than placebo (1708.00 U.l−1, SEM 184.60). mRNA gene expression of inflammatory markers was significantly decreased by treatment with LLLT (p<0.05): TNF-α (placebo-control = 0.51 µg/µl [SEM 0.12], - LLLT = 0.048 µg/µl [SEM 0.01]), IL-1β (placebo-control = 2.292 µg/µl [SEM 0.74], - LLLT = 0.12 µg/µl [SEM 0.03]), IL-6 (placebo-control = 3.946 µg/µl [SEM 0.98], - LLLT = 0.854 µg/µl [SEM 0.33]), IL-10 (placebo-control = 1.116 µg/µl [SEM 0.22], - LLLT = 0.352 µg/µl [SEM 0.15]), and COX-2 (placebo-control = 4.984 µg/µl [SEM 1.18], LLLT = 1.470 µg/µl [SEM 0.73]). Conclusion: Irradiation of superpulsed LLLT on successive days five times per week for 14 weeks decreased morphological changes, skeletal muscle damage and inflammation in mdx mice. This indicates that LLLT has potential to decrease progression of Duchenne muscular dystrophy

Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes

Free PMC Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242839/Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.The European Union is gratefully acknowledged for the support of the project “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP, GA 612347. We thank the Management Authorities of the European Regional Development Fund and the National Strategic Reference Framework for the support of the Incentive System - Research and Technological Development Co-Promotion FACIB Project number 21457. Fundação para a Ciência e a Tecnologia is also acknowledged for the support of projects UID/Multi/00612/2013, FCT/UID/ Multi/04046/2013, IF/00808/2013/CP1159/CT0003, PTDC/BBBBQB/6071/2014, as well as for the post-doc grant SFRH/BPD/42567/2007 (A.M.), the Ph.D. grants SFRH/BDE/51998/2012 (C.D.), and SFRH/BDE/51957/2012 (J.P.P.), both co-sponsored by CIPAN, and also for the Ph.D. grant SFRH/BD/116614/2016 (R.N.).info:eu-repo/semantics/publishedVersio

Access to infertility consultations: what women tell us about it?

The main objective of the present paper is to evaluate the perception of women concerning the barriers and access to infertility consultations. Socio cultural and economic access to infertility consultations is detached and three municipalities of the northwest of Portugal were chosen as an example of a peripheral country. A quantitative/qualitative study was done with 60 women. Three dimensions were evaluated: geographic and structural and functional access; economic access; and sociocultural access. The main barriers were mainly identified in the last two dimensions. The economic access was the less well evaluated by women being the cost of treatment (medication, and concentration of costs in a short period) difficult to bear. This can justify a greater involvement of the Portuguese Government, by developing policies for the reimbursement of part of the costs. Also, some changes in structural and functional access must be done with special regard to the separation of the infertility consultations from the reproductive medicine section. The setting of the teams, with a follow-up by the same team of health professionals is also needed