The old guard: Age-related changes in microglia and their consequences.

Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and animal models have revealed a plethora of age-related changes in the brain, including reduced neurogenesis, oxidative damage, mitochondrial dysfunction and cell senescence. As the main immune effectors and first responders of the nervous tissue, microglia are at the center of these events.

MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy.

Glioblastoma (GB) is the most aggressive and common form of primary brain tumor, characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide.

A biocompatible redox MRI probe based on a Mn(ii)/Mn(iii) porphyrin.

For the development of redox responsive MRI probes based on the MnIII/MnII couple, stable complexation of both reduced and oxidized forms of the metal ion and appropriate tuning of the redox potential in the biologically relevant range are key elements. The water soluble fluorinated Mn-porphyrin derivative Mn-3 satisfies both requirements. In aqueous solutions, it can reversibly switch between MnIII/MnII oxidation states.

miRNAs: New Biomarkers and Therapeutic Targets in Dementia.

Background: Dementia is a complex pathological state that affects millions of individuals worldwide and is responsible for a huge socioeconomic burden, making it a major health concern of current times. Given the impact of dementia in both patients and caregivers, it is crucial to fully clarify the molecular mechanisms underlying dementia-associated disorders, since without this knowledge our ability to correctly diagnose and treat these diseases is severely hampered.

Methods: Epigenetic mechanisms, such as miRNA-mediated post-transcriptional regulation, have been reported to play a role in dementia pathogenesis.

The quest for biocompatible phthalocyanines for molecular imaging: Photophysics, relaxometry and cytotoxicity studies.

Water soluble phthalocyanines bearing either four PEG500 or four choline substituents in the macrocyclic structure, as well as their Zn(II) and Mn(III) complexes were synthesized. The metal-free and Zn(II) complexes present relatively high fluorescence quantum yields (up to 0.30), while the Mn(III) complexes show no fluorescence as a consequence of rapid non-radiative deactivation of the Mn(III) phthalocyanine excited states through low-lying metal based or charge-transfer states.

Sustained release of naltrexone from poly(n-isopropylacrylamide) microgels.

The release of the opioid antagonist naltrexone from neutral poly(N-isopropylacrylamide) (PNIPAAM) microgels and negatively charged PNIPAAM microgels containing acrylic acid groups (PNIPAAM-co-PAA) has been studied at various microgel and drug concentrations. The release curves were found to be well represented by the Weibull equation. The release rates were observed to be dependent on the microgel concentration.

Temperature-responsive cationic block copolymers as nanocarriers for gene delivery.

Cationic block copolymers have been regarded as promising alternatives to the use of viral vectors for gene delivery. In this work, poly(N-isopropylacrylamide)n-block-poly((3-acrylamidopropyl)trimethylammonium chloride)m (PNIPAAMn-b-PAMPTMA(+)m) block copolymers with n=48 or 65 and m=6, 10 or 20 were synthesized and evaluated in terms of their potential for in vitro transfection of HeLa cells. These block copolymers collapse above a phase transition temperature, allowing the entrapment of the DNA molecules they are adsorbed to.

Cell-penetrating peptides as nucleic acid delivery systems: from biophysics to biological applications.

The increasing knowledge on the genetic basis of disease has allowed the development of promising gene-targeted therapies that can be applied to numerous diseases. Such genetic-based approaches involve the use of nucleic acids as therapeutic agents, either for the insertion or repair and regulation of specific genes. However, the clinical application of these large and charged molecules remains highly dependent on the development of delivery systems capable of mediating efficient cellular uptake.

In vitro cytotoxicity of a thermoresponsive gel system combining ethyl(hydroxyethyl) cellulose and lysine-based surfactants.

The cytotoxicity of three lysine-derived surfactants with a gemini-like structure was evaluated on HeLa cells. The half maximal effective concentration (EC(50)) was estimated from the dose-response curves and the values indicated an increase in toxicity with the increase in alkyl chain length. The shorter chain length surfactant (C(6)) was shown to be less cytotoxic than sodium dodecyl sulfate (SDS), and all the lysine-derived surfactants were less toxic than the cationic cetyl trimethylammonium bromide (CTAB).

Thermoresponsive hydrogels with low toxicity from mixtures of ethyl(hydroxyethyl) cellulose and arginine-based surfactants.

Ethyl(hydroxyethyl) cellulose (EHEC) is known to form hydrogels in water at elevated temperatures in the presence of an ionic surfactant. In this paper, the potential use of arginine-based surfactants is explored considering the production of a low toxicity thermoresponsive hydrogel for pharmaceutical and biomedical applications. The interactions between EHEC and the monomeric surfactant N(α)-lauroyl-L-arginine methyl ester (LAM) and two gemini surfactants N(α),N(ω)-bis(N(α)-acylarginine) α,ω-dialkyl amides were evaluated by Rheo-Small Angle Light Scattering measurements.

Cell-penetrating peptide-based systems for nucleic acid delivery: a biological and biophysical approach.

The increasing knowledge on the genetic basis of disease provides a platform for the development of promising gene-targeted therapies that can be applied to numerous pathological conditions, including cancer. Such genetic-based approaches involve the use of nucleic acids as therapeutic agents, either for the insertion or for the repair and regulation of specific genes. However, despite the huge pharmacological potential of these molecules, their application remains highly dependent on the development of delivery systems capable of mediating efficient cellular uptake.

S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes: implications for cell internalization.

The present work aims to gain insights into the role of peptide-lipid interactions in the mechanisms of cellular internalization and endosomal escape of the S4(13)-PV cell-penetrating peptide, which has been successfully used in our laboratory as a nucleic acid delivery system. A S4(13)-PV analogue, S4(13)-PVscr, displaying a scrambled amino acid sequence, deficient cell internalization and drug delivery inability, was used in this study for comparative purposes. Differential scanning calorimetry, fluorescence polarization and X-ray diffraction at small and wide angles techniques showed that both peptides interacted with anionic membranes composed of phosphatidylglycerol or a mixture of this lipid with phosphatidylethanolamine, increasing the lipid order, shifting the phase transition to higher temperatures and raising the correlation length between the bilayers.

Gemini surfactant dimethylene-1,2-bis(tetradecyldimethylammonium bromide)-based gene vectors: a biophysical approach to transfection efficiency.

Cationic liposomes have been proposed as biocompatible gene delivery vectors, able to overcome the barriers imposed by cell membranes. Besides lipids, other surfactant molecules have been successfully used in the composition of gene carriers. In the present work, we used a Gemini surfactant, represented by the general structure [C(14)H(29)(CH(3))(2)N(+)(CH(2))(2)N(+)(CH(3))(2)C(14)H(29)]2Br(-) and herein designated 14-2-14, to prepare cationic gene carriers, both as the sole component and in combination with neutral helper lipids, cholesterol and DOPE.