Simultaneous Formation of Polyhydroxyurethanes and Multicomponent Semi-IPN Hydrogels.

This study introduces an efficient strategy for synthesizing polyhydroxyurethane-based multicomponent hydrogels with enhanced rheological properties. In a single-step process, 3D materials composed of Polymer 1 (PHU) and Polymer 2 (PVA or gelatin) were produced. Polymer 1, a crosslinked polyhydroxyurethane (PHU), grew within a colloidal solution of Polymer 2, forming an interconnected network. The synthesis of Polymer 1 utilized a Non-Isocyanate Polyurethane (NIPU) methodology based on the aminolysis of bis(cyclic carbonate) (bisCC) monomers derived from 1-thioglycerol and 1,2-dithioglycerol (monomers A and E, respectively). This method, applied for the first time in Semi-Interpenetrating Network (SIPN) formation, demonstrated exceptional orthogonality since the functional groups in Polymer 2 do not interfere with Polymer 1 formation. Optimizing PHU formation involved a 20-trial methodology, identifying influential variables such as polymer concentration, temperature, solvent (an aprotic and a protic solvent), and the organo-catalyst used [a thiourea derivative (TU) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)]. The highest molecular weights were achieved under near-bulk polymerization conditions using TU-protic and DBU-aprotic as catalyst-solvent combinations. Monomer E-based PHU exhibited higher Mw¯ than monomer A-based PHU (34.1 kDa and 16.4 kDa, respectively). Applying the enhanced methodology to prepare 10 multicomponent hydrogels using PVA or gelatin as the polymer scaffold revealed superior rheological properties in PVA-based hydrogels, exhibiting solid-like gel behavior. Incorporating monomer E enhanced mechanical properties and elasticity (with loss tangent values of 0.09 and 0.14). SEM images unveiled distinct microstructures, including a sponge-like pattern in certain PVA-based hydrogels when monomer A was chosen, indicating the formation of highly superporous interpenetrated materials. In summary, this innovative approach presents a versatile methodology for obtaining advanced hydrogel-based systems with potential applications in various biomedical fields.

The loss of antioxidant activities impairs intestinal epithelium homeostasis by altering lipid metabolism.

Reactive oxygens species (ROS) are common byproducts of metabolic reactions and could be at the origin of many diseases of the elderly. Here we investigated the role of ROS in the renewal of the intestinal epithelium in mice lacking catalase (CAT) and/or nicotinamide nucleotide transhydrogenase (NNT) activities. Cat-/- mice have delayed intestinal epithelium renewal and were prone to develop necrotizing enterocolitis upon starvation. Interestingly, crypts lacking CAT showed fewer intestinal stem cells (ISC) and lower stem cell activity than wild-type. In contrast, crypts lacking NNT showed a similar number of ISCs as wild-type but increased stem cell activity, which was also impaired by the loss of CAT. No alteration in the number of Paneth cells (PCs) was observed in crypts of either Cat-/- or Nnt-/- mice, but they showed an evident decline in the amount of lysozyme. Cat deficiency caused fat accumulation in crypts, and a fall in the remarkable high amount of adipose triglyceride lipase (ATGL) in PCs. Notably, the low levels of ATGL in the intestine of Cat -/- mice increased after a treatment with the antioxidant N-acetyl-L-cysteine. Supporting a role of ATGL in the regulation of ISC activity, its inhibition halt intestinal organoid development. These data suggest that the reduction in the renewal capacity of intestine originates from fatty acid metabolic alterations caused by peroxisomal ROS.

Bioethanol lignin-rich residue from olive stones for electrospun nanostructures development and castor oil structuring.

This work describes the chemical and structural characterization of a lignin-rich residue from the bioethanol production of olive stones and its use for nanostructures development by electrospinning and castor oil structuring. The olive stones were treated by sequential acid/steam explosion pretreatment, further pre-saccharification using a hydrolytic enzyme, and simultaneous saccharification and fermentation (PSSF). The chemical composition of olive stone lignin-rich residue (OSL) was evaluated by standard analytical methods, showing a high lignin content (81.3 %). Moreover, the structural properties were determined by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and size exclusion chromatography. OSL showed a predominance of ß-ß' resinol, followed by ß-O-4' alkyl aryl ethers and ß-5' phenylcoumaran substructures, high molecular weight, and low S/G ratio. Subsequently, electrospun nanostructures were obtained from solutions containing 20 wt% OSL and cellulose triacetate with variable weight ratios in N, N-Dimethylformamide/Acetone blends and characterized by scanning electron microscopy. Their morphologies were highly dependent on the rheological properties of polymeric solutions. Gel-like dispersions can be obtained by dispersing the electrospun OSL/CT bead nanofibers and uniform nanofiber mats in castor oil. The rheological properties were influenced by the membrane concentration and the OSL:CT weight ratio, as well as the morphology of the electrospun nanostructures.

Oleogels and reverse emulsions stabilized by acetylated Kraft lignins.

Acetylated Kraft lignins were evaluated for their ability of structuring vegetable oils into oleogels. Microwave-assisted acetylation was used to adjust lignin's degree of substitution according to reaction temperature (130 to 160 °C), and its effect in improving the viscoelasticity of the oleogels, which was related to the hydroxyl group content. The results were compared with those obtained by Kraft lignins acetylated using conventional methods at room temperature. A higher microwave temperature resulted in gel-like oil dispersions with improved viscoelastic properties, and stronger shear-thinning character, along with enhanced long-term stability. Lignin nanoparticles structured castor oil by enhancing hydrogen bonding between the hydroxyl groups of the oil and the nanoparticles. The oil structuring capacity of the modified lignins enhanced the stability of water-in-oil Pickering emulsions that resulted from low-energy mixing.

Impact of the Morphology of Electrospun Lignin/Ethylcellulose Nanostructures on Their Capacity to Thicken Castor Oil.

This study reports on a novel strategy for manufacturing thickened gel-like castor oil formulations by dispersing electrospun lignin/ethylcellulose nanostructures. These thickened formulations were rheologically and tribologically evaluated with the aim of being proposed as alternative ecofriendly lubricating greases. Low-sulfonate kraft lignin (LSL) and ethylcellulose (EC) were dissolved in a DMAc:THF mixture at different concentrations (8, 10, and 15 wt.%) and LSL:EC ratios (50:50, 70:30, and 90:10) and subjected to electrospinning. The resulting electrospun nanostructures were morphologically characterized. EC acting as the cospinning polymer improved both LSL spinnability and the oil structuring ability. Solutions with a high lignin content achieved microsized particles connected by fibrils, whereas solutions with a high EC content (50:50 ratio) and LSL/EC total concentration (10 and 15 wt.%) yielded beaded or bead-free nanofibers, due to enhanced extensional viscoelastic properties and nonNewtonian characteristics. The gel-like properties of electrospun nanostructure dispersions in castor oil were strengthened with the nanostructure concentration and the EC:LSL ratio, as a result of the formation of a more interconnected fiber network. The oleodispersions studied exhibited a satisfactory frictional response in a tribological contact, with friction coefficient values that were comparable to those achieved with traditional lithium-lubricating greases.

Development of Bio-Based Materials: Synthesis, Characterization and Applications.

The need to find suitable biomaterials and procedures from alternative products able to imitate or even enhance the performance of currently used products has become an important focus of research today due to the depletion of non-renewable resources and the increasing concern related to climate change, sustainability and environmental preservation [...].

Different Kraft lignin sources for electrospun nanostructures production: Influence of chemical structure and composition.

This work focuses on the structural features and physicochemical properties of different Kraft lignins and how they can influence the electrospinning process to obtain nanostructures. Structural features of Kraft lignins were characterized by nuclear magnetic resonance, size exclusion chromatography, fourier-transform infrared spectroscopy, and thermal analysis, whereas chemical composition was analyzed by standard method. The addition of cellulose acetate (CA) improves the electrospinning process of Kraft lignins (KL). Thus, solutions of KL/CA at 30 wt% with a KL:CA weight ratio of 70:30 were prepared and then physicochemical and rheologically characterized. The morphology of electrospun nanostructures depends on the intrinsic properties of the solutions and the chemical structure and composition of Kraft lignins. Then, surface tension, electrical conductivity and viscosity of eucalypt/CA and poplar/CA solutions were suitable to obtain electrospun nanostructures based on uniform cross-linked nanofibers with a few beaded fibers. It could be related with the higher purity and higher linear structure, phenolic content and S/G ratios of lignin samples. However, the higher values of electrical conductivity and viscosity of OTP/CA solutions resulted in electrospun nanostructure with micro-sized particles connected by thin fibers, due to a lower purity, S/G ratio and phenolic content and higher branched structure in OTP lignin.

Lignocellulosic Materials for the Production of Biofuels, Biochemicals and Biomaterials and Applications of Lignocellulose-Based Polyurethanes: A Review.

The present review is devoted to the description of the state-of-the-art techniques and procedures concerning treatments and modifications of lignocellulosic materials in order to use them as precursors for biomaterials, biochemicals and biofuels, with particular focus on lignin and lignin-based products. Four different main pretreatment types are outlined, i.e., thermal, mechanical, chemical and biological, with special emphasis on the biological action of fungi and bacteria. Therefore, by selecting a determined type of fungi or bacteria, some of the fractions may remain unaltered, while others may be decomposed. In this sense, the possibilities to obtain different final products are massive, depending on the type of microorganism and the biomass selected. Biofuels, biochemicals and biomaterials derived from lignocellulose are extensively described, covering those obtained from the lignocellulose as a whole, but also from the main biopolymers that comprise its structure, i.e., cellulose, hemicellulose and lignin. In addition, special attention has been paid to the formulation of bio-polyurethanes from lignocellulosic materials, focusing more specifically on their applications in the lubricant, adhesive and cushioning material fields. High-performance alternatives to petroleum-derived products have been reported, such as adhesives that substantially exceed the adhesion performance of those commercially available in different surfaces, lubricating greases with tribological behaviour superior to those in lithium and calcium soap and elastomers with excellent static and dynamic performance.

Lignin-enriched residues from bioethanol production: Chemical characterization, isocyanate functionalization and oil structuring properties.

Lignin-enriched waste products from bioethanol production of agriculture residues were tested as structuring agents in castor oil once functionalized with hexamethylene diisocyanate. Cane bagasse, barley and wheat straw were processed through steam explosion, pre-saccharification and simultaneous saccharification and fermentation (PSSF). Alternatively, cane bagasse was submitted to steam explosion and enzymatic hydrolysis (EH). Several Nuclear Magnetic Resonance techniques were used to characterize both residues and NCO-functionalized counterparts. The ß-O-4'/resinol/phenylcoumaran content and hydroxyphenyl/guaiacyl/syringyl distribution depend on biomass source, pretreatment, and enzymatic hydrolysis. Total hydroxyl content (from 1.23 for cane bagasse to 1.85 for wheat straw residues), aromatic/aliphatic hydroxyl ratio (0.78 for cane bagasse and 0.61 and 0.49 for barley and wheat straw residues, respectively) and S/G ratio (ranging from 0.25 to 0.86) influence the NCO-functionalization and oleogel rheological response. Oleogels obtained with barley straw residues exhibited the highest values of the storage modulus; around 2 × 105 Pa and 104 Pa for 25% and 20% contents, respectively. PSSF process showed weaker modification, leading to softer viscoelastic response compared to EH. These oleogels exhibited rheological properties similar to lubricating greases of different NLGI grades. Therefore, we herein show an integrative protocol for the valorization of lignin-enriched residues from bioethanol production as potential thickeners of lubricating greases.

Dll1 haploinsufficiency causes brain abnormalities with functional relevance.

Introduction: The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects. Methods: Brains of Dll1 +/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1 +/lacZ and WT mice. Results: Brain weight and size of Dll1 +/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1 +/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1 +/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7-P24) were an additional penetrant phenotype in Dll1 +/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization. Discussion: Our observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.

Electrohydrodynamic Processing of PVP-Doped Kraft Lignin Micro- and Nano-Structures and Application of Electrospun Nanofiber Templates to Produce Oleogels.

The present work focuses on the development of lignin micro- and nano-structures obtained by means of electrohydrodynamic techniques aimed to be potentially applicable as thickening or structuring agents in vegetable oils. The micro- and nano-structures used were mainly composed of eucalyptus kraft lignin (EKL), which were doped to some extent with polyvinylpyrrolidone (PVP). EKL/PVP solutions were prepared at different concentrations (10-40 wt.%) and EKL:PVP ratios (95:5-100:0) in N, N-dimethylformamide (DMF) and further physico-chemically and rheologically characterized. Electrosprayed micro-sized particles were obtained from solutions with low EKL/PVP concentrations (10 and 20 wt.%) and/or high EKL:PVP ratios, whereas beaded nanofiber mats were produced by increasing the solution concentration and/or decreasing EKL:PVP ratio, as a consequence of improved extensional viscoelastic properties. EKL/PVP electrospun nanofibers were able to form oleogels by simply dispersing them into castor oil at nanofiber concentrations higher than 15 wt.%. The rheological properties of these oleogels were assessed by means of small-amplitude oscillatory shear (SAOS) and viscous flow tests. The values of SAOS functions and viscosity depended on both the nanofiber concentration and the morphology of nanofiber templates and resemble those exhibited by commercial lubricating greases made from traditional metallic soaps and mineral oils.

Electrospun lignin-PVP nanofibers and their ability for structuring oil.

This work explores the electrospinnability of low-sulfonate Kraft lignin (LSL)/polyvinylpyrrolidone (PVP) solutions in N,N-dimethylformamide (DMF) and the ability of the different micro- and nano-architectures generated to structure castor oil. LSL/PVP solutions were prepared at different concentrations (8-15 wt%) and LSL:PVP ratios (90:10-0:100) and physico-chemically and rheologically characterized. The morphology of electrospun nanostructures mainly depends on the rheological properties of the solution. Electrosprayed nanoparticles or micro-sized particles connected by thin filaments were obtained from solutions with low LSL/PVP concentrations and/or high LSL:PVP ratios, whereas beaded or bead-free nanofibers were produced by increasing concentration and/or decreasing LSL:PVP ratio, due to enhanced extensional viscoelastic properties and non-Newtonian characteristics. Electrospun LSL/PVP nanofibers are able to form oleogels by simply dispersing them into castor oil at concentrations between 10 and 30 wt%. The rheological properties of the oleogels may be tailored by modifying the LSL:PVP ratio and nanofibers content. The potential application of these oleogels as bio-based lubricants was also explored in a tribological cell. Satisfactory friction and wear results are achieved when using oleogels structured by nanofibers mats with enhanced gel-like properties as lubricants. Overall, electrospinning of lignin/PVP solutions can be proposed as a simple and effective method to produce nanofibers for oil structuring.

Assessment of Sustainability of Bio Treated Lignocellulose-Based Oleogels.

The development of biological strategies to obtain new high-added value biopolymers from lignocellulosic biomass is a current challenge for scientific community. This study evaluates the biodegradability and ecotoxicity of new formulated oleogels obtained from fermented agricultural residues with Streptomyces, previously reported to show improved rheological and tribological characteristics compared to commercial mineral lubricants. Both new oleogels exhibited higher biodegradation rates than the commercial grease. Classical ecotoxicological bioassays using eukaryotic organisms (Lactuca sativa, Caenorhabditis elegans) showed that the toxic impact of the produced bio-lubricants was almost negligible and comparable to the commercial grease for the target organisms. In addition, high throughput molecular techniques using emerging next-generation DNA-sequencing technologies (NGS) were applied to study the structural changes of lubricant-exposed microbial populations of a standard soil. Results obtained showed that disposal of biomass-based lubricants in the soil environment did not substantially modify the structure and phylogenetic composition of the microbiome. These findings point out the feasibility and sustainability, in terms of biodegradability and eco-safety, of the new bio-lubricants in comparison with commercial mineral greases. This technology entails a promising biological strategy to replace fossil and non-renewable raw materials as well as to obtain useful biopolymers from agricultural residues with potential for large-scale applications.

The levels of reprogramming factors influence the induction and maintenance of pluripotency: the case of CD1 mouse strain cells.

The amount of proteins of the regulatory pluripotency network can be determinant for somatic cell reprogramming into induced pluripotent stem cells (iPSCs) as well as for the maintenance of pluripotent stem cells (PSCs). Here, we report a transposon-based reprogramming system (PB-Booster) that allowed high expression levels of a polycistronic transgene containing Myc, Klf4, Oct4 and Sox2 (MKOS) and showed increased reprogramming efficiency of fresh mouse embryonic fibroblasts (MEFs) into iPSCs under low, but not under high, MKOS expression levels. In contrast, MEFs after 2 passages derived into a similar number of iPSC colonies as fresh MEFs at a high MKOS dose, but this number was reduced at a low MKOS dose. Timing of reprogramming was not affected by MKOS expression levels but, importantly, exogenous MKOS expression in established PSCs caused a significant cell loss. At high but not at low MKOS expression levels, MEFs of the CD1 strain produced more initial cell clusters than iPSCs and, although reprogrammed at a similar efficiency as MEFs of the 129/Sv strain, iPSCs could not be maintained in the absence of exogenous MKOS. In CD1-iPSCs, Oct4, Nanog, Rex1 and Esrrb expression levels were reduced when compared with the levels in PSCs derived from the 129/Sv strain. Culture of CD1-iPSCs in medium with MEK and GSK3ß inhibitors allowed their self-renewal in the absence of exogenous MKOS, but the expression levels of Oct4, Nanog, Rex1 and Esrrb were only partially increased. Despite the reduced levels of those pluripotency factors, CD1-iPSC kept high capacity for contribution to chimeric mouse embryos. Therefore, levels of regulatory pluripotency factors influence reprogramming initiation and PSC maintenance in vitro without affecting their differentiation potential in vivo.

Populus alba L., an Autochthonous Species of Spain: A Source for Cellulose Nanofibers by Chemical Pretreatment.

In order to identify new sustainable sources for producing cellulose nanofibers (CNFs), fast-growing poplar (Populus alba L.) wood was evaluated herein. For that purpose, bleached poplar kraft pulp was produced and submitted to TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical) mediated oxidation (TEMPO-ox) chemical pretreatment followed by microfluidization. The resulting CNFs were thoroughly characterized, including a rheological study at different pH values. Poplar CNFs showed properties comparable to eucalypt CNFs (reference material for CNFs production), showing high carboxylate content (1048 ± 128 µmol g-1), fibrillation yield (87.3% ± 8.1%), optical transmittance (83% at 700 nm) and thermal stability (up to more than 200 °C). Regarding the rheological study, whereas pH from 4 to 10 did not produce significant changes in rheological behavior, a reduction of pH down to 1 led to an order-of-magnitude increase on the viscoelastic functions. Therefore, poplar CNF shows potential in the pH-sensitive hydrogels application field. Finally, the possible ecotoxicity of poplar CNF was assessed. The decrease in cell viability was very low so that only concentrations causing a 10% cytotoxicity could be calculated for the assay detecting alterations in cell metabolism (10 µg mL-1) and plasma membrane integrity (60 µg mL-1).

Cellulose Pulp- and Castor Oil-Based Polyurethanes for Lubricating Applications: Influence of Streptomyces Action on Barley and Wheat Straws.

The replacement of mineral oils and non-renewable gelling agents is an imperative requirement for the lubricant industry in the near future. In this framework, cellulose pulp and castor oil are proposed as sustainable substitutes for these components. Biological treatment has been explored and evaluated to enhance the dispersing and thickening properties of cellulose pulp in oil media. Streptomyces sp. MDG147 and MDG301 strains were employed to modify agricultural wheat and barley straw residues from which cellulose pulp was obtained afterwards. In addition, an environmentally friendly process for the production of cellulose-pulp-/castor-oil-based polyurethanes was applied, in which neither catalysts nor harmful solvents were used, resulting in chemical oleogels. These oleogels were rheologically and tribologically characterized to evaluate their performance as lubricating greases. The enzymatic activity pattern developed was dependent on the raw material, the strain type, and the temperature, influencing the cellulose pulp's composition, polymerization degree, and crystallinity. These modified characteristics tuned the rheological behavior of the different oleogels, providing a beneficial range of viscoelastic responses and viscosity values that were generally favored by the Streptomyces action. Furthermore, the friction coefficient and dimensions of wear scars measured in a tribological contact were comparable to, or even lower than, those found with commercial and other bio-based lubricating greases that have previously been studied.

Biodegradable double cross-linked chitosan hydrogels for drug delivery: Impact of chemistry on rheological and pharmacological performance.

This study investigates the impact of dual ionic and covalent cross-links (ion-XrL and cov-XrL) on the properties of chitosan-based (CTS) hydrogels as eco-friendly drug delivery systems (DDS) for the model drug diclofenac sodium (DCNa). Citric acid and a diiodo-trehalose derivative (ITrh) were the chosen ionic and covalent cross-linker, respectively. The novel hydrogels completely disintegrated within 96 h by means of a hydrolysis process mediated by the enzyme trehalase. As far as the authors are aware, this is the first time that a trehalose derivative has been used as a covalent cross-linker in the formation of biodegradable hydrogels. The impact of CTS concentration and degree of cov-XrL on rheological parameters were examined by means of an experimental model design and marked differences were found between the materials. Hydrogels with maximum elastic properties were achieved at high CTS concentrations and high degrees of cov-XrL. DCNa-loaded formulations displayed well-controlled drug-release profiles strongly dependent on formulation composition (from 17% to 40% in 72 h). Surprisingly, higher degrees of covalent cross-linking led to a boost in drug release. The formulations presented herein provides a simple and straightforward pathway to design fully biodegradable, tailor-made controlled drug delivery systems with improved rheological properties.

Evaluation of lignin-enriched side-streams from different biomass conversion processes as thickeners in bio-lubricant formulations.

This study explores the suitability of residual lignin-containing fractions generated as side-streams in different conversion processes of eucalypt and pine woods as thickening agents in bio-lubricant formulations. These conversion processes included fermentable sugars extraction by autohydrolysis or steam explosion and kraft pulping. Structural properties of lignin fractions were characterized by FTIR, 1H and 13C NMR, two-dimensional NMR, TGA and SEC, whereas their compositions were analysed by standard analytical methods. On the other hand, chemical oleogels were prepared with NCO-functionalized residual lignin fractions, and characterized by means of rheological, tribological and AFM techniques. Hydrolysis lignin fractions exhibited a great content of carbohydrates, especially glucose (46.0-48.5%), xylose (4.3-15.6%) and lignin (32.5-39.9%) with a well-maintained structure, displaying the main inter-unit linkages and low phenolic content. By contrast, kraft lignin fractions presented a lower carbohydrate content, mainly xylose (3.4-4.3%), and higher content (44.9-67%) of severely degraded lignin, showing a dramatic reduction of inter-unit linkages, and thereby high phenolic content. The rheological response of NCO-functionalized lignin fractions-based oleogels is highly influenced by the composition and chemical structure of residual lignin fractions. Moreover, these oleogels presented suitable tribological properties with values of the friction coefficient lower than those typically exhibited by standard lubricating greases.

The E6/E7 oncogenes of human papilloma virus and estradiol regulate hedgehog signaling activity in a murine model of cervical cancer.

Human papilloma virus oncogenes and estradiol are major etiologic factors associated with cervical cancer. In order to understand the mechanism by which these two factors promote carcinogenesis, the role of the Hedgehog (Hh) signaling pathway was evaluated during the normal growth of cervical epithelium and in the presence of E6/E7 oncogenes and exogenous estradiol. Hh signaling activity was determined in live animals (i.e., Gli-Luc reporter levels) during the estrous cycle and was found to be higher in the cervical area during the major growth phases, proestrus-estrus, in comparison to the diestrus phase. The same pattern was observed in transgenic mice expressing the E6/E7 oncogenes, though with notably higher levels than in control mice. Adding estradiol also markedly increased Gli activity in the cervix and the skin. In agreement with the correlation between high bioluminescence and tissue growth in different context, cervical cell proliferation was reduced upon Hh signaling inhibition in mice. Treatment with itraconazole, a putative novel Hh inhibitor, at an early stage of cervical carcinogenesis, did not decrease Hh signaling but it did reduce growth. Therefore, Hh signaling likely contributes to cervical carcinogenesis and itraconazole is effective to reduce growth but by a mechanism involving additional signaling pathways.

Reversible pH-Sensitive Chitosan-Based Hydrogels. Influence of Dispersion Composition on Rheological Properties and Sustained Drug Delivery.

The present work deals with the synthesis of micro-structured biomaterials based on chitosan (CTS) for their applications as biocompatible carriers of drugs and bioactive compounds. Twelve dispersions were prepared by means of functional cross-linking with tricarballylic acid (TCA); they were characterized by Fourier transform infrared spectroscopy (FT-IR), modulated temperature differential scanning calorimetry (MTDSC) and scanning electron microscopy (SEM), and their rheological properties were studied. To the best of the authors' knowledge, no study has been carried out on the influence of CTS concentration, degree of cross-linking and drug loading on chitosan hydrogels for drug delivery systems (DDS) and is investigated herein for the first time. The influence of dispersion composition (polymer concentration and degree of cross-linking) revealed to exert a marked impact on its rheological properties, going from liquid-like to viscoelastic gels. The release profiles of a model drug, diclofenac sodium (DCNa), as well as their relationships with polymer concentration, drug loading and degree of cross-linking were evaluated. Similar to the findings on rheological properties, a wide range of release profiles was encountered. These formulations were found to display a well-controlled drug release strongly dependent on the formulation composition. Cumulative drug release under physiological conditions for 96 h ranged from 8% to 67%. For comparative purpose, Voltaren emulgel® from Novartis Pharmaceuticals was also investigated and the latter was the formulation with the highest cumulative drug release (85%). Some formulations showed similar spreadability values to the commercial hydrogel. The comparative study of three batches confirmed the reproducibility of the method, leading to systems particularly suitable for their use as drug carriers.