Pectins from Aloe Vera: Extraction and production of gels for regenerative medicine

Extraction, purification, and gel preparation of Aloe Vera pectin and the evaluation of the biocompatibility of the pectin gels were studied, considering as end use as implantable materials for regenerative medicine. A. Vera was chosen as source of pectin, as this pectin was described to possess high molecular weight and a low degree of esterification. As the properties of pectins are strictly dependent upon the extraction methods in combination with the natural source, the extraction method was modified in order to optimize the yield of the final product, its purity, the duration of the process and the selection of non‐toxic chemical reagents. Changing the experimental conditions resulted in four different extraction processes and products with different physical and chemical characteristics. The optimal extraction resulted to be the process: with enzimatic deactivation by microwave and the use of sodium citrate as chelating agent the molecular weight of the pectin extracted was estimated to be 118 kDa and the 2.93% esterification degree. Cytocompatibility of pectin gels, prepared by ionotropic gelation, showing an improved cell adhesion if compared to commercial pectin. The results suggest that the extracted A. Vera pectins possess interesting properties to be exploited for the production of mechanically stable gels by ionotropic gelation and high rhamnose content matrices for application in regenerative medicine. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39760.     

Isothermal crystallization kinetics of poly(lactic acid)/synthetic mica nanocomposites

The isothermal crystallization kinetics of PLA/fluoromica nanocomposites was studied. Three types of synthetic mica at three concentrations (2.5, 5.0, and 7.5 wt % mica) were used and the effect of these micas on the crystallization and thermal properties of PLA was investigated by differential scanning calorimetry (DSC). The Avrami and Hoffman‐Weeks equations were used to describe the isothermal crystallization kinetics and melting behavior. Addition of these micas to the PLA matrix increased the crystallization rate, and this effect depended on the mica type and concentration. While the nonmodified Somasif ME‐100 exerted the smallest effect, the effect observed for the organically modified Somasif MPE was the most pronounced. The lower half‐time of crystallization t_1/2 was around 3 min for the PLA/Somasif MPE nanocomposites containing 7.5 wt % of filler at 90°C, which is about 16 min below that found for neat PLA. The equilibrium melting temperature ( ) of PLA were estimated for these systems, showing an increase in the composites and an increase with increasing loading, except for PLA/Somasif MPE, in which the increase of the mica content decreased about 5°C. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40322.     

Synthesis,structural and morphological characteristics,magnetic and optical properties of Co doped ZnO nanoparticles

Zn_1−xCo_xO (x==0.05, 0.10, 0.15) nanoparticles have been synthesized by an alternative wet-chemical synthesis route using the SimAdd technique. The as-obtained powders were investigated by FT-IR spectroscopy, X-ray diffraction and thermal analysis correlated with evolved gas analysis (TG–DTA–FT-IR) in order to determine their chemical nature, crystalline structure and to establish the decomposition sequences. The precipitates are generally amorphous, but low-intensity reflection peaks assigned both to the zinc oxalate dihydrate, and zinc hydroxide can be observed in the recorded patterns, indicating that hydroxy-oxalate precipitates were obtained. The structure, morphology and magnetic properties of the thermally treated samples have been investigated by X-ray diffraction, FT-IR, HRTEM, SAED, UV–vis and EPR. XRD studies reveal a hexagonal wurtzite-type structure for all Zn_1−xCo_xO samples. TEM investigations show particle size between 28 and 37 nm, with spherical and polyhedral shapes and with tendency to form aggregates. The presence of a Co₃O₄ secondary phase was evidenced by XRD, UV–vis and EPR for the Zn_0.85Co_0.15O sample. The ferromagnetic behavior of the samples was revealed. The paper highlights that by varying the cobalt concentration it is possible to modulate the structural, morphological, optical and magnetic properties.     

Treatment of Chronic Kidney Disease with Extracellular Vesicles from Mesenchymal Stem Cells and CD133+ Expanded Cells: A Comparative Preclinical Analysis

Chronic kidney disease (CKD) is characterized by structural abnormalities and the progressive loss of kidney function. Extracellular vesicles (EVs) from human umbilical cord tissue (hUCT)-derived mesenchymal stem cells (MSCs) and expanded human umbilical cord blood (hUCB)-derived CD133⁺ cells (eCD133⁺) maintain the characteristics of the parent cells, providing a new form of cell-free treatment. We evaluated the effects of EVs from hUCT-derived MSCs and hUCB-derived CD133⁺ cells on rats with CDK induced by an adenine-enriched diet. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The animals were randomized and divided into the MSC-EV group, eEPC-EV group and control group. Infusions occurred on the seventh and 14th days after CKD induction. Evaluations of kidney function were carried out by biochemical and histological analyses. Intense labeling of the α-SMA protein was observed when comparing the control with MSC-EVs. In both groups treated with EVs, a significant increase in serum albumin was observed, and the increase in cystatin C was inhibited. The results indicated improvements in renal function in CKD, demonstrating the therapeutic potential of EVs derived from MSCs and eCD133⁺ cells and suggesting the possibility that in the future, more than one type of EV will be used concurrently.     

The BDNF/TrkB Neurotrophin System in the Sensory Organs of Zebrafish

The brain-derived neurotrophic factor (BDNF) was discovered in the last century, and identified as a member of the neurotrophin family. BDNF shares approximately 50% of its amino acid with other neurotrophins such as NGF, NT-3 and NT-4/5, and its linear amino acid sequences in zebrafish (Danio rerio) and human are 91% identical. BDNF functions can be mediated by two categories of receptors: p75NTR and Trk. Intriguingly, BDNF receptors were highly conserved in the process of evolution, as were the other NTs’ receptors. In this review, we update current knowledge about the distribution and functions of the BDNF-TrkB system in the sensory organs of zebrafish. In fish, particularly in zebrafish, the distribution and functions of BDNF and TrkB in the brain have been widely studied. Both components of the system, associated or segregated, are also present outside the central nervous system, especially in sensory organs including the inner ear, lateral line system, retina, taste buds and olfactory epithelium.     

ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (q-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and p-value = 9.6 × 10⁻⁶) and non-lobar ICH (z-score = −4.8 and p-value = 1.58 × 10⁻⁶) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (p-value = 3.66 × 10⁻⁵) and non-lobar ICH (p-value = 1.81 × 10⁻⁵). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.     

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.     

Methylmercury Causes Neurodegeneration and Downregulation of Myelin Basic Protein in the Spinal Cord of Offspring Rats after Maternal Exposure

Methylmercury (MeHg) is one of the most dangerous toxic pollutants spread throughout the earth. Chronic MeHg intoxication by contaminated food ingestion is the most common threat to human health, including impairment to the developing fetus. The present study aims at investigating the effects of maternal exposure to MeHg during gestation and lactation on the spinal cord of offspring. Pregnant rats received oral doses of MeHg (40 μg/kg/day) over a period of 42 days (21 gestation and 21 lactation). Control animals received the vehicle only. Total mercury concentration was measured in blood samples from offspring collected at the 41st postnatal day. Counting of motor neurons and immunoreactivity for myelin basic protein (MBP) were assessed in the spinal cords in both control and MeHg-intoxicated animals. Our results showed that MeHg promoted an increase in blood Hg levels. In addition, it caused a reduction in the number of spinal cord motor neurons as well as decreased MBP immunoreactivity in the cervical, thoracic and lumbar segments. Our present findings suggest that MeHg intoxication during rat pregnancy and lactation is associated with a pattern of motor neuron degeneration and downregulation of myelin basic protein in different segments of a developing spinal cord. Further studies are needed to establish the effect of MeHg intoxication in both young and adult rats.     

Targeting the DNA Damage Response to Increase Anthracycline-Based Chemotherapy Cytotoxicity in T-Cell Lymphoma

Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are urgently needed to improve survival. Genomic instability is a common feature of cancer cells and can be caused by aberrations in the DNA damage response (DDR) and DNA repair mechanisms. Consistently, molecules involved in DDR are being targeted to successfully sensitize cancer cells to chemotherapy. Recent studies showed that some hematological malignancies display constitutive DNA damage and intrinsic DDR activation, but these features have not been investigated yet in MTCLs. In this study, we employed a panel of malignant T cell lines, and we report for the first time the characterization of intrinsic DNA damage and basal DDR activation in preclinical models in T-cell lymphoma. Moreover, we report the efficacy of targeting the apical kinase ATM using the inhibitor AZD0156, in combination with standard chemotherapy to promote apoptotic cell death. These findings suggest that DDR is an attractive pathway to be pharmacologically targeted when developing novel therapies and improving MTCL patients’ outcomes.