Transcriptomic Profiles of CD47 in Breast Tumors Predict Outcome and Are Associated with Immune Activation

Targeting the innate immune system has attracted attention with the development of anti- CD47 antibodies. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 on tumor cells. In this study, public genomic data was used to identify genes highly expressed in breast tumors with elevated CD47 expression and analyzed the association between the presence of tumor immune infiltrates and the expression of the selected genes. We found that 142 genes positively correlated with CD47, of which 83 predicted favorable and 32 detrimental relapse-free survival (RFS). From those associated with favorable RFS, we selected the genes with immunologic biological functions and defined a CD47-immune signature composed of PTPRC, HLA-E, TGFBR2, PTGER4, ETS1, and OPTN. In the basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome, correlated with the presence of tumor immune infiltrates, and with gene expression signatures of T cell activation. Moreover, CD47 up-regulated genes associated with favorable survival correlated with pro-tumoral macrophages. In summary, we described a CD47-immune gene signature composed of 6 genes associated with favorable prognosis, T cell activation, and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47.     

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.     

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient’s hormonal status.     

Ethylene and Nitric Oxide Involvement in the Regulation of Fe and P Deficiency Responses in Dicotyledonous Plants

Iron (Fe) and phosphorus (P) are two essential elements for plant growth. Both elements are abundant in soils but with poor availability for plants, which favor their acquisition by developing morphological and physiological responses in their roots. Although the regulation of the genes related to these responses is not totally known, ethylene (ET) and nitric oxide (NO) have been involved in the activation of both Fe-related and P-related genes. The common involvement of ET and NO suggests that they must act in conjunction with other specific signals, more closely related to each deficiency. Among the specific signals involved in the regulation of Fe- or P-related genes have been proposed Fe-peptides (or Fe ion itself) and microRNAs, like miR399 (P), moving through the phloem. These Fe- or P-related phloem signals could interact with ET/NO and confer specificity to the responses to each deficiency, avoiding the induction of the specific responses when ET/NO increase due to other nutrient deficiencies or stresses. Besides the specificity conferred by these signals, ET itself could confer specificity to the responses to Fe- or P-deficiency by acting through different signaling pathways in each case. Given the above considerations, there are preliminary results suggesting that ET could regulate different nutrient responses by acting both in conjunction with other signals and through different signaling pathways. Because of the close relationship among these two elements, a better knowledge of the physiological and molecular basis of their interaction is necessary to improve their nutrition and to avoid the problems associated with their misuse. As examples of this interaction, it is known that Fe chlorosis can be induced, under certain circumstances, by a P over- fertilization. On the other hand, Fe oxides can have a role in the immobilization of P in soils. Qualitative and quantitative assessment of the dynamic of known Fe- and P-related genes expression, selected ad hoc and involved in each of these deficiencies, would allow us to get a profound knowledge of the processes that regulate the responses to both deficiencies. The better knowledge of the regulation by ET of the responses to these deficiencies is necessary to properly understand the interactions between Fe and P. This will allow the obtention of more efficient varieties in the absorption of P and Fe, and the use of more rational management techniques for P and Fe fertilization. This will contribute to minimize the environmental impacts caused by the use of P and Fe fertilizers (Fe chelates) in agriculture and to adjust the costs for farmers, due to the high prices and/or scarcity of Fe and P fertilizers. This review aims to summarize the latest advances in the knowledge about Fe and P deficiency responses, analyzing the similarities and differences among them and considering the interactions among their main regulators, including some hormones (ethylene) and signaling substances (NO and GSNO) as well as other P- and Fe-related signals.     

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.     

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

Embryonic Trophectoderm Secretomics Reveals Chemotactic Migration and Intercellular Communication of Endometrial and Circulating MSCs in Embryonic Implantation

Embryonic implantation is a key step in the establishment of pregnancy. In the present work, we have carried out an in-depth proteomic analysis of the secretome (extracellular vesicles and soluble proteins) of two bovine blastocysts embryonic trophectoderm primary cultures (BBT), confirming different epithelial–mesenchymal transition stages in these cells. BBT-secretomes contain early pregnancy-related proteins and angiogenic proteins both as cargo in EVs and the soluble fraction. We have demonstrated the functional transfer of protein-containing secretome between embryonic trophectoderm and maternal MSC in vitro using two BBT primary cultures eight endometrial MSC (eMSC) and five peripheral blood MSC (pbMSC) lines. We observed that eMSC and pbMSC chemotax to both the soluble fraction and EVs of the BBT secretome. In addition, in a complementary direction, we found that the pattern of expression of implantation proteins in BBT-EVs changes depending on: (i) their epithelial–mesenchymal phenotype; (ii) as a result of the uptake of eMSC- or pbMSC-EV previously stimulated or not with embryonic signals (IFN-τ); (iii) because of the stimulation with the endometrial cytokines present in the uterine fluid in the peri-implantation period.     

Performance of Green Solvents in the Extraction of Sunflower Oil from Enzyme-Treated Collets

The main goal of this work is to evaluate the extraction of sunflower oil from enzyme-treated collets using ethanol and isopropanol (IPA) as solvents. The sunflower collets are pretreated with the multienzyme complex Viscozyme L prior to solvent extraction by the Soxhlet method. The influence of the moisture content of the collets, pretreatment, processing time, and solvent type on the amount of total extracted material and the oil extraction efficiency is studied. Some quality parameters such as phospholipid content of the oil and chlorogenic acid content of the residual meal are also analyzed. At low moisture content (7%) the solvents exhibit similar oil extraction ability (98–99%), but with increasing moisture the extraction efficiency of ethanol decreases to about 85%, while no significant differences are observed for IPA. The enzymatic treatment increases the extraction efficiency for all times, especially for ethanol. It is observed that IPA is more efficient in the extraction compared to ethanol, and the amount of nonlipid material is reduced by ≈70%. In addition, the oil extracted with IPA have lower phospholipid content and the residual meal presents a higher chlorogenic acid content. Practical Applications:This work would contribute toward the use of green solvents in the extraction of sunflower oil from collets. Ethanol and isopropanol, used as solvents, present attractive advantages, including low toxicity, good operational security, as well as being obtained from a renewable source. The obtained data provide up-to-date information on the use of these alcohols in the extraction of sunflower oil from collets and the influence of operating conditions, such as moisture content, enzymatic pretreatment of the collets, and the extraction time. Information about oil and meal quality is also reported.     

Porous structures printed by fused deposition of granules processed from a novel polyamide/alumina-based system

Alumina ceramic porous structures were shaped by the fused deposition of alumina/polyamide 612 composite granules using an FDM 3D printer with a modified extruder to process granulated powder instead of a filament. The composite granules were prepared via thermally induced phase separation (TIPS). Firstly, in order to determine the proportion of polymer/solvent to be used in the TIPS process, different volume fractions of PA612 in dimethyl sulfoxide (DMSO) were studied (0.01 to 0.20), and the granules obtained were characterized by SEM, DSC, and Raman spectroscopy. Secondly, the addition of different ceramic loadings to the PA612/DMSO solution was studied with the aim of determining the amount to be used for preparing the composite granules by TIPS. In particular, the effect of the alumina content on the morphology and size of the obtained composite granules was studied. In addition, rheological properties (oscillatory and rotational tests) of the feed materials were studied. Finally, the printing conditions, including the nozzle temperature and nozzle diameter, and the extrusion process, were optimized in order to obtain porous structures with good quality. Alumina porous structures were successfully printed, debinded, and sintered. Adequate bonding between layers was achieved, and no defects at interfaces were detected.