Role of sonic hedgehog signaling pathway in the regulation of ion channels: focus on its association with cardio-cerebrovascular diseases

Sonic hedgehog (SHH) signaling is vital for cell differentiation and proliferation during embryonic development, yet its role in cardiac, cerebral, and vascular pathophysiology is under debate. Recent studies have demonstrated that several compounds of SHH signaling regulate ion channels, which in turn affect the behavior of target cells. Some of these ion channels are involved in the cardio-cerebrovascular system. Here, we first reviewed the SHH signaling cascades, then its interaction with ion channels, and their impact on cardio-cerebrovascular diseases. Considering the complex cross talk of SHH signaling with other pathways that also affect ion channels and their potential impact on the cardio-cerebrovascular system, we highlight the necessity of thoroughly studying the effect of SHH signaling on ion homeostasis, which could serve as a novel mechanism for cardio-cerebrovascular diseases. (AU)

Understanding the role of Cripto-1 in cancer progression and therapeutic strategies

During the initial stages of gastrulation during embryonic differentiation and wound healing, Cripto-1 is a critical protein for human growth. The epithelial adhesion molecules’ downregulation, the mesenchymal overexpression, and mobile proteins are important mechanisms by which Cripto-1 initiates epithelial to mesenchymal transition (EMT). As a result, the function of Cripto-1 for inducing EMT to increase cell migration is advantageous during embryogenesis; however, it is deleterious during the formation, growth, and malignant tumor metastasis. The majority of malignancies are reported to have elevated levels of Cripto-1. Cripto-1 can modify cancerous cells through its function in EMT, which enables these cells to migrate via the extracellular matrix, bloodstream, and lymphatic vessels, on their way for metastasizing to other organs. The goal of this review is to explain what role Cripto-1 plays in common cancers and to summarize how therapeutic strategies are used to interfere with this molecule to target cancers (AU)

Osteoclast generation from RAW 264.7 and PBMC cells. The set up in our lab / Generación de osteoclastos a partir de células RAW 264.7 y PBMC. El montaje en nuestro laboratorio

Introduction and objectives: osteoclasts are terminally differentiated giant multinucleated cells derived from the fusionof mononuclear progenitors of the monocyte/macrophage hematopoietic lineage. The objective of our group was to achie-ve the best method for osteoclast differentiation, from both RAW 264.7 cells and peripheral blood monocytes.Material and methods: RAW 264.7 cells and human PBMCs were differentiated into osteoclasts. Success in differentiationwas assessed by TRAP staining. Osteoclast activity was detected by the resorption pits in Corning® Osteo Assay SurfacePlates.Results: the optimal cell density for RAW 264.7 cell differentiation was 25,000 cells/cm2 with 30 ng/mL of RANKL for6 days. Osteoclasts differentiated from PBMCs were observed after 4 weeks with 25 ng/mL M-CSF and 30 ng/mL RANKL.Individual pits or multiple pit clusters were observed on the surface plates.Conclusions: we report optimal conditions for the differentiation of osteoclasts from.(AU)

The stem cell-specific long non-coding RNAs in leukemia

Leukemia is defined as a heterogeneous group of hematological cancers whose prevalence is on the rise worldwide. Despite the large body of studies, the etiology of leukemia has not been fully elucidated. Leukemia stem cells (LSCs) are a subpopulation of cancer cells that sustain the growth of the leukemic clone and are the main culprit for the maintenance of the neoplasm. In contrast to most leukemia cells, LSCs are resistant to chemo- and radiotherapy. Several recent studies demonstrated the altered expression profile of long non-coding RNAs (lncRNAs) in LSCs and shed light on the role of lncRNAs in the survival, proliferation, and differentiation of LSCs. LncRNAs are transcripts longer than 200 nucleotides that are implicated in several cellular and molecular processes such as gene expression, apoptosis, and carcinogenesis. Likewise, lncRNAs have shown a prognostic marker in leukemia patients and represent novel treatment options. Herein, we review the current knowledge concerning lncRNAs’ implication in the pathogenesis of LSCs and discuss their prognostic, diagnostic, and therapeutic potential (AU)

Galangin inhibits lipopolysaccharide-induced inflammation and stimulates osteogenic differentiation of bone marrow mesenchymal stem cells via regulation of AKT/mTOR signaling

Background: Bone marrow mesenchymal stem cells (BMSCs), with the abilities of multidirectional differentiation and self-renewal, have been widely used in bone repair and regeneration of inflammation-stimulated oral diseases. Galangin is a flavonoid isolated from Alpinia officinarum, exerts anti-obesity, antitumor, and anti-inflammation pharmacological effects. The roles of galangin in lipopolysaccharide-induced inflammation and osteogenic differentiation of BMSCs were investigated. Methods: BMSCs were isolated from rat bone marrow and identified by flow cytometry. The isolated BMSCs were treated with 1 μg/mL lipopolysaccharides or cotreated with lipopolysaccharides and different concentrations of galangin. Cell viability and apoptosis were detected by MTT (tetrazolium component) and flow cytometry. ELISA was used to detect inflammation. Alizarin red staining was used to investigate osteogenic differentiation. Results: The rat BMSCs showed negative rate of CD34, and positive rate of CD29 and CD44. Lipopolysaccharides treatment reduced cell viability of BMSCs, and promoted the cell apoptosis. Incubation with galangin enhanced cell viability of lipopolysaccharide-stimulated BMSCs, and suppressed the cell apoptosis. Galangin decreased levels of TNF-α, IL-1β, and IL-6 in lipopolysaccharide-stimulated BMSCs through down-regulation of NF-κB phosphorylation (p-NF-κB). Galangin up-regulated expression of osteo-specific proteins, collagen type I alpha 1 (COL1A1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), to promote the osteogenic differentiation of lipopolysaccharide-stimulated BMSCs. Protein expression of p-AKT and p-mTOR in lipopolysaccharide-stimulated BMSCs were increased by galangin treatment. Conclusion: Galangin exerted an anti-inflammatory effect against lipopolysaccharide- stimulated BMSCs and promoted osteogenic differentiation through the activation of AKT/ mTOR signaling (AU)

Research progress on the role of Ndfip1 (Nedd4 family interacting protein 1) in immune cells

Nedd4 family interacting protein 1 (Ndfip1) was first mentioned in an article in 2000. Since its discovery, related studies have shown that this protein is associated with apoptosis, neuroprotection, substance transport, ubiquitination, and immune regulation. It is noteworthy that the lack of Ndfip1 can lead to death in fetal mice. Researchers generally believe that the function of Ndfip1 is closely related to individual immune capacity and have published a large number of articles. However, a comprehensive classification of the immune regulatory function of Ndfip1 is still lacking. In this review, we will overview and discuss this new perspective, focusing on the role of Ndfip1 in the proliferation, differentiation, and cell activity of CD4+ T cells, CD8+ T cells, mast cells, and eosinophils. This review provides an updated summary of Ndfip1, which will unveil novel therapeutic targets. Finally, the conclusion is that Ndfip1 mainly plays a negative regulatory role in immune cells by maintaining the stability of the immune response and limiting its overexpression (AU)

Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer

Purpose Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism. Methods Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation. Results It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge. Conclusions This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC (AU)

Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCB2, cytoplasmic Ca+2, and AKT

The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1’s role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal’s molecules T1R3, PLCβ2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development. (AU)

Mechanisms of regulating NIS transport to the cell membrane and redifferentiation therapy in thyroid cancer

Iodine is an essential constituent of thyroid hormone. Active iodide accumulation in the thyroid is mediated by the sodium iodide symporter (NIS), comprising the first step in thyroid hormone biosynthesis, which relies on the functional expression of NIS on the cell membrane. The retention of NIS expressed in differentiated thyroid cancer (DTC) cells allows further treatment with post-operative radioactive iodine (RAI) therapy. However, compared with normal thyroid tissue, differentiated thyroid tumors usually show a decrease in the active iodide conveyance and NIS is generally retained within the cells, indicating that posttranslational protein transfer to the plasma membrane is abnormal. In recent years, through in vitro studies and studies of patients with DTC, various methods have been tested to increase the transport rate of NIS to the cell membrane and increase the absorption of iodine. An in-depth understanding of the mechanism of NIS transport to the plasma membrane could lead to improvements in RAI therapy. Therefore, in this review, we discuss the current knowledge concerning the post-translational mechanisms that regulate NIS transport to the cell membrane and the current status of redifferentiation therapy for patients with RAI-refractory (RAIR)-DTC (AU)

Senescent thyroid tumor cells promote their migration by inducing the polarization of M2-like macrophages

Purpose An in-depth understanding of the mechanism of thyroid cancer progression will help identify patients with thyroid cancer with a high risk of recurrence and metastasis. Although studies have pointed out that the senescence of thyroid tumor cells may stimulate TAMs and cause a series of changes. However, the role of TAMs in aging thyroid cancer cells is still unknown. The aim of this study was to investigate the function of TAMs in aging thyroid cancer cells. Methods We conducted in vitro model studies based on the K1 cell line to induce tumor cell senescence and study its effect on the differentiation of macrophages, flow cytometry was used to confirm polarization of macrophages, transwell assay was used to confirm changes of invasion and migration of tumor cells. Result Our data indicate that aging thyroid tumor cell lines trigger the polarization of M2-like macrophages, accompanied by increased expression of CCL17, CCL18, IL-18, and TGFβ1. This event is caused by the activation of the NFκB pathway upregulation of CXCL2 and CXCL3 is related. Further studies have shown that differentiated M2-like macrophages promote tumor cell migration (but have no effect on cell proliferation). Conclusion Our study indicating that the interaction between tumor and TAMs also occurs in the advanced stages of thyroid tumors and will lead to faster tumors progress (AU)

Coexpresión de NG2/GFAP tras la diferenciación en células transfectadas con las mutaciones de GFAP y en células procedentes de gliomas indiferenciados / NG2 and GFAP co-expression after differentiation in cells transfected with mutant GFAP and in undifferentiated glioma cells

INTRODUCCIÓN: La enfermedad de Alexander es una enfermedad rara causada por mutaciones en el gen que codifica la proteína glial ácida fibrilar (GFAP). En un estudio previo hemos observado que la diferenciación de neuroesferas transfectadas con estas mutaciones genera un tipo celular que comparte la expresión de GFAP y NG2. OBJETIVOS: Determinar el efecto de las mutaciones en marcadores moleculares en comparación con células de glioma diferenciados que expresan simultáneamente GFAP y NG2. MÉTODOS: Se utilizaron muestras de glioblastoma humana (GLM) y neuroesferas procedentes de rata transfectadas con mutaciones de GFAP para el análisis de la expresión tras diferenciación de GFAP y NG2, así como el análisis inmunocitoquímico de diferenciación de ambos tipos celulares y detección de ambas proteínas, junto a nestina, vimentina, Olig2 y caspasa 3 a los 3 y 7 días de diferenciación. RESULTADOS: Tanto las células transfectadas con mutaciones de GFAP como las células procedentes de GLM mostraron un incremento de NG2 y GFAP. Sin embargo, la expresión de células caspasa 3 positiva era marcadamente mayor entre las células transfectadas que entre las células procedentes de GLM. CONCLUSIÓN: Nuestros resultados parecen indicar que la expresión de GFAP no es el único factor que condiciona la muerte celular en la enfermedad de Alexander y que la expresión de caspasa 3 y el potencial papel de la NG2 en incrementar la resistencia a la apoptosis en las células que coexpresan GFAP y NG2 deben ser considerados en la búsqueda de acciones terapéuticas en esta enfermedad

INTRODUCTION: Alexander disease is a rare disorder caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP). In a previous study, differentiation of neurospheres transfected with these mutations resulted in a cell type that expresses both GFAP and NG2. OBJECTIVE: To determine the effect of molecular marker mutations in comparison to undifferentiated glioma cells simultaneously expressing GFAP and NG2. METHODS: We used samples of human glioblastoma (GBM) and rat neurospheres transfected with GFAP mutations to analyse GFAP and NG2 expression after differentiation. We also performed an immunocytochemical analysis of neuronal differentiation for both cell types and detection of GFAP, NG2, vimentin, Olig2, and aspase-3 at 3 and 7 days from differentiation. RESULTS. Both the cells transfected with GFAP mutations and GBM cells showed increased NG2 and GFAP expression. However, expression of caspase-3-positive cells was found to be considerably higher in transfected cells than in GBM cells. CONCLUSIONS: Our results suggest that GFAP expression is not the only factor associated with cell death in Alexander disease. Caspase-3 expression and the potential role of NG2 in increasing resistance to apoptosis in cells co-expressing GFAP and NG2 should be considered in the search for new therapeutic strategies for the disease

Estudio de biocompatibilidad y osteointegración de nuevos materiales protésicos / Biocompatibility and osseointegration study of new prosthetic materials

OBJETIVO: Los implantes óseos son utilizados cada vez con mayor frecuencia en la práctica clínica y, entre los materiales, el Ti o sus aleaciones son los de mejor rendimiento por sus propiedades fisicoquímicas. Aleaciones como TiNbTa han demostrado mejorar las características biomecánicas del Ti puro comercial (c.p.), sin embargo, su capacidad osteointegradora necesita ser evaluada. El objetivo del presente estudio fue valorar la citotoxicidad y la capacidad de adhesión, proliferación y diferenciación de células osteoblásticas en cultivo, influida por discos de material TiNbTa frente a Ti c.p. MATERIALES Y MÉTODOS: Analizamos a los 4 y 7 días del cultivo la línea celular MC3T3, la viabilidad celular (AlamarBlue Cell Viability Reagent. Invitrogen, España), así como la proliferación y diferenciación celular (actividad de fosfatasa alcalina (ALP) y microscopía electrónica de barrido (Fijación para SEM). Se realizó la prueba t de Student para determinar diferencias estadísticamente significativas entre los dos grupos de discos de estudio. RESULTADOS: Los resultados obtenidos demuestran muy buena viabilidad celular durante el periodo de estudio, sin diferencias significativas para ambos materiales. Así mismo, detectamos una caída en los niveles de ALP que fue significativa para ambos componentes entre los días 4 y 7 del estudio (p < 0,05). Las imágenes de microscopía electrónica revelaron buena capacidad de adhesión al material, así como diferenciación celular frente a ambos tipos de discos. CONCLUSIONES: La aleación de TiNbTa como material para implantes óseos cuenta con una buena capacidad osteointegradora, además de resolver problemas de biomecánica que presenta el titanio puro como componente

OBJETIVE: Bone implants are increasingly used in clinical practice and, among the materials, Ti or its alloys are offer the best performance given their physicochemical properties. Alloys such as TiNbTa have been shown to improve the biomechanical characteristics of commercial pure Ti (c.p.), however, its osseointegration capacity needs to be evaluated. The objective of the present study was to assess the cytotoxicity and the adhesion, proliferation and differentiation capacity of osteoblastic cells in culture, influenced by discs of TiNbTa material versus Ti c.p. MATERIAL AND METHODS: At 4 and 7 days after culture, we analyzed the MC3T3 cell line, cell viability (AlamarBlue Cell Viability Reagent. Invitrogen, Spain), as well as cell proliferation and differentiation (alkaline phosphatase activity (ALP) and scanning electron microscopy (Fixation for SEM) Student's t test was performed to determine statistically significant differences between the two groups of study discs. RESULTS: The results obtained show very good cell viability during the study period, with no significant differences for both materials. Likewise, we detected a drop in ALP levels that was significant for both components between days 4 and 7 of the study (p < 0.05). Electron microscopy images revealed good adhesion capacity to the material, as well as cell differentiation against both types of discs. CONCLUSIONS: The TiNbTa alloy as a material for bone implants offers good osseointegrative capacity, in addition to solving biomechanical problems that pure titanium presents as a component

Clinical and Immunohistochemical epithelial profile of non-healing chronic traumatic ulcers

BACKGROUND: Chronic wounds were previously related to cancer. Chronic Traumatic Ulcers (CTU) are lesions caused by chronic mechanical irritation (CMI) frequently diagnosed in Oral Medicine. Although these conditions may reflect a benign nature, some authors have proposed its relationship with malignant transformation. Currently, there are scarce investigations that evaluate biomarkers within CTU. The aim of this study was to evaluate cell differentiation and proliferation biomarkers patterns of CTU and OSCC through recognized markers such as cytokeratin 19 and Ki67 and correlate it with clinical features of both groups of patients. MATERIAL AND METHODS: A Cross-sectional study of adult patients (n = 79), both sexes, attended at Oral Medicine Department, Facultad de Odontología, Universidad Nacional de Córdoba. The patients were classified into two groups: CTU (n = 41), and OSCC (n = 38). A subset of specimens were immunolabeled with Ki67 and Ck19. RESULTS: The population consisted of 51.9% male and 48.1% female, with an average of 57.0 ± 13.9. years (OSCC group) and 60.9 ± 14.9 years (CTU group). OSCC group presented higher scores for both biomarkers (Ki67 and Ck19), but only there were differences statistically significant for Ki67 (p = 0.032). 25% of non-healing CTU were positive with medium scores of Ck19 and showed an immunohistochemical profile similar to OSCC. The lateral tongue was the most frequent site in both groups. CONCLUSION: The altered immunohistochemical pattern found in many specimens of CTU was also observed in OSCC. The tongue border presents physiological conditions that could offer a suitable environment for the development of neoplastic events associated with CMI. Further studies are needed to understand the underlying mechanisms that could link oral non-healing ulcers with early malignant changes

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Immunohistochemical analysis of cancer-associated fibroblasts and podoplanin in head and neck cancer

BACKGROUND: To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. MATERIAL AND METHODS: A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. RESULTS: Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. CONCLUSIONS: The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN

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Dissecting the localization of lipopolysaccharide-responsive and beige-like anchor protein (LRBA) in the endomembrane system

Introduction and objectives: LRBA deficiency is caused by loss of LRBA protein expression, due to either homozygous or compounds heterozygous mutations in LRBA. LRBA deficiency has been shown to affect vesicular trafficking and autophagy. To date, LRBA has been observed in the cytosol, Golgi apparatus and some lysosomes in LPS-stimulated murine macrophages. The objectives of the present study were to study the LRBA localization in organelles involved in vesicular traffic, phagocytosis, and autophagy in mononuclear phagocytes (MP). Materials and methods: We analyzed LRBA colocalization with different endosomes markets using confocal microscopy in MP. We used the autophagy inhibitors to determine the role of LRBA in formation, maturation or degradation of the autophagosome. Results: LRBA intracellular trafficking depends on the activity of the GTPase ADP ribosylation factor-1 (ARF) in MP. LRBA was identified in early, late endosomes but did not colocalize strongly with lysosomal markers. Although LRBA appears not to be recruited during the phagocytic cargo uptake, it greatly colocalized with the microtubule-associated protein 1A/1B-light chain 3 (LC3) under a steady state and this decreased after the induction of autophagy flux. Although the use of inhibitors of lysosome fusion did not restore the LRBA/LC3 colocalization, inhibitors of either early to late endosomes trafficking or PI3K pathway did. Conclusions: Taken together, our results show that LRBA is located in endomembrane system vesicles, mainly in the early and late endosomes. Although LRBA appears not to be involved in the phagocytic uptake, it is recruited in the early steps of the autophagy flux

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Regulatory roles of miR-155 and let-7b on the expression of inflammation-related genes in THP-1 cells: effects of fatty acids

The main aim of this investigation was to study the regulatory roles of let-7b and miR-155-3p on the expression of inflammation-associated genes in monocytes, macrophages, and lipopolysaccharide (LPS)-activated macrophages (AcM). A second goal was to analyze the potential modulatory roles of different fatty acids, including oleic, palmitic, eicosapentaenoic (EPA), and docosahexaenoic (DHA), on the expression of these miRNAs in the three cell types. This hypothesis was tested in human acute monocytic leukemia cells (THP-1), which were differentiated into macrophages with 2-O-tetradecanoylphorbol-13-acetate (TPA) and further activated with LPS for 24 h. Monocytes, macrophages, and AcM were transfected with a negative control, or mimics for miR-155-3p and miR-let-7b-5p. The expression of both miRNAs and some proinflammatory genes was analyzed by qRT-PCR. Interestingly, let-7b mimic reduced the expression of IL6 and TNF in monocytes, and SERPINE1 expression in LPS-activated macrophages. However, IL6, TNF, and SERPINE1 were upregulated in macrophages by let-7b mimic. IL6 expression was higher in the three types of cells after transfecting with miR-155-3p mimic. Similarly, expression of SERPINE1 was increased by miR-155-3p mimic in monocytes and macrophages. However, TLR4 was downregulated by miR-155-3p in monocytes and macrophages. Regarding the effects of the different fatty acids, oleic acid increased the expression of let-7b in macrophages and AcM and also increased the expression of miR-155 in monocytes when compared with DHA but not when compared with non-treated cells. Overall, these results suggest anti- and proinflammatory roles of let-7b and miR-155-3p in THP-1 cells, respectively, although these outcomes are strongly dependent on the cell type. Noteworthy, oleic acid might exert beneficial anti-inflammatory effects in immune cells (i.e., non-activated and LPS-activated macrophages) by upregulating the expression of let-7b

Terapia de diferenciación: desarrollo de una nueva plataforma de descubrimiento de fármacos / Differentiation therapy: development of a new drug discovery platform

La mayor parte de los tumores están estructurados jerárquicamente, siendo la población de células madre del cáncer la encargada de iniciar y mantener el tumor. Estas células madre del cáncer, debido a sus similitudes con las células madre sanas, tienen capacidad de auto-renovación y diferenciación. Existe un balance altamente regulado que controla ambos procesos. De forma que la eliminación de la auto-renovación directamente o la inducción terminal de diferenciación producen la eliminación de las células madre del cáncer y, por lo tanto, la capacidad de mantenimiento y regeneración de la neoplasia. El desarrollo de dos plataformas distintas para buscar compuestos de pequeño tamaño bioactivos que induzcan la diferenciación terminal de las células madre del cáncer ha permitido identificar distintos fármacos con potencial acción neoplásica. Estas plataformas están basadas en cribados de alto rendimiento y alto contenido usando un sistema de células madre embrionarias transformadas y un análisis bioinformático in silico. Usando la leucemia mieloide aguda como modelo de tumor jerárquico, estos compuestos se estudiado ex vivo y in vivo y se han optimizado para su evaluación clínica. Estas plataformas de descubrimiento de fármacos se han validado como una nueva aproximación experimental para identificar nuevos fármacos con actividad diferenciadora anti-tumoral

Most of the tumors are hierarchically organized, with a cellular subpopulation of cancer stem cells in the apex. This population is responsible for the initiation and maintenance of the tumor. Due to their "stem cell"-like properties, cancer stem cells display self-renewal and differentiation potential, both properties are tightly regulated. Thus, direct inhibition of self-renewal or induction of terminal differentiation will eradicate cancer stem cells and, thus, the maintenance and regeneration capacity of the neoplasia will be eliminated. Two distinct drug discovery platforms were developed to identify small bioactive compounds that induce terminal differentiation of cancer stem cells. These platforms are based on highthroughput and high-content screenings using a transformed embryonic stem cell system and an in silico bioinformatics analysis. Using acute myeloid leukemia as a hierarchically organized tumor model, these compounds were studied ex vivo and in vivo and optimized for clinical settings. These platforms have been validated as a new experimental approach to identify differentiating-inducing drugs as anti-neoplastic compounds

Effects of ole e 1 on human bronchial epithelial cells cultured at the air-liquid interface

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Polaridad y totipotencia durante el desarrollo preimplantatorio / Polarity and totipotency during preimplantational development

Durante mucho tiempo se ha intentado hallar las primeras diferencias entre células que ocurren durante el desarrollo preimplantacional en el embrión de mamífero, y que posteriormente darán lugar a diferentes destinos celulares. En los últimos años los estudios han demostrado que este proceso está regulado por diferencias en interacciones célula-célula, expresión génica y el microambiente de cada célula, en vez de por la división diferencial de determinantes maternos como pasa en otras especies. Sin embargo como aparecen estas diferencias en un primer momento y como regulan los factores moleculares y celulares implicados en la diferenciación celular es una pregunta por resolver. La escasez de material y las limitaciones éticas complican el estudio en embriones humanos. Poco a poco los nuevos avances en técnicas de imagen y análisis de transcriptómica de una única célula proveen nuevos conocimientos que ayudarán a resolver las dudas que se plantean hoy en día

For a long time, it has been tried to find the first differences between cells taking place during preimplantational development of the mammalian embryo, arising different cell fates. Instead of differential divisions of maternal determinants as occurs in other species. It has been shown that this process is regulated by differences in cell to cell interactions, gene expression and individual cell microenvironment. However, how this differences at first appear and how molecular and cellular factors involved in differentiation are regulated, is still unknown. Material shortage and ethical limitations complicate the study on human embryos. Gradually the new advances in imaging techniques and transcriptome analysis of a single cell provide new insights that will help to solve questions that arise today

Plasticidad neural: la sinaptogénesis durante el desarrollo normal y su implicación en la discapacidad intelectual / Neuroplasticity: synaptogenesis during normal development and its implication in intellectual disability

La neuroplasticidad es la capacidad biológica que tiene el sistema nervioso de modificar su estructura y función para adaptarse a las variaciones del entorno, tanto fisiológicas como patológicas. Sus principales consecuencias fisiológicas son el aprendizaje y la memoria, y las patológicas, la rehabilitación neurológica. El continuo cambio y la fragilidad inicial del cerebro en desarrollo hacen especialmente plásticos los períodos embrionario y fetal (lo que se conoce como neuroplasticidad del desarrollo). Ahora bien, la reducción progresiva de la plasticidad nunca es total, permaneciendo a lo largo de toda la vida la capacidad de modificar los circuitos cerebrales en respuesta a nuevos aprendizajes (neuroplasticidad adaptativa) o a lesiones cerebrales (neuroplasticidad reactiva). El principal mecanismo neurobiológico de la neuroplasticidad es la formación de contactos sinápticos entre neuronas. Los trastornos del neurodesarrollo están asociados a anomalías funcionales del cerebro, muchas veces derivadas de la falta de capacidad adaptativa o reactiva del cerebro para modificar los circuitos malformados o dañados por anomalías genéticas o ambientales. Clásicamente se asocian con la aparición de discapacidad intelectual y enfermedades mentales. Esta revisión trata sobre el desarrollo de la neuroplasticidad cerebral y sus mecanismos neurobiológicos. También se analizan algunos de los procesos celulares y moleculares que están implicados en su desarrollo normal y las posibles consecuencias derivadas de sus alteraciones (AU)

Neuroplasticity is the biological capacity of the nervous system to modify its structure and functioning to adapt to both physiological and pathological variations in the environment. Its main physiological consequences are learning and memory, and its pathological outcome is neurological rehabilitation. The continuous change and initial fragility of the developing brain make the embryonic and foetal periods especially plastic (what is known as developmental neuroplasticity). The progressive reduction in plasticity, however, is never complete and the capacity to modify the brain circuits in response to new learning (adaptive neuroplasticity) or brain injuries (reactive neuroplasticity) remains throughout the individual’s entire lifespan. The main neurobiological mechanism underlying neuroplasticity is the formation of synaptic contacts between neurons. Neurodevelopmental disorders are associated to functional anomalies of the brain, often derived from the lack of adaptive or reactive capacity of the brain to modify circuits that are malformed or damaged by genetic or environmental anomalies. They are traditionally associated with the appearance of intellectual disability and mental illnesses. This review deals with the development of the neuroplasticity of the brain and its neurobiological mechanisms. Some of the cellular and molecular processes involved in its normal development are also examined, together with the possible consequences deriving from alterations affecting them (AU)