RESUMEN
Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3-5. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain.
Asunto(s)
Proteína Morfogenética Ósea 2 , Interneuronas , Neocórtex , Red Nerviosa , Inhibición Neural , Neuronas , Transducción de Señal , Proteína Smad1 , Animales , Femenino , Humanos , Masculino , Ratones , Proteína Morfogenética Ósea 2/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatología , Interneuronas/metabolismo , Neocórtex/metabolismo , Neocórtex/citología , Red Nerviosa/metabolismo , Neuronas/metabolismo , Parvalbúminas/metabolismo , Proteína Smad1/metabolismo , Sinapsis/metabolismo , Ácido Glutámico/metabolismoRESUMEN
Non-small-cell lung cancer (NSCLC), the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide, has been extensively investigated in the last decade in terms of developing new therapeutic options that increase patient survival. In this context, marine animals are a source of new, interesting bioactive molecules that have been applied to the treatment of different types of cancer. Many efforts have been made to search for new therapeutic strategies to improve the prognosis of lung cancer patients, including new bioactive compounds and cytotoxic drugs from marine sponges. Their antitumoral effect can be explained by several cellular and molecular mechanisms, such as modulation of the cell cycle or induction of apoptosis. Thus, this systematic review aims to summarize the bioactive compounds derived from marine sponges and the mechanisms by which they show antitumor effects against lung cancer, exploring their limitations and the challenges associated with their discovery. The search process was performed in three databases (PubMed, SCOPUS, and Web of Science), yielding a total of 105 articles identified in the last 10 years, and after a screening process, 33 articles were included in this systematic review. The results showed that these natural sponge-derived compounds are a valuable source of inspiration for the development of new drugs. However, more research in this field is needed for the translation of these novel compounds to the clinic.
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Antineoplásicos , Productos Biológicos , Neoplasias Pulmonares , Poríferos , Animales , Poríferos/química , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Organismos AcuáticosRESUMEN
Plants provide a wide array of compounds that can be explored for potential anticancer properties. Siphonochilone, a furanoterpene that represents one of the main components of the African plant Siphonochilus aethiopicus, shows numerous health benefits. However, to date, its antiproliferative properties have not been tested. The aim of this study was to analyze the cytotoxic effects of siphonochilone on a panel of cancer cell lines and its underlying mechanism of action. Our results demonstrated that siphonochilone exhibited significant cytotoxic effects on pancreatic, breast, lung, colon, and liver cancer cell lines showing a IC50 ranging from 22 to 124 µM at 72 h of treatment and highlighting its cytotoxic effect against MCF7 and PANC1 breast and pancreas cancer cell lines (22.03 and 39.03 µM, respectively). Cell death in these tumor lines was mediated by apoptosis by the mitochondrial pathway, as evidenced by siphonochilone-induced depolarization of the mitochondrial membrane potential. In addition, siphonochilone treatment involves the generation of reactive oxygen species that may contribute to apoptosis induction. In this work, we described for the first time the cytotoxic properties of siphonochilone and provided data about the molecular processes of cell death. Although future studies will be necessary, our results support the interest in this molecule in relation to their clinical application in cancer, and especially in breast and pancreatic cancer.
Asunto(s)
Apoptosis , Potencial de la Membrana Mitocondrial , Especies Reactivas de Oxígeno , Humanos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Zingiber officinale/química , Supervivencia Celular/efectos de los fármacosRESUMEN
Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.
Asunto(s)
Tumores Neuroendocrinos , Octreótido , Receptores de Somatostatina , Somatostatina , Humanos , Octreótido/uso terapéutico , Octreótido/farmacología , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Somatostatina/farmacología , Tumores Neuroendocrinos/tratamiento farmacológico , Receptores de Somatostatina/análisis , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Adulto , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.
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Antineoplásicos/farmacología , Azepinas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Poríferos , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Azepinas/química , Azepinas/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-ActividadRESUMEN
Paclitaxel (PTX), a chemotherapy agent widely used to treat lung cancer, is characterised by high toxicity, low bioavailability and the need to use of excipients with serious side effects that limit its use. Paclitaxel encapsulation into nanoparticles (NPs) generates drug pharmacokinetic and pharmacodynamic advantages compared to free PTX. In this context, a NP carrier formed from a copolymer of lactic acid and glycolic acid (PLGA) has demonstrated high biocompatibility and low toxicity and therefore being approved by FDA to be used in humans. We synthesised a new PLGA NP and loaded it with PTX to improve drug efficacy and reduce side effects. This nanoformulation showed biocompatibility and no toxicity to human immune system. These NPs favor the intracellular uptake of PTX and enhance its antitumor effect in human and murine lung cancer cells, with up to 3.6-fold reductions in the PTX's IC50. Although PLGA NPs did not show any inhibitory capacity against P-glycoprotein, they increased the antitumor activity of PTX in cancer stem cells. Treatment with PLGA-PTX NPs increased apoptosis and significantly reduced the volume of the tumorspheres derived from A549 and LL2 cells by up to 36% and 46.5%, respectively. Biodistribution studies with PLGA-PTX NPs revealed an increase in drug circulation time, as well as a greater accumulation in lung and brain tissues compared to free PTX. Low levels of PTX were detected in the dorsal root ganglion with PLGA-PTX NPs, which could exert a protective effect against peripheral neuropathy. In vivo treatment with PLGA-PTX NPs showed a greater decrease in tumor volume (44.6%) in immunocompetent mice compared to free PTX (24.4%) and without increasing the toxicity of the drug. These promising results suggest that developed nanosystem provide a potential strategy for improving the chemotherapeutic effect and reducing the side effects of PTX.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Células A549 , Animales , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones Endogámicos C57BL , Nanopartículas/química , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Paclitaxel/farmacocinética , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Distribución TisularRESUMEN
Most of the anatomic variations of the extensor hallucis longus (EHL) muscle are related to the tendon of insertion. We show a double origin of the EHL from the medial aspect of the fibula and the lateral aspect of the tibia. A 27-year-old male with a double closed fracture of tibia and fibula showed an involuntary extension of the big toe during foot plantar flexion after surgery. A tendon fibrosis by the fixation plates could be the cause of the foot functional alteration. Interestingly, the anatomic variation described could be related to the postsurgical foot dysfunction, since when the fibrotic tissue was removed the normal extension of big toe recovered. As illustrated in this case report, knowledge of anatomic variations is very useful, particularly in the context of foot surgery.
Asunto(s)
Variación Anatómica , Músculo Esquelético/anomalías , Complicaciones Posoperatorias/fisiopatología , Tendones/anomalías , Fracturas de la Tibia/cirugía , Adulto , Tobillo/anomalías , Tobillo/diagnóstico por imagen , Placas Óseas , Fibrosis , Peroné/anomalías , Fijación Interna de Fracturas/efectos adversos , Fijación Interna de Fracturas/instrumentación , Hallux/fisiopatología , Humanos , Masculino , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Complicaciones Posoperatorias/etiología , Radiografía , Tendones/patología , Tibia/anomalías , Tibia/cirugíaRESUMEN
Protein tagging is widely used in approaches ranging from affinity purification to fluorescence-based detection in live cells. However, an intrinsic limitation of tagging is that the native function of the protein may be compromised or even abolished by the presence of the tag. Here we describe and characterize a set of small, innocuous protein tags (inntags) that we anticipate will find application in a variety of biological techniques.
Asunto(s)
Epítopos/análisis , Epítopos/química , Técnica del Anticuerpo Fluorescente/métodos , Inmunoprecipitación/métodos , Proteínas/análisis , Proteínas/inmunología , Animales , Anticuerpos Monoclonales , Epítopos/genética , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Conformación Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Curcumin, the main active compound of the curcuma root, shows antioxidant, anti-inflammatory, and antitumor properties which have been demonstrated in preclinical and clinical trials. Its antitumor activity is mediated by its ability to act directly on the tumor cell, activating apoptosis pathways and indirectly inhibiting the process of inflammation, angiogenesis, and metastasis in the tumor microenvironment. In addition, it has a preventive activity such as radio and/or chemosensitizer. These effects have been evident in in vitro assays but have also been corroborated in patient trials either through the isolated use of curcumin or through its association with other agents. Moreover, curcumin has demonstrated a low induction of side effects. Numerous patents have been developed in connection with the administration and use of curcumin against different types of cancer. All this justifies the interest for the development of new laboratory studies and especially of clinical trials to validate this compound as a dietary supplement in both the healthy and the oncological population. The present review aims to address the most recent in vitro investigations and the latest clinical trials and patents related to the curcumin agent to provide an up-to-date overview of the latest advances in relation to its antitumor effect.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Curcumina/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Curcumina/administración & dosificación , Curcumina/uso terapéutico , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Neovascularización Patológica/tratamiento farmacológico , Patentes como AsuntoRESUMEN
Pancreatic cancer (PC) is a lethal disease representing the seventh most frequent cause of death from cancer worldwide. Resistance of pancreatic tumors to current treatments leads to disappointing survival rates, and more specific and effective therapies are urgently needed. In recent years, immunotherapy has been proposed as a promising approach to the treatment of PC, and encouraging results have been published by various preclinical and clinical studies. This review provides an overview of the latest developments in the immunotherapeutic treatment of PC and summarizes the most recent and important clinical trials.
Asunto(s)
Inmunoterapia , Neoplasias Pancreáticas/terapia , HumanosRESUMEN
Local regulation of protein synthesis allows a neuron to rapidly alter the proteome in response to synaptic signals, an essential mechanism in synaptic plasticity that is altered in many neurological diseases. Synthesis of many synaptic proteins is under local control and much of this regulation occurs through structures termed RNA granules. KIS is a protein kinase that associates with stathmin, a modulator of the tubulin cytoskeleton. Furthermore, KIS is found in RNA granules and stimulates translation driven by the ß-actin 3'UTR in neurites. Here we explore the physiological and molecular mechanisms underlying the action of KIS on hippocampal synaptic plasticity in mice. KIS downregulation compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. The absence of KIS results in a significant decrease of protein levels of PSD-95, a postsynaptic scaffolding protein, and the AMPAR subunits GluR1 and GluR2 in a CPEB3-dependent manner. Underlying its role in spine maturation, KIS is able to suppress the spine developmental defects caused by CPEB3 overexpression. Moreover, either by direct or indirect mechanisms, KIS counteracts the inhibitory activity of CPEB3 on the GluR2 3'UTR at both mRNA translation and polyadenylation levels. Our study provides insights into the mechanisms that mediate dendritic spine morphogenesis and functional synaptic maturation, and suggests KIS as a link regulating spine cytoskeleton and postsynaptic activity in memory formation.
Asunto(s)
Espinas Dendríticas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/fisiología , Microtúbulos/fisiología , Plasticidad Neuronal/fisiología , Biosíntesis de Proteínas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Receptores AMPA/biosíntesis , Animales , Hipocampo/citología , Hipocampo/metabolismo , Ratones , Técnicas de Cultivo de ÓrganosRESUMEN
BACKGROUND: New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients. METHODS: MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade. RESULTS: Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and ≥50% CD133 expression had the poorest DFS and OS outcomes. CONCLUSIONS: Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility.
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Adenocarcinoma/patología , Antígenos CD/metabolismo , Neoplasias Colorrectales/patología , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Glicoproteínas/metabolismo , Péptidos/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Antígeno AC133 , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Estudios Transversales , Metilación de ADN , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with poor survival rates. Fast detection of PDAC appears to be the most relevant strategy to improve the long-term survival of patients. AIMS: Our objective was to identify new markers in peripheral blood that differentiates between PDAC patients and healthy controls. METHODS: Peripheral blood samples from PDAC patients (n = 18) and controls (n = 18) were analyzed by whole genome cDNA microarray hybridization. The most relevant genes were validated by quantitative real-time PCR (RT-qPCR) in the same set of samples. Finally, our gene prediction set was tested in a blinded set of new peripheral blood samples (n = 30). RESULTS: Microarray studies identified 87 genes differentially expressed in peripheral blood samples from PDAC patients. Four of these genes were selected for analysis by RT-qPCR, which confirmed the previously observed changes. In our blinded validation study, the combination of CLEC4D and IRAK3 predicted the diagnosis of PDAC with 93 % accuracy, with a sensitivity of 86 % and specificity of 100 %. CONCLUSIONS: Peripheral blood gene expression profiling is an useful tool for the diagnosis of PDAC. We present a validated four-gene predictor set (ANKRD22, CLEC4D, VNN1, and IRAK3) that may be useful in PDAC diagnosis.
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Carcinoma Ductal Pancreático/sangre , Neoplasias Pancreáticas/sangre , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismoRESUMEN
BACKGROUND: Liposomal Doxorubicin (Doxil®) was one of the first nanoformulations approved for the treatment of solid tumors. Although there is already extensive experience in its use for different tumors, there is currently no grouped evidence of its therapeutic benefits in non-small cell lung cancer (NSCLC). A systematic review of the literature was performed on the therapeutic effectiveness and benefits of Liposomal Doxil® in NSCLC. METHODS: A total of 1022 articles were identified in publications up to 2020 (MEDLINE, Cochrane, Web of Science Core Collection and Scopus). After applying inclusion criteria, the number was restricted to 114, of which 48 assays, including in vitro (n=20) and in vivo (animals, n=35 and humans, n=6) studies, were selected. RESULTS: The maximum inhibitory concentration (IC50), tumor growth inhibition rate, response and survival rates were the main indices for evaluating the efficacy and effectiveness of Liposomal DOX. These have shown clear benefits both in vitro and in vivo, improving the IC50 of free DOX or untargeted liposomes, depending on their size, administration, or targeting. CONCLUSION: Doxil® significantly reduced cellular proliferation in vitro and improved survival in vivo in both experimental animals and NSCLC patients, demonstrating optimal safety and pharmacokinetic behavior indices. Although our systematic review supports its benefits for the treatment of NSCLC, additional clinical trials with larger sample sizes are necessary to obtain more precise clinical data on its activity and effects in humans.
Asunto(s)
Antibióticos Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Doxorrubicina , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Polietilenglicoles/química , Proliferación Celular/efectos de los fármacos , LiposomasRESUMEN
A new eusdesmane sesquiterpenoid, characterized as 3,5,8a-trimethyl-8-oxo-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-b]furan-5-yl acetate (1), has been isolated from the rhizomes of the South African variety of wild ginger (Siphonochilus aethiopicus (Schweinf) B. L. Burtt). The compound was obtained by silica gel column chromatography. Its structure was elucidated by nuclear magnetic resonance spectroscopy (NMR) and mass-spectrometric (MS) analyses, including 1D-, 2D-NMR, and HR-LCMS. We also investigated the cytotoxic effect of 1 on a panel of cancer cell lines, human breast, pancreas, lung, colon, and central nervous system cancer lines. The data are not encouraging since its antitumor effect is poor. Nonetheless, the discovery of new molecules may provide a source of new compounds with important biological effects applicable to the field of medicine.
RESUMEN
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
Asunto(s)
Empalme Alternativo , Exones , Neuronas , Proteína de Unión al Tracto de Polipirimidina , Proteínas Serina-Treonina Quinasas , Animales , Humanos , Ratones , Exones/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Fosforilación , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Adult stem cells have an enormous potential for clinical use in regenerative medicine that avoids many of the drawbacks characteristic of embryonic stem cells and induced pluripotent stem cells. In this context, easily obtainable human adipose-derived stem cells offer an interesting option for future strategies in regenerative medicine. However, little is known about their repertoire of differentiation capacities, how closely they resemble the target primary tissues, and the potential safety issues associated with their use. DNA methylation is one of the most widely recognized epigenetic factors involved in cellular identity, prompting us to consider how the analyses of 27,578 CpG sites in the genome of these cells under different conditions reflect their different natural history. We show that human adipose-derived stem cells generate myogenic and osteogenic lineages that share much of the DNA methylation landscape characteristic of primary myocytes and osteocytes. Most important, adult stem cells and in vitro-generated myocytes and osteocytes display a significantly different DNA methylome from that observed in transformed cells from these tissue types, such as rhabdomyosarcoma and osteosarcoma. These results suggest that the plasticity of the DNA methylation patterns plays an important role in lineage commitment of adult stem cells and that it could be used for clinical purposes as a biomarker of efficient and safely differentiated cells.
Asunto(s)
Tejido Adiposo/citología , Linaje de la Célula/genética , Metilación de ADN/genética , Células Madre/citología , Células Madre/metabolismo , Adulto , Diferenciación Celular/genética , Línea Celular Tumoral , Células Cultivadas , Epigénesis Genética , Humanos , Persona de Mediana Edad , Células Madre Multipotentes/citología , Células Madre Multipotentes/metabolismo , Células Musculares/citología , Células Musculares/metabolismo , Desarrollo de Músculos/genética , Osteocitos/citología , Osteocitos/metabolismo , Osteogénesis/genética , Fenotipo , Regiones Promotoras Genéticas/genéticaRESUMEN
The incidence of gastrointestinal cancers has increased in recent years. Current treatments present numerous challenges, including drug resistance, non-specificity, and severe side effects, needing the exploration of new therapeutic strategies. One promising avenue is the use of magnetic nanoparticles, which have gained considerable interest due to their ability to generate heat in tumor regions upon the application of an external alternating magnetic field, a process known as hyperthermia. This review conducted a systematic search of in vitro and in vivo studies published in the last decade that employ hyperthermia therapy mediated by magnetic nanoparticles for treating gastrointestinal cancers. After applying various inclusion and exclusion criteria (studies in the last 10 years where hyperthermia using alternative magnetic field is applied), a total of 40 articles were analyzed. The results revealed that iron oxide is the preferred material for magnetism generation in the nanoparticles, and colorectal cancer is the most studied gastrointestinal cancer. Interestingly, novel therapies employing nanoparticles loaded with chemotherapeutic drugs in combination with magnetic hyperthermia demonstrated an excellent antitumor effect. In conclusion, hyperthermia treatments mediated by magnetic nanoparticles appear to be an effective approach for the treatment of gastrointestinal cancers, offering advantages over traditional therapies.
RESUMEN
Recently, the classical anatomy of the quadriceps femoris has been questioned after the publication of various morphological variations that differ from the classical description. Therefore, it is necessary to collect information to reach an agreement on its structure. For this, a systematic review was carried out using the Web of Science, Pubmed and ProQuest scientific databases, obtaining a total of 29 papers finally included in the systematic review after being subjected to inclusion and exclusion criteria. The results obtained showed an important and variable prevalence of new configurations described, such as additional heads in the rectus femoris, a different origin of the vastus intermedius, various portions of the vastus lateralis, or the involvement of the vastus medialis in the patellofemoral musculature. For this reason, understanding the anatomy of the quadriceps femoris is a matter that has not yet been fully resolved, with high variability among people that must be studied prior to the application of an invasive and/or surgical procedure.
RESUMEN
The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.