RESUMEN
INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.
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Caenorhabditis elegans , Modelos Animales de Enfermedad , Desarrollo de Medicamentos , Descubrimiento de Drogas , Enfermedades Neurodegenerativas , Caenorhabditis elegans/efectos de los fármacos , Animales , Humanos , Descubrimiento de Drogas/métodos , Desarrollo de Medicamentos/métodos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/fisiopatología , Ensayos Analíticos de Alto Rendimiento/métodos , Evaluación Preclínica de Medicamentos/métodos , Trastornos del Neurodesarrollo/tratamiento farmacológico , Trastornos del Neurodesarrollo/fisiopatología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/fisiopatologíaRESUMEN
The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.
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Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Células Madre Embrionarias Humanas/fisiología , Hipotálamo/embriología , Neuronas/fisiología , Diferenciación Celular/genética , Línea Celular , Mapeo Cromosómico , Estudio de Asociación del Genoma Completo , Humanos , Hipotálamo/citología , Herencia Multifactorial , RNA-Seq , Elementos Reguladores de la Transcripción/genéticaRESUMEN
Tuberculosis (TB) is a slow growing, potentially debilitating disease that has plagued humanity for centuries and has claimed numerous lives across the globe. Concerted efforts by researchers have culminated in the development of various strategies to combat this malady. This review aims to raise awareness of the rapidly increasing incidences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, highlighting the significant modifications that were introduced in the TB treatment regimen over the past decade. A description of the role of pathogen-host immune mechanisms together with strategies for prevention of the disease is discussed. The struggle to develop novel drug therapies has continued in an effort to reduce the treatment duration, improve patient compliance and outcomes, and circumvent TB resistance mechanisms. Herein, we give an overview of the extensive medicinal chemistry efforts made during the past decade toward the discovery of new chemotypes, which are potentially active against TB-resistant strains.
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Antituberculosos/química , Tuberculosis Extensivamente Resistente a Drogas/patología , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Ciprofloxacina/química , Ciprofloxacina/farmacología , Ciprofloxacina/uso terapéutico , Progresión de la Enfermedad , Portadores de Fármacos/química , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana/genética , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Tuberculosis Extensivamente Resistente a Drogas/inmunología , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Estreptomicina/química , Estreptomicina/farmacología , Estreptomicina/uso terapéutico , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Tiofenos/uso terapéutico , Receptores Toll-Like/metabolismoRESUMEN
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.
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Síndrome de Bardet-Biedl/metabolismo , Chaperoninas/metabolismo , Hipotálamo/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación Missense , Neuronas/metabolismo , Sistemas de Mensajero Secundario , Sustitución de Aminoácidos , Animales , Síndrome de Bardet-Biedl/genética , Chaperoninas/genética , AMP Cíclico/genética , AMP Cíclico/metabolismo , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
Therapeutic drug development is a long, expensive, and complex process that usually takes 12-15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.
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Caenorhabditis elegans/fisiología , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Animales , Evaluación Preclínica de Medicamentos/economía , Ensayos Analíticos de Alto Rendimiento/economía , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Modelos Animales , Especificidad de la EspecieRESUMEN
The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.
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Síntomas Afectivos/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Síntomas Afectivos/metabolismo , Síntomas Afectivos/fisiopatología , Antipsicóticos/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/metabolismo , Trastorno Bipolar/fisiopatología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Humanos , Trastornos de la Personalidad/tratamiento farmacológico , Trastornos de la Personalidad/metabolismo , Trastornos de la Personalidad/fisiopatología , Psicopatología/métodos , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Ideación SuicidaRESUMEN
Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.
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Betacoronavirus/química , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2 , Antivirales/metabolismo , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pandemias , Neumonía Viral/tratamiento farmacológico , Dominios Proteicos , SARS-CoV-2RESUMEN
Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.