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1.
Nat Rev Neurosci ; 24(4): 252-265, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36658346

RESUMEN

With sweeping advances in precision delivery systems and manipulation of the genomes and transcriptomes of various cell types, medical biotechnology offers unprecedented selectivity for and control of a wide variety of biological processes, forging new opportunities for therapeutic interventions. This perspective summarizes state-of-the-art gene therapies enabled by recent innovations, with an emphasis on the expanding universe of molecular targets that govern the activity and function of primary sensory neurons and which might be exploited to effectively treat chronic pain.


Asunto(s)
Dolor Crónico , Nociceptores , Humanos , Nociceptores/metabolismo , Dolor Crónico/genética , Dolor Crónico/terapia , Dolor Crónico/metabolismo , Transcriptoma
2.
Eur J Neurosci ; 57(1): 17-31, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36380588

RESUMEN

Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the effects of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild-type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/-) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90 and 365). The elevated plus-maze test revealed a reduction of anxiety by enrichment, whereas the mobility of young and adult Eker rats in the open field was lower compared to the wild type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90- and 365-day-old rats. Self-grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age-related changes in spine morphology and density, which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.


Asunto(s)
Trastorno del Espectro Autista , Ratas , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Células Piramidales/metabolismo , Hipocampo/metabolismo , Plasticidad Neuronal , Modelos Animales de Enfermedad
3.
Int J Mol Sci ; 24(18)2023 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-37762660

RESUMEN

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC.

4.
Int J Mol Sci ; 23(11)2022 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-35682780

RESUMEN

Celiac disease (CeD) manifests with autoimmune intestinal inflammation from gluten and genetic predisposition linked to human leukocyte antigen class-II (HLA-II) gene variants. Antigen-presenting cells facilitate gluten exposition through the interaction of their surface major histocompatibility complex (MHC) with the T cell receptor (TCR) on T lymphocytes. This fundamental mechanism of adaptive immunity has broadened upon recognition of extracellular exosomal MHC, raising awareness of an alternative means for antigen presentation. This study demonstrates that conditioned growth media (CGM) previously exposed to monocyte-derived dendritic cells from CeD significantly downregulates the CD3+ lineage marker of control T cells. Such increased activation was reflected in their elevated IL-2 secretion. Exosome localization motif identification and quantification within HLA-DQA1 and HLA-DQB1 transcripts highlighted their significant prevalence within HLA-DQB1 alleles associated with CeD susceptibility. Flow cytometry revealed the strong correlation between HLA-DQ and the CD63 exosomal marker in T cells exposed to CGM from MoDCs sourced from CeD patients. This resulted in lower concentrations of CD25+ CD127- T cells, suggestive of their compromised induction to T-regulatory cells associated with CeD homeostasis. This foremost comparative study deciphered the genomic basis and extracellular exosomal effects of HLA transfer on T lymphocytes in the context of CeD, offering greater insight into this auto-immune disease.


Asunto(s)
Enfermedad Celíaca , Alelos , Glútenes/genética , Antígenos HLA-DQ/genética , Humanos , Linfocitos T Reguladores
5.
Nature ; 526(7573): 443-7, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26322584

RESUMEN

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-ß peptide. Two principal physiological pathways either prevent or promote amyloid-ß generation from its precursor, ß-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-ß fragments generated by the α- and ß-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (ß-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-ß). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/citología , Metaloproteinasas de la Matriz Asociadas a la Membrana/metabolismo , Neuronas/fisiología , Proteolisis , Proteínas ADAM/metabolismo , Proteína ADAM10 , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/deficiencia , Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/deficiencia , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Señalización del Calcio , Modelos Animales de Enfermedad , Femenino , Hipocampo/enzimología , Hipocampo/fisiología , Humanos , Técnicas In Vitro , Potenciación a Largo Plazo , Masculino , Metaloproteinasas de la Matriz Asociadas a la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Ratones , Peso Molecular , Neuritas/enzimología , Neuritas/metabolismo , Neuronas/enzimología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Placa Amiloide , Procesamiento Proteico-Postraduccional , Análisis de la Célula Individual
6.
Alzheimers Dement ; 17(5): 888-905, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33336545

RESUMEN

Schizophrenia is a chronic neuropsychiatric brain disorder that has devastating personal impact and rising healthcare costs. Dysregulation of glutamatergic neurotransmission has been implicated in the pathobiology of the disease, attributed largely to the hypofunction of the N-methyl-d-aspartate (NMDA) receptor. Currently, there is a major gap in mechanistic analysis as to how endogenous modulators of the NMDA receptors contribute to the onset and progression of the disease. We present a systematic review of the neurobiology and the role of endogenous NMDA receptor antagonists in animal models of schizophrenia, and in patients. We discuss their neurochemical origin, release from neurons and glia with action mechanisms, and functional effects, which might contribute toward the impairment of neuronal processes underlying this complex pathological state. We consider clinical evidence suggesting dysregulations of endogenous NMDA receptor in schizophrenia, and highlight the pressing need in future studies and emerging directions, to restore the NMDA receptor functions for therapeutic benefits.


Asunto(s)
Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/fisiopatología , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos
7.
J Cell Physiol ; 234(11): 19464-19470, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31058319

RESUMEN

Radiation exposure can evoke cellular stress responses. Emerging recognition that long non-coding RNAs (lncRNAs) act as regulators of gene expression has broadened the spectra of molecules controlling the genomic landscape upon alterations in environmental conditions. Knowledge of the mechanisms responding to low dose irradiation (LDR) exposure is very limited yet most likely involve subtle ancillary molecular pathways other than those protecting the cell from direct cellular damage. The discovery that transcription of the lncRNA PARTICLE (promoter of MAT2A- antisense radiation-induced circulating lncRNA; PARTICL) becomes dramatically instigated within a day after LDR exposure introduced a new gene regulator onto the biological landscape. PARTICLE affords an RNA binding platform for genomic silencers such as DNA methyltransferase 1 and histone tri-methyltransferases to reign in the expression of tumor suppressors such as its neighboring MAT2A in cis as well as WWOX in trans. In silico evidence offers scope to speculate that PARTICLE exploits the abundance of Hoogsten bonds that exist throughout mammalian genomes for triplex formation, presumably a vital feature within this RNA silencer. PARTICLE may provide a buffering riboswitch platform for S-adenosylmethionine. The correlation of PARTICLE triplex formation sites within tumor suppressor genes and their abundance throughout the genome at cancer-related hotspots offers an insight into potential avenues worth exploring in future therapeutic endeavors.


Asunto(s)
Neoplasias/genética , Interferencia de ARN/efectos de la radiación , ARN Largo no Codificante/genética , Exposición a la Radiación/efectos adversos , ADN (Citosina-5-)-Metiltransferasa 1/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genoma Humano/efectos de la radiación , Genómica , Histona Metiltransferasas/genética , Humanos , Metionina Adenosiltransferasa/genética , Neoplasias/radioterapia , Regiones Promotoras Genéticas/genética , Dosis de Radiación , Proteínas Supresoras de Tumor/genética , Oxidorreductasa que Contiene Dominios WW/genética
8.
Int J Mol Sci ; 20(13)2019 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-31277281

RESUMEN

Aging and chronic sleep deprivation (SD) are well-recognized risk factors for Alzheimer's disease (AD), with N-methyl-D-aspartate receptor (NMDA) and downstream nitric oxide (NO) signalling implicated in the process. Herein, we investigate the impact of the age- and acute or chronic SD-dependent changes on the expression of NMDA receptor subunits (NR1, NR2A, and NR2B) and on the activities of NO synthase (NOS) isoforms in the cortex of Wistar rats, with reference to cerebral lateralization. In young adult controls, somewhat lateralized seasonal variations in neuronal and endothelial NOS have been observed. In aged rats, overall decreases in NR1, NR2A, and NR2B expression and reduction in neuronal and endothelial NOS activities were found. The age-dependent changes in NR1 and NR2B significantly correlated with neuronal NOS in both hemispheres. Changes evoked by chronic SD (dysfunction of endothelial NOS and the increasing role of NR2A) differed from those evoked by acute SD (increase in inducible NOS in the right side). Collectively, these results demonstrate age-dependent regulation of the level of NMDA receptor subunits and downstream NOS isoforms throughout the rat brain, which could be partly mimicked by SD. As described herein, age and SD alterations in the prevalence of NMDA receptors and NOS could contribute towards cognitive decline in the elderly, as well as in the pathobiology of AD and the neurodegenerative process.


Asunto(s)
Envejecimiento/metabolismo , Corteza Cerebral/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transducción de Señal , Privación de Sueño/metabolismo , Factores de Edad , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/etiología , Animales , Regulación de la Expresión Génica , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Riesgo , Privación de Sueño/fisiopatología
9.
Alzheimers Dement ; 14(4): 502-513, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29494806

RESUMEN

The synaptic vesicle cycle (SVC) holds center stage in the biology of presynaptic terminals. Through recurrent exocytosis and endocytosis, it facilitates a sequence of events enabling chemical neurotransmission between functionally related neurons. As a fundamental process that links the interior of nerve cells with their environment, the SVC is also critical for signaling and provides an entry route for a range of pathogens and toxins, enabling detrimental effects. In Alzheimer's disease, the SVC is both the prime site of amyloid ß production and toxicity. In this study, we discuss the emerging evidence for physiological and pathological effects of Aß on various stages of the SVC, from postfusion membrane recovery to trafficking, docking, and priming of vesicles for fusion and transmitter release. Understanding of the mechanisms of Aß interaction with the SVC within the unifying calcium hypothesis of aging and Alzheimer's disease should further elucidate the fundamental biology of the presynaptic terminal and reveal novel therapeutic targets for Alzheimer's disease and other age-related dementias.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Vesículas Sinápticas/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Humanos
10.
Opt Lett ; 41(12): 2708-10, 2016 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-27304269

RESUMEN

We propose the implementation of hybrid optical and acoustic resolution optoacoustic endoscopy. Laser light is transmitted to tissue by two types of illumination for achieving optical and acoustic resolution imaging. A 20 MHz ultrasound detector is used for recording optoacoustic signals. The endoscopy probe attains a 3.6 mm diameter and is fully encapsulated into a catheter system. We validate the imaging performance of the hybrid endoscope on phantoms and ex vivo, and discuss the necessity for the extended resolution and depth range of endoscopy achieved.


Asunto(s)
Acústica , Endoscopía/instrumentación , Técnicas Fotoacústicas/métodos , Humanos , Aumento de la Imagen/métodos , Fantasmas de Imagen , Ultrasonografía
11.
Rev Neurosci ; 25(6): 821-32, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25051277

RESUMEN

Paracrine signaling and coupling via intercellular conduits are widely utilized for cell-cell interactions from primitive eukaryotes to advanced metazoa. Here, we review the functional and molecular data suggestive of a phylogenic continuum between these primeval forms of communication with the chemical and electrical synaptic transmission of neurons. We discuss selective evidence for the essential role played by the shift of function in early cellular morphologies and protosynaptic scaffolds, with their co-optation for new functionality, which ultimately lead to the rise of the chemical synapse. It is proposed that, rather than representing a transitional element, mixed electrochemical synapses exemplify an exaptive effect. The nonadaptive model of the synaptic origin described herein supports the pluralistic hypothesis of evolutionary change.


Asunto(s)
Evolución Biológica , Sinapsis Eléctricas/fisiología , Neuronas/fisiología , Comunicación Paracrina/fisiología , Transmisión Sináptica/fisiología , Animales , Uniones Comunicantes/fisiología , Humanos , Red Nerviosa/fisiología
12.
Proc Natl Acad Sci U S A ; 108(48): 19113-20, 2011 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-22080607

RESUMEN

Dendritic exocytosis underpins a broad range of integrative and homeostatic synaptic functions. Emerging data highlight the essential role of SNAREs in trafficking and fusion of secretory organelles with release of peptides and neurotransmitters from dendrites. This Perspective analyzes recent evidence inferring axo-dendritic polarization of vesicular release machinery and pinpoints progress made with existing challenges in this rapidly progressing field of dendritic research. Interpreting the relation of new molecular data to physiological results on secretion from dendrites would greatly advance our understanding of this facet of neuronal mechanisms.


Asunto(s)
Polaridad Celular/fisiología , Dendritas/metabolismo , Fusión de Membrana/fisiología , Neuronas/fisiología , Proteínas SNARE/metabolismo , Sinapsis/fisiología , Calcio/metabolismo , Modelos Biológicos , Vesículas Transportadoras/metabolismo
13.
Technol Cancer Res Treat ; 23: 15330338241275403, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39149973

RESUMEN

Early diagnosis is crucial for enhancing the survival rate of renal cell cancer patients, and exosomes present potential advantages in this area. Their small size, high mobility, and lipid bilayer structure enable exosomes to cross biological membranes easily, protecting the bioactive cargo within from degradation. Exosomes significantly influence the invasion and metastasis of RCC, and they also contribute to tumor drug resistance and immune evasion.


Asunto(s)
Carcinoma de Células Renales , Exosomas , Neoplasias Renales , Humanos , Exosomas/metabolismo , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Biomarcadores de Tumor , Nanopartículas/química , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología
14.
Brain Struct Funct ; 229(1): 1-14, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37999738

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.


Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Animales , Neuronas Motoras , Modelos Animales de Enfermedad
15.
J Mol Med (Berl) ; 102(6): 761-771, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38653825

RESUMEN

Epilepsy is a neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to diverse etiology, pathobiology, and pharmacotherapy-resistant variants. The anticonvulsive effects of herbal leads with biocompatibility and toxicity considerations have attracted much interest, inspiring mechanistic analysis with the view of their use for engagement of new targets and combination with antiseizure pharmacotherapies. This article presents a comprehensive overview of the key molecular players and putative action mechanisms of the most common antiepileptic herbals demonstrated in tissue culture and preclinical models. From the review of the literature, it emerges that their effects are mediated via five distinct mechanisms: (1) reduction of membrane excitability through inhibition of cation channels, (2) improvement of mitochondrial functions with antioxidant effects, (3) enhancement in synaptic transmission mediated by GABAA receptors, (4) improvement of immune response with anti-inflammatory action, and (5) suppression of protein synthesis and metabolism. While some of the primary targets and action mechanisms of herbal anticonvulsants (1, 3) are shared with antiseizure pharmacotherapies, herbal leads also engage with distinct mechanisms (2, 4, and 5), suggesting new drug targets and opportunities for their integration with antiseizure medications. Addressing outstanding questions through research and in silico modeling should facilitate the future use of herbals as auxiliary therapy in epilepsy and guide the development of treatment of pharmacoresistant seizures through rigorous trials and regulatory approval.


Asunto(s)
Anticonvulsivantes , Humanos , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/farmacología , Animales , Epilepsia Refractaria/tratamiento farmacológico , Epilepsia Refractaria/metabolismo , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo
16.
Biomedicines ; 12(5)2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38790894

RESUMEN

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

17.
Pharmaceutics ; 16(1)2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38258133

RESUMEN

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study's objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer.

18.
J Physiol ; 591(7): 1771-91, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23318870

RESUMEN

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with K(V)1 channels produced by mandatory multi-merization of K(V)1.1, 1.2 α and KV ß2 subunits. Being constitutively active, the K(+) current (IK(V)1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IK(V)1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IK(V)1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of back-propagating action potentials into the somato-dendritic compartment. The latter is also demonstrated to secure the dominance of clock-like somatic pacemaking in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modelling and retro-axonal labelling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is established.


Asunto(s)
Núcleos Cerebelosos/fisiología , Neuronas/fisiología , Canales de Potasio de la Superfamilia Shaker/fisiología , Tálamo/fisiología , Animales , Relojes Biológicos , Núcleos Cerebelosos/citología , Técnicas In Vitro , Subunidades de Proteína/fisiología , Ratas
19.
Mol Pharm ; 10(11): 4195-206, 2013 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-24066863

RESUMEN

Treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, is hampered by its complex etiology and lack of efficient means for targeted transfer of therapeutics into motoneurons. The objective of this research was engineering of a versatile motoneuron targeting adapter--a full-length atoxic tetanus toxin fused to core-streptavidin (CS-TeTIM)--for retro-axonal transduction of viral vectors; validation of the targeting efficiency of CS-TeTIM in vivo, by expression of green fluorescence protein (GFP) reporter in motoneurons of presymptomatic and symptomatic ALS-like SOD1(G93A) mice, and comparison with age-matched controls; and appraisal of lentiviral transduction with CS-TeTIM relative to (1) a HC binding fragment of tetanus toxin CS-TeTx(HC), (2) rabies glycoprotein (RG), and (3) a CS-TeTIM-RG dual targeting approach. CS-TeTIM and CS-TeTx(HC) were engineered using recombinant technology and site-directed mutagenesis. Biotinylated vectors, pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) or RG, were linked to these adaptors and injected intraperitoneally (ip) into presymptomatic (12 weeks old), symptomatic SOD1(G93A) (22 weeks old) or wild type control mice, followed by monitoring of GFP expression in the spinal cord and supraspinal motor structures with quantitative PCR and immuno-histochemistry. Transcripts were detected in the spinal cord and supraspinal motor structures of all mice 2 weeks after receiving a single ip injection, although in symptomatic SOD1(G93A) animals reporter RNA levels were lower compared to presymptomatic and wild-type controls irrespective of the targeting approach. GFP transduction with CS-TeTIM proved more efficient than CS-TeTx(HC) across all groups while CS-TeTIM-RG dual-targeted vectors yielded the highest transcript numbers. Importantly, in both wild-type and presymptomatic SOD1(G93A) mice strong colabeling of choline-acetyltransferase (ChAT) and GFP was visualized in neurons of the brain stem and spinal cord. CS-TeTIM, a versatile adaptor protein for targeted lentiviral transduction of motoneurons, has been engineered and its competence assessed relative to CS-TeTx(HC) and RG. Evidence has been provided that highlights the potential usefulness of this novel recombinant tool for basic research with implications for improved transfer of therapeutic candidates into motoneurons for the amelioration of ALS and related diseases.


Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Sistema Nervioso Central/citología , Lentivirus/genética , Estreptavidina/química , Toxina Tetánica/uso terapéutico , Animales , Células Cultivadas , Femenino , Glicoproteínas/química , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Médula Espinal/citología , Toxina Tetánica/química
20.
Biochem J ; 441(1): 443-52, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21929507

RESUMEN

Intracellular protein transport routes can be studied using toxins that exploit these to enter cells. BoNTA (botulinum neurotoxin type A) is a protease that binds to peripheral nerve terminals, becomes endocytosed and causes prolonged blockade of transmitter release by cleaving SNAP-25 (synaptosome-associated protein of 25 kDa). Retrograde transport of the toxin has been suggested, but not of the transient muscle relaxant, BoNTE (botulinum neurotoxin type E). In the present study, dispersal of these proteases in compartmented cultures of rat sympathetic neurons was examined after focal application of BoNTA or BoNTE to neurites. A majority of cleaved SNAP-25 was seen locally, but some appeared along neurites and accumulated in the soma over several weeks. BoNTE yielded less cleaved SNAP-25 at distal sites due to shorter-lived enzymic activity. Neurite transection prevented movement of BoNTA. The BoNTA protease could be detected only in the supernatants of neurites or cell body lysates, hence these proteases must move along neuronal processes in the axoplasm or are reversibly associated with membranes. Substitution into BoNTE of the BoNTA acceptor-binding domain did not alter its potency or mobility. Spontaneous or evoked transmission to cell bodies were not inhibited by retrogradely migrated BoNTA except with high doses, concurring with the lack of evidence for a direct central action when used clinically.


Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas/farmacología , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Animales Recién Nacidos , Toxinas Botulínicas/metabolismo , Toxinas Botulínicas Tipo A/metabolismo , Células Cultivadas , Regulación de la Expresión Génica/fisiología , Transporte de Proteínas , Ratas , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo
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