RESUMEN
Cancer will remain one of the most significant challenges for public health, locally and globally. Currently, cancer is the leading cause of death in our country. Thanks to the enormous knowledge accumulated in recent decades on the cellular and molecular bases of cancer, precision oncology has been developed, an approach that allows for increasingly precise pharmacological treatment based on diagnostic tests. Advanced technologies such as next-generation sequencing are used for this purpose. It is essential to implement these technologies in current and future health systems to optimize the arsenal of strategies for cancer control. This review discusses some of the achievements of precision oncology, particularly applied to solid tumors. It addresses the state-of-the-art minimum biomarkers required for the diagnosis of this important group of neoplasms, the local situation regarding technological capabilities installed in the national territory, either for research or diagnosis, and the potential health impact of applying all this practical knowledge to serve people with cancer, both in the public and private sectors.
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Neoplasias , Medicina de Precisión , Humanos , Chile , Neoplasias/diagnóstico , Neoplasias/genética , Medicina de Precisión/métodos , Biomarcadores de Tumor/genética , Técnicas de Diagnóstico Molecular/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Oncología Médica/tendencias , Oncología Médica/métodosRESUMEN
BACKGROUND: Wnt signaling plays key roles in cellular and physiological processes, including cell proliferation, differentiation and migration during development and tissue homeostasis in adults. This pathway can be defined as Wnt/ß-catenin-dependent or ß-catenin-independent or "non-canonical", both signaling are involved in neurite and synapse development/maintenance. Porcupine (PORCN), an acylase that o-acylates Wnt ligands, a major modification in secretion and interaction with its receptors. We use Wnt-C59, a specific PORCN inhibitor, to block the secretion of endogenous Wnts in embryonic hippocampal neurons (DIV 4). Under these conditions, the activity of exogenous Wnt ligands on the complexity of the dendritic tree and axonal polarity were evaluated METHODS: Cultured primary embryonic hippocampal neurons obtained from Sprague-Dawley rat fetuses (E18), were cultured until day in vitro (DIV) 4 (according to Banker´s protocol) and treated with Wnt-C59 for 24 h, Wnt ligands were added to the cultures on DIV 3 for 24 h. Dendritic arbors and neurites were analysis by fluorescence microscopy. Transfection with Lipofectamine 2000 on DIV 2 of plasmid expressing eGFP and KIF5-Cherry was carried out to evaluate neuronal polarity. Immunostaining was performed with MAP1B and Tau protein. Immunoblot analysis was carried out with Wnt3a, ß-catenin and GSK-3ß (p-Ser9). Quantitative analysis of dendrite morphology was carried out with ImageJ (NIH) software with Neuron J Plugin. RESULTS: We report, here, that Wnt-C59 treatment changed the morphology of the dendritic arbors and neurites of embryonic hippocampal neurons, with decreases ß-catenin and Wnt3a and an apparent increase in GSK-3ß (p-Ser9) levels. No effect was observed on axonal polarity. In sister cultures, addition of exogenous Wnt3a, 5a and 7a ligands rescued the changes in neuronal morphology. Wnt3a restored the length of neurites to near that of the control, but Wnt7a increased the neurite length beyond that of the control. Wnt5a also restored the length of neurites relative to Wnt concentrations. CONCLUSIONS: Results indicated that Wnt ligands, added exogenously, restored dendritic arbor complexity in embryonic hippocampal neurons, previously treated with a high affinity specific Porcupine inhibitor. We proposed that PORCN is an emerging molecular target of interest in the search for preclinical options to study and treat Wnt-related diseases. Video Abstract.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/genética , Neuronas/metabolismo , Proteína Wnt3A/genética , beta Catenina/genética , Animales , Axones/metabolismo , Bencenoacetamidas/farmacología , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Polaridad Celular/genética , Proliferación Celular/efectos de los fármacos , Feto , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Ligandos , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas/genética , Piridinas/farmacología , Ratas , Proteínas Wnt/genética , Proteína Wnt-5a/genéticaRESUMEN
With or without a COVID19 pandemic, cancer is and will continue to be one of the greatest health challenges on the planet. In Chile, during 2016, this disease was the second cause of death in the country and during 2019, it was the first cause in seven Chilean regions, surpassing cardiovascular diseases. With the advent of precision medicine as a powerful tool for cancer control, it is necessary to have genomic, proteomic, and molecular data in general, ideally on a population scale. This is essential for decision-making, for example in public and private oncology, to be as cost-effective as possible. Chile has a mass of high-quality researchers in cancer. However, until today the investment in research and development is far below the peers in the OECD. In this work we put into perspective the role of precision medicine and omic sciences as essential tools for public health. We offer a brief national diagnosis of the knowledge collected to date by the local scientific community regarding onco-genomic data from our own population. We finally discuss the potential behind the strengthening of this scientific knowledge, aiming to optimize the comprehensive management of cancer.
Asunto(s)
COVID-19 , Neoplasias , Chile/epidemiología , Atención a la Salud , Humanos , Neoplasias/terapia , ProteómicaRESUMEN
The increase of the elderly population with a significant load of non-communicable diseases, accelerates pathological aging and increases the risk of dementia, generating a huge health, social and economic cost for any country. Dementia does not have an effective treatment yet, therefore, the focus must remain on prevention and early diagnosis. The early stages of dementia are known as mild cognitive impairment; at this stage is still possible to mitigate the progression of the disease, however, health systems worldwide face difficulties to provide universal access to health services, due to a lack of specialists and geographical distances, interfering with the access to healthcare centers. In this scenario, WHO urged countries to implement strategies to democratize and to expand the reach of health institutions. In this document, we briefly review the global and local situation of dementias and discuss some attempts to control their progression by using revolutionary digital tools. We believe the focus should be on the population that is just beginning to show cognitive impairment.
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Demencia , Tecnología Digital , Servicios de Salud , Anciano , Demencia/prevención & control , HumanosRESUMEN
BACKGROUND: In the adult central nervous system (CNS), Wnt signaling regulates dendritic structure and synaptic plasticity. The Wnt signaling pathway can be divided into the canonical (ß-catenin-dependent) and non-canonical pathways. In the canonical pathway, the binding of canonical ligands such as Wnt3a to the Frizzled receptor induces inactivation of glycogen synthase kinase-3ß (GSK-3ß), which stabilizes ß-catenin and allows its translocation to the nucleus. However, to date, few studies have focused on ß-catenin-independent Wnt signaling or explained the underlying mechanisms connecting Wnt signaling to cellular energy metabolism. A recent study demonstrated negative regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a major target of GSK-3ß that regulates cellular metabolism under diverse conditions. Mainly based on these observations, we evaluated whether Wnt3a ligand modulates autophagy by regulating the GSK-3ß/AMPK axis. METHODS: Cultured primary hippocampal neurons and slices of the CA1 region of rat hippocampus were used. GSK-3ß inhibition, AMPK activation, PP2Ac expression, and LC3 processing were examined by western blotting. Autophagic compartments were studied using the CYTO-ID® fluorescent probe, and mature autophagosomes were observed via transmission electron microscopy (TEM). RESULTS: Wnt3a ligand, acting through the Frizzled receptor, promotes the rapid activation of AMPK by inactivating GSK-3ß. Biochemical analysis of downstream targets indicated that Wnt3a ligand modulates autophagy in hippocampal neurons. CONCLUSIONS: Our results revealed new aspects of Wnt signaling in neuronal metabolism. First, AMPK is an additional target downstream of the Wnt cascade, suggesting a molecular mechanism for the metabolic effects previously observed for Wnt signaling. Second, this mechanism is independent of ß-catenin, suggesting a relevant role for non-genomic activity of the Wnt pathway in cellular metabolism. Finally, these results have new implications regarding the role of Wnt signaling in the modulation of autophagy in neurons, with a possible role in the removal of accumulated intracellular proteins.
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Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ligandos , Animales , Autofagia/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Células Cultivadas , Receptores Frizzled/metabolismo , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Litio/farmacología , Metformina/farmacología , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación/efectos de los fármacos , Proteína Fosfatasa 2/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-ß peptide (Aß). Monomeric soluble Aß can switch from helicoidal to ß-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aß can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aß nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aß analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aß related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aß oligomers was observed. Our results show that Aß nitrotyrosination is a post-translational modification that increases Aß synaptotoxicity. SIGNIFICANCE STATEMENT: We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-ß (Aß) favors the stabilization of highly toxic oligomers and inhibits the formation of Aß fibrils. The nitrated Aß oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.
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Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Modelos Químicos , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Amiloide/química , Amiloide/ultraestructura , Péptidos beta-Amiloides/ultraestructura , Animales , Sitios de Unión , Supervivencia Celular/fisiología , Células Cultivadas , Simulación por Computador , Ratones , Modelos Moleculares , Neuronas/citología , Nitrocompuestos/química , Nitrocompuestos/metabolismo , Unión Proteica , Multimerización de Proteína , Receptores de N-Metil-D-Aspartato/química , Tirosina/química , Tirosina/metabolismoRESUMEN
In previous studies, we have demonstrated the beneficial effects of classic PPARγ agonists on neuroprotection against Aß oligomer neurotoxicity in a double transgenic mouse model of Alzheimer' disease (AD). INT-131, a novel, non-thiazolidinedione compound that belongs to a new family of drugs, selective PPARγ modulators (SPPARMs), has provided an emerging opportunity for the treatment of type 2 diabetes mellitus and metabolic syndrome. However, its role in the central nervous system has not been studied. The aim of this study was to evaluate the putative neuroprotective role of INT131 in hippocampal neurons. We found that INT131 increased dendritic branching, promoted neuronal survival against Aß amyloid, increased expression of PGC1-1α and modulated neuronal mitochondrial dynamics. Our results suggest that INT131, a drug that has been shown to be safe and effective in metabolic disorders, may constitute a new therapeutic alternative for AD.
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Péptidos beta-Amiloides/metabolismo , Hipocampo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/metabolismo , Quinolinas/farmacología , Sulfonamidas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Células Cultivadas , Hipocampo/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Neuronas/metabolismo , Neuronas/ultraestructura , PPAR gamma/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Hippocampal synapses play a key role in memory and learning processes by inducing long-term potentiation and depression. Wnt signaling is essential in the development and maintenance of synapses via several mechanisms. We have previously found that Wnt5a induces the production of nitric oxide (NO), which modulates NMDA receptor expression in the postsynaptic regions of hippocampal neurons. Here, we report that Wnt5a selectively inhibits a voltage-gated K(+) current (Kv current) and increases synaptic activity in hippocampal slices. Further supporting a specific role for Wnt5a, the soluble Frizzled receptor protein (sFRP-2; a functional Wnt antagonist) fully inhibits the effects of Wnt5a. We additionally show that these responses to Wnt5a are mediated by activation of a ROR2 receptor and increased NO production because they are suppressed by the shRNA-mediated knockdown of ROR2 and by 7-nitroindazole, a specific inhibitor of neuronal NOS. Together, our results show that Wnt5a increases NO production by acting on ROR2 receptors, which in turn inhibit Kv currents. These results reveal a novel mechanism by which Wnt5a may regulate the excitability of hippocampal neurons.
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Hipocampo/citología , Neuronas/fisiología , Óxido Nítrico/metabolismo , Canales de Potasio/fisiología , Sinapsis/fisiología , Proteínas Wnt/fisiología , Animales , Células Cultivadas , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Técnicas In Vitro , Indazoles/farmacología , Ratones , Ratones Endogámicos C57BL , Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Transducción Genética , Proteína Wnt-5a , omega-N-Metilarginina/farmacologíaRESUMEN
The Wnt signaling pathway plays an important role in developmental processes, including embryonic patterning, cell specification, and cell polarity. Wnt components participate in the development of the central nervous system, and growing evidence indicates that this pathway also regulates the function of the adult nervous system. In this study, we report that Wnt-5a, a noncanonical Wnt ligand, is a potent activator of mitochondrial dynamics and induces acute fission and fusion events in the mitochondria of rat hippocampal neurons. The effect of Wnt-5a was inhibited in the presence of sFRP, a Wnt scavenger. Similarly, the canonical Wnt-3a ligand had no effect on mitochondrial fission-fusion events, suggesting that this effect is specific for Wnt-5a alone. We also show that the Wnt-5a effects on mitochondrial dynamics occur with an increase in both intracellular and mitochondrial calcium (Ca(2+)), which was correlated with an increased phosphorylation of Drp1(Ser-616) and a decrease of Ser-637 phosphorylation, both indicators of mitochondrial dynamics. Electron microscope analysis of hippocampal tissues in the CA1 region showed an increase in the number of mitochondria present in the postsynaptic region, and this finding correlated with a change in mitochondrial morphology. We conclude that Wnt-5a/Ca(2+) signaling regulates the mitochondrial fission-fusion process in hippocampal neurons, a feature that might help to further understand the role of Wnt-related pathologies, including neurodegenerative diseases associated with mitochondrial dysfunction, and represents a potentially important link between impaired metabolic function and degenerative disorders.
Asunto(s)
Dinámicas Mitocondriales , Proteínas Wnt/fisiología , Animales , Región CA1 Hipocampal/citología , Señalización del Calcio , Células Cultivadas , Dinaminas/metabolismo , Potencial de la Membrana Mitocondrial , Ratones Endogámicos C57BL , Mitocondrias/fisiología , Mitocondrias/ultraestructura , Neuronas/metabolismo , Neuronas/ultraestructura , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Ratas Sprague-Dawley , Proteína Wnt-5aRESUMEN
Amyloid-ß oligomers (Aßo) play a major role in the synaptic dysfunction of Alzheimer's disease (AD). Neuroligins are postsynaptic cell-adhesion molecules, that share an extracellular domain with high degree of similarity to acetylcholinesterase (AChE), one of the first putative Aßo receptors. We recently found that Aßo interact with the soluble N-terminal fragment of neuroligin-1 (NL-1). We report here that Aßo associate with NL-1 at excitatory hippocampal synapses, whereas almost no association was observed with neuroligin-2, an isoform present at inhibitory synapses. Studies using purified hippocampal postsynaptic densities indicate that NL-1 interacts with Aßo in a complex with GluN2B-containing NMDA receptors. Additionally, the soluble fragment of NL-1 was used as a scavenger for Aßo. Field excitatory postsynaptic potentials indicate that fragments of NL-1 protect hippocampal neurons from the impairment induced by Aßo. To our knowledge, this is the first report of the interaction between this extracellular fragment of NL-1 and Aßo, strongly suggest that NL-1 facilitates the targeting of Aßo to the postsynaptic regions of excitatory synapses.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Moléculas de Adhesión Celular Neuronal/química , Células Cultivadas , Potenciales Postsinápticos Excitadores , Hipocampo/citología , Humanos , Neuronas/citología , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , SolubilidadRESUMEN
Tau phosphorylated at the PHF-1 epitope (S396/S404) is likely involved in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which tau phosphorylated at these sites negatively impacts neuronal functions are still under scrutiny. Previously, we showed that expression of tau truncated at D421 enhances mitochondrial dysfunction induced by Aß in cortical neurons. To extend these findings, we expressed tau pseudo-phosphorylated at S396/404 (T42EC) in mature and young cortical neurons and evaluated different aspects of mitochondrial function in response to Aß. Expression of T42EC did not induce significant changes in mitochondrial morphology, mitochondrial length, or mitochondrial transport, compared to GFP and full-length tau. However, T42EC expression enhanced Aß-induced mitochondrial membrane potential loss and increased superoxide levels compared to what was observed in mature neurons expressing full-length tau. The same effect was observed in mature neurons that expressed both pseudo-phosphorylated and truncated tau when they were treated with Aß. Interestingly, the mitochondrial failure induced by Aß in mature neurons that expressed T42EC, was not observed in young neurons expressing T42EC. These novel findings suggest that phosphorylated tau (PHF-1 epitope) enhances Aß-induced mitochondrial injury, which contributes to neuronal dysfunction and to the pathogenesis of AD.
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Enfermedades Mitocondriales/inducido químicamente , Neuronas/efectos de los fármacos , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Células Cultivadas , Corteza Cerebral/citología , Embrión de Mamíferos , Proteínas Fluorescentes Verdes/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Enfermedades Mitocondriales/metabolismo , Mutación/genética , Fosforilación/genética , Presenilina-1/genética , Ratas , Superóxidos/metabolismo , TransfecciónRESUMEN
Wnt signaling has a crucial role in synaptic function at the central nervous system. Here we evaluate whether Wnts affect nitric oxide (NO) generation in hippocampal neurons. We found that non-canonical Wnt-5a triggers NO production; however, Wnt-3a a canonical ligand did not exert the same effect. Co-administration of Wnt-5a with the soluble Frizzled related protein-2 (sFRP-2) a Wnt antagonist blocked the NO production. Wnt-5a activates the non-canonical Wnt/Ca(2+) signaling through a mechanism that depends on Ca(2+) release from Ryanodine-sensitive internal stores. The increase in NO levels evoked by Wnt-5a promotes the insertion of the GluN2B subunit of the NMDA receptor (NMDAR) into the neuronal cell surface. To the best of our knowledge, this is the first time that Wnt-5a signaling is related to NO production, which in turn increases NMDARs trafficking to the cell surface.
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Neuronas/metabolismo , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Wnt/metabolismo , Animales , Western Blotting , Calcio/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Células HEK293 , Hipocampo/citología , Hipocampo/embriología , Humanos , Células L , Proteínas de la Membrana/farmacología , Ratones , Modelos Biológicos , Neuronas/citología , Neuronas/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/antagonistas & inhibidores , Proteínas Wnt/farmacología , Proteína Wnt-5aRESUMEN
Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-ß aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.
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Enfermedad de Alzheimer/metabolismo , Vía de Señalización Wnt , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Humanos , Sirtuina 1/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Lithium therapy received approval during the 1970s, and it has been used for its antidepressant, antimanic, and anti-suicidal effects for acute and long-term prophylaxis and treatment of bipolar disorder (BPD). These properties have been well established; however, the molecular and cellular mechanisms remain controversial. In the past few years, many studies demonstrated that at the cellular level, lithium acts as a regulator of neurogenesis, aging, and Ca2+ homeostasis. At the molecular level, lithium modulates aging by inhibiting glycogen synthase kinase-3ß (GSK-3ß), and the phosphatidylinositol (PI) cycle; latter, lithium specifically inhibits inositol production, acting as a non-competitive inhibitor of inositol monophosphatase (IMPase). Mitochondria and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) have been related to lithium activity, and its regulation is mediated by GSK-3ß degradation and inhibition. Lithium also impacts Ca2+ homeostasis in the mitochondria modulating the function of the lithium-permeable mitochondrial Na+-Ca2+exchanger (NCLX), affecting Ca2+ efflux from the mitochondrial matrix to the endoplasmic reticulum (ER). A close relationship between the protease Omi, GSK-3ß, and PGC-1α has also been established. The purpose of this review is to summarize some of the intracellular mechanisms related to lithium activity and how, through them, neuronal aging could be controlled.
Asunto(s)
Senescencia Celular , Compuestos de Litio , Neuronas , Neuronas/efectos de los fármacos , Compuestos de Litio/farmacología , Fármacos Neuroprotectores/farmacología , Enzimas/metabolismo , Inositol/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Calcio/metabolismo , Humanos , Animales , Senescencia Celular/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.
RESUMEN
Porphyromonas gingivalis (P. gingivalis) is a gram-negative oral pathogen associated with chronic periodontitis. Previous studies have linked poor oral health and periodontitis with oral cancer. Severe cases of periodontal disease can result in advanced periodontitis, leading to tissue degradation, tooth loss, and may also correlate with higher gastric cancer (GC) risk. In fact, tooth loss is associated with an elevated risk of cancer. However, the clinical evidence for this association remains inconclusive. Periodontitis is also characterized by chronic inflammation and upregulation of members of the Programmed Death 1/PD1 Ligand 1 (PD1/PDL1) axis that leads to an immunosuppressive state. Given that chronic inflammation and immunosuppression are conditions that facilitate cancer progression and carcinogenesis, we hypothesize that oral P. gingivalis and/or its virulence factors serve as a mechanistic link between oral health and gastric carcinogenesis/GC progression. We also discuss the potential impact of P. gingivalis' virulence factors (gingipains, lipopolysaccharide (LPS), and fimbriae) on inflammation and the response to immune checkpoint inhibitors in GC which are part of the current standard of care for advanced stage patients.
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GABA(A) receptors (GABA(A)-Rs) play a significant role in mediating fast synaptic inhibition and it is the main inhibitory receptor in the CNS. The role of Wnt signaling in coordinating synapse structure and function in the mature CNS is poorly understood. In previous studies we found that Wnt ligands can modulate excitatory synapses through remodeling both presynaptic and postsynaptic regions. In this current study we provide evidence for the effect of Wnt-5a on postsynaptic GABA(A)-Rs. We observed that Wnt-5a induces surface expression and maintenance of this receptor in the neuronal membrane. The evoked IPSC recordings in rat hippocampal slice indicate that Wnt-5a can regulates postsynaptically the hippocampal inhibitory synapses. We found also that Wnt-5a: (a) induces the insertion and clustering of GABA(A)-Rs in the membrane; (b) increases the amplitude of GABA-currents due exclusively to postsynaptic mechanisms; (c) does not affect the endocytic process, but increases the receptor recycling. Finally, all these effects on the GABA(A)-Rs are mediated by the activation of calcium/calmodulin-dependent kinase II (CaMKII). Therefore, we postulate that Wnt-5a, by activation of CaMKII, induces the recycling of functional GABA(A)-Rs on the mature hippocampal neurons.
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Hipocampo/metabolismo , Neuronas/metabolismo , Receptores de GABA-A/metabolismo , Sinapsis/metabolismo , Proteínas Wnt/metabolismo , Análisis de Varianza , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Electrofisiología , Endocitosis/fisiología , Ensayo de Inmunoadsorción Enzimática , Potenciales Postsinápticos Inhibidores/fisiología , Potenciales Postsinápticos Miniatura/fisiología , Inhibición Neural/fisiología , Neuronas/citología , Terminales Presinápticos/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/fisiología , Estadísticas no Paramétricas , Proteína Wnt-5aRESUMEN
Wnt signaling regulates a wealth of aspects of nervous system development and function in embryonic stages and in adulthood. The expression of Wnt ligands and components of the Wnt signaling machinery in early stages of neural development has been related to its role in neurite patterning and in synaptogenesis. Moreover, its expression in the mature nervous system suggests a role for this pathway in synaptic maintenance and function. Therefore, it is of crucial relevance the understanding of the mechanisms by which Wnt signaling regulates these processes. Herein, we discuss how different Wnt ligands, acting through different Wnt signaling pathways, operate in pre- and postsynaptic regions to modulate synapse structure and function. We also elaborate on the idea that Wnt signaling pathways are a target for the treatment of neurodegenerative diseases that affect synaptic integrity, such as Alzheimer's disease.
Asunto(s)
Axones/metabolismo , Dendritas/metabolismo , Sistema Nervioso/embriología , Enfermedades Neurodegenerativas/metabolismo , Transducción de Señal/fisiología , Sinapsis/fisiología , Proteínas Wnt/metabolismo , Animales , Humanos , Ligandos , Modelos Neurológicos , Neuritas/fisiologíaRESUMEN
Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.
Asunto(s)
Envejecimiento/fisiología , Calcio/metabolismo , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/etiología , Neuronas/fisiología , Animales , Homeostasis , Humanos , Inflamación/metabolismo , Inflamación/patología , Resistencia a la Insulina , Mitocondrias/patología , Neuronas/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Communication between cells occurs through secreted molecules, among which Wnt ligands play a critical role in balancing cell proliferation, differentiation and cellular homeostasis. The action of Wnt signaling can be modulated at several levels, including posttranslational modification of the Wnt ligands, whose acylation is critical for biological activity. At least three enzymes are necessary for Wnt acylation/deacylation: stearoyl CoA desaturase (SCD), porcupine (PORCN) and Notum. At the endoplasmic reticulum (ER), SCD provides the monounsaturated fatty acid to PORCN, which adds it to the Wnt ligand; at the extracellular matrix, the fatty acid is removed by Notum. Obviously, the interplay between these enzymes will define Wnt signaling ligand secretion and activity. Excessive activation of Wnt signaling has been observed in a variety of solid tumors, which has led the pharmaceutical industry to develop specific inhibitors for this pathway that mainly target PORCN, some of which are in early clinical trials. In the central nervous system (CNS), Wnt signaling activation has been shown to have a neuroprotective effect, and conversely, its inhibition induces neurodegeneration, which implies that the inhibition of PORCN in cancer therapies should be used with caution, and the cognitive performance of the patient should be monitored during treatment. This review collects information about the PORCN enzyme in relation to its role in the Wnt pathway through the acylation of Wnt ligands, its inhibition by drugs in the treatment of some cancers, and its putative modulation in the treatment of neurodegenerative diseases.