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1.
Adv Sci (Weinh) ; 11(18): e2307734, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38430535

RESUMEN

The hepatic content of amyloid beta (Aß) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aß deficiency in the liver. This is especially relevant in view of recent advances in anti-Aß therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aß in transgenic AD mice immunized with Aß antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. Aß absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-ß (TGFß), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aß42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl4)-induced injury. Transcriptomic analysis of CCl4-treated transgenic AD mouse livers uncovers the regulatory effects of Aß42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aß as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Hígado , Ratones Transgénicos , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Ratones Noqueados
2.
Molecules ; 29(2)2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38276593

RESUMEN

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.


Asunto(s)
Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Receptor trkB , Fármacos Neuroprotectores/farmacología , Serotonina , Células Cultivadas , Factor Neurotrófico Derivado del Encéfalo , Enfermedades Neurodegenerativas/tratamiento farmacológico
3.
Eur J Med Chem ; 248: 115111, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36645981

RESUMEN

Numerous studies have been published about the implication of the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis and motor neuron disease. BDNF activates the TrkB receptor with high potency and specificity, promoting neuronal survival, differentiation and synaptic plasticity. Based on the main structural characteristics of LM22A-4, a previously published small molecule that acts as activator of the TrkB receptor, we have designed and synthesized a small data set of compounds. The lead idea for the design of the new compounds was to modify the third position of the LM22A-4, by introducing different substitutions in order to obtain compounds which will have not only better physicochemical properties but selective activity as well. ADME and toxicity profiles of molecules have been evaluated as well as their biological properties through the TrkB receptor and affinity to promote neurite differentiation.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Receptor trkB , Receptor trkB/metabolismo , Factor Neurotrófico Derivado del Encéfalo/fisiología , Benzamidas , Transducción de Señal
4.
Biomedicines ; 10(3)2022 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-35327415

RESUMEN

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer's Disease (AD) progression. However, its low bioavailability and its blood-brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-ß actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid ß-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer's Disease, selectively targeting TrkA-mediated pro-survival signals.

5.
Nanomaterials (Basel) ; 11(4)2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33916037

RESUMEN

The UV-nanoimprint lithography(UV-NIL) fabrication of a novel network of micron-sized channels, forming an open channel microfluidic system is described. Details about the complete manufacturing process, from mastering to fabrication in small batches and in high throughput with up to 1200 micro titer plates per hour is presented. Deep insight into the evaluation of a suitable UV-curable material, mr-UVCur26SF is given, presenting cytotoxic evaluation, cell compatibility tests and finally a neuronal assay. The results indicate how the given pattern, in combination with the resist, paves the way to faster, cheaper, and more reliable drug screening.

6.
Sci Rep ; 11(1): 2591, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510370

RESUMEN

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.


Asunto(s)
Lipocalina 2/antagonistas & inhibidores , Lipocalina 2/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Masculino , Ratones
7.
PLoS Negl Trop Dis ; 12(1): e0006180, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29357372

RESUMEN

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.


Asunto(s)
Antiprotozoarios/metabolismo , Enfermedad de Chagas/parasitología , Inhibidores Enzimáticos/metabolismo , Proteínas Protozoarias/antagonistas & inhibidores , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones , Niacinamida/metabolismo , Quinolonas/metabolismo , Espermina/análogos & derivados , Espermina/metabolismo , Resultado del Tratamiento
8.
Eur J Heart Fail ; 19(2): 177-191, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28157267

RESUMEN

Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.


Asunto(s)
Insuficiencia Cardíaca/patología , Miocardio/patología , Animales , Investigación Biomédica , Fibrosis , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Investigación Biomédica Traslacional
9.
Antimicrob Agents Chemother ; 60(4): 2532-6, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26787703

RESUMEN

Current treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives againstTrypanosoma brucei BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showedin vitroinhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration.


Asunto(s)
Naftalimidas/farmacología , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico , Animales , Línea Celular , Estabilidad de Medicamentos , Femenino , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Naftalimidas/síntesis química , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Carga de Parásitos , Pentamidina/farmacología , Cultivo Primario de Células , Relación Estructura-Actividad , Análisis de Supervivencia , Tripanocidas/síntesis química , Trypanosoma brucei brucei/crecimiento & desarrollo , Trypanosoma brucei brucei/metabolismo , Tripanosomiasis Africana/mortalidad , Tripanosomiasis Africana/parasitología , Tripanosomiasis Africana/patología
10.
Nucleic Acids Res ; 42(2): 1311-25, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24121686

RESUMEN

The role of Nucleoplasmin (NP) as a H2A-H2B histone chaperone has been extensively characterized. To understand its putative interaction with other histone ligands, we have characterized its ability to bind H3-H4 and histone octamers. We find that the chaperone forms distinct complexes with histones, which differ in the number of molecules that build the assembly and in their spatial distribution. When complexed with H3-H4 tetramers or histone octamers, two NP pentamers form an ellipsoidal particle with the histones located at the center of the assembly, in stark contrast with the NP/H2A-H2B complex that contains up to five histone dimers bound to one chaperone pentamer. This particular assembly relies on the ability of H3-H4 to form tetramers either in solution or as part of the octamer, and it is not observed when a variant of H3 (H3C110E), unable to form stable tetramers, is used instead of the wild-type protein. Our data also suggest that the distal face of the chaperone is involved in the interaction with distinct types of histones, as supported by electron microscopy analysis of the different NP/histone complexes. The use of the same structural region to accommodate all type of histones could favor histone exchange and nucleosome dynamics.


Asunto(s)
Histonas/química , Nucleoplasminas/química , Secuencia de Aminoácidos , Animales , Histonas/metabolismo , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/metabolismo , Datos de Secuencia Molecular , Nucleoplasminas/metabolismo , Multimerización de Proteína , Proteolisis , Xenopus laevis
11.
J Biol Chem ; 285(44): 33771-8, 2010 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-20696766

RESUMEN

Nucleoplasmin (NP) is a pentameric chaperone that regulates the condensation state of chromatin extracting specific basic proteins from sperm chromatin and depositing H2A-H2B histone dimers. It has been proposed that histones could bind to either the lateral or distal face of the pentameric structure. Here, we combine different biochemical and biophysical techniques to show that natural, hyperphosphorylated NP can bind five H2A-H2B dimers and that the amount of bound ligand depends on the overall charge (phosphorylation level) of the chaperone. Three-dimensional reconstruction of NP/H2A-H2B complex carried out by electron microscopy reveals that histones interact with the chaperone distal face. Limited proteolysis and mass spectrometry indicate that the interaction results in protection of the histone fold and most of the H2A and H2B C-terminal tails. This structural information can help to understand the function of NP as a histone chaperone.


Asunto(s)
Histonas/química , Nucleoplasminas/química , Animales , Dimerización , Espectrometría de Masas/métodos , Microscopía Electrónica/métodos , Fosforilación , Pliegue de Proteína , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Xenopus laevis/metabolismo
12.
J Biol Chem ; 282(29): 21213-21, 2007 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-17510054

RESUMEN

Nucleoplasmin (NP) is a histone chaperone involved in nucleosome assembly, chromatin decondensation at fertilization, and apoptosis. To carry out these activities NP has to interact with different types of histones, an interaction that is regulated by phosphorylation. Here we have identified a number of phosphorylated residues by mass spectrometry and generated mutants in which these amino acids are replaced by Asp to mimic the effect of phosphorylation. Our results show that, among the eight phosphoryl groups experimentally detected, four are located at the flexible N terminus, and the rest are found at the tail domain, flanking the nuclear localization signal. Phosphorylation-mimicking mutations render a recombinant protein as active in chromatin decondensation as hyperphosphorylated NP isolated from Xenopus laevis eggs. Comparison of mutants in which the core and tail domains of the protein were independently or simultaneously "activated" indicates that activation or phosphorylation of both protein domains is required for NP to efficiently extract linker-type histones from chromatin.


Asunto(s)
Proteínas Nucleares/química , Fosfoproteínas/química , Secuencia de Aminoácidos , Aminoácidos/química , Animales , Cromatina/química , Cromatina/metabolismo , Histonas/química , Espectrometría de Masas , Chaperonas Moleculares/química , Datos de Secuencia Molecular , Mutación , Nucleoplasminas , Péptidos/química , Fosforilación , Estructura Terciaria de Proteína , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Xenopus laevis/metabolismo
13.
Biochemistry ; 44(23): 8274-81, 2005 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-15938617

RESUMEN

We have previously characterized the interaction of nucleoplasmin with core histones and studied the possible involvement of this chaperone molecule in transcription. Here we study the interaction of nucleoplasmin with chromatin. We show that highly phosphorylated Xenopus laevis egg nucleoplasmin can unfold sperm and somatic chromatin in a way that involves the removal of chromosomal proteins from linker DNA regions without a stable interaction with the nucleosome. The complexes between egg nucleoplasmin and both somatic and sperm-specific linker proteins have been hydrodynamically characterized using sedimentation equilibrium in the analytical ultracentrifuge. The results are discussed within the context of the possible implication of nucleoplasmin in processes such as transcription and replication licensing which take place after egg fertilization at the onset of development.


Asunto(s)
Cromatina/química , Proteínas Nucleares/química , Fosfoproteínas/química , Pliegue de Proteína , Proteínas de Xenopus/química , Animales , Pollos , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Proteínas del Huevo/química , Proteínas del Huevo/metabolismo , Eritrocitos/química , Eritrocitos/metabolismo , Femenino , Histonas/química , Histonas/metabolismo , Masculino , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/metabolismo , Nucleoplasminas , Nucleosomas/química , Nucleosomas/metabolismo , Oocitos/química , Oocitos/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis
14.
Biochem Cell Biol ; 82(4): 437-45, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15284896

RESUMEN

In this article, we briefly review the structural and functional information currently available on nucleoplasmin. Special emphasis is placed on the discussion of the molecular mechanism involved in the sperm chromatin remodelling activity of this protein. A model is proposed based on current crystallographic data, recent biophysical and functional studies, as well as in the previously available information.


Asunto(s)
Núcleo Celular/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/fisiología , Fosfoproteínas/fisiología , Transporte Activo de Núcleo Celular , Animales , Cromatina/metabolismo , Cristalografía por Rayos X , Drosophila , Proteínas de Drosophila , Humanos , Masculino , Modelos Biológicos , Modelos Moleculares , Proteínas Nucleares/metabolismo , Nucleoplasminas , Fosfoproteínas/metabolismo , Fosforilación , Conformación Proteica , Espermatozoides/metabolismo , Xenopus
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