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Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer's disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by a cocktail of neurotrophic factors and derived peptides named Nosustrophine, a nootropic supplement made by a peptide complex extracted from the young porcine brain, ensuring neuroprotection and improving neuro-functional recovery. Experimental 3xTg-APP/Bin1/COPS5 transgenic mice models of AD were treated with Nosustrophine at two different early ages, and their neuropathological hallmark and behavior response were analyzed. Results showed that Nosustrophine increased the activity of the immune system and reduced pathological changes in the hippocampus and cortex by halting the development of amyloid plaques, mainly seen in mice of 3-4 months of age, indicating that its effect is more preventive than therapeutic. Taken together, the results indicate the potent neuroprotective activity of Nosustrophine and its stimulating effects on neuronal plasticity. This study shows for the first time an effective therapy using nootropic supplements against degenerative diseases, although further investigation is needed to understand their molecular pathways.
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Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2, that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.
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Dyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.
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Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.
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Obesity is a major health challenge worldwide, with implications for diabetes, hypertension and cardiovascular disease (CVD). Regular consumption of dark-meat fish is linked to a lower incidence of CVD and associated metabolic disorders due to the presence of long-chain omega-3 fatty acid ethyl esters in fish oils. The aim of the present study was to determine whether a marine compound like a sardine lipoprotein extract (RCI-1502), regulates fat accumulation in the heart of a high-fat diet-induced (HFD) mouse model of obesity. To investigate its effects in the heart and liver, we conducted a randomized, 12-week placebo-controlled study in which we analyzed the expression of vascular inflammation markers, obesity biochemical patterns and related CVD pathologies. Male HFD-fed mice treated with a RCI-1502-supplemented diet showed reduced body weight, abdominal fat tissue and pericardial fat pad mass density without systemic toxicity. RCI-1502 significantly reduced triacylglyceride, low-density lipoprotein and total-cholesterol concentrations in serum, but increased HDL-cholesterol levels. Our data show that RCI-1502 is beneficial for reducing obesity associated with a long-term HFD, possibly by exerting a protective effect on lipidic homeostasis, indicated also by histopathological analysis. These results collectively indicate that RCI-1502 acts as a cardiovascular therapeutic nutraceutical agent, which modulates fat-induced inflammation and improves metabolic health.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Animales , Masculino , Ratones , Colesterol , Dieta Alta en Grasa/efectos adversos , Lipoproteínas , Obesidad/tratamiento farmacológico , PericardioRESUMEN
There is a lack of effective diagnostic biomarkers for neurodegenerative disorders (NDDs). Here, we established gene expression profiles for diagnosing Alzheimer's disease (AD), Parkinson's disease (PD), and vascular (VaD)/mixed dementia. Patients with AD had decreased APOE, PSEN1, and ABCA7 mRNA expression. Subjects with VaD/mixed dementia had 98% higher PICALM mRNA levels, but 75% lower ABCA7 mRNA expression than healthy individuals. Patients with PD and PD-related disorders showed increased SNCA mRNA levels. There were no differences in mRNA expression for OPRK1, NTRK2, and LRRK2 between healthy subjects and NDD patients. APOE mRNA expression had high diagnostic accuracy for AD, and moderate accuracy for PD and VaD/mixed dementia. PSEN1 mRNA expression showed promising accuracy for AD. PICALM mRNA expression was less accurate as a biomarker for AD. ABCA7 and SNCA mRNA expression showed high-to-excellent diagnostic accuracy for AD and PD, and moderate-to-high accuracy for VaD/mixed dementia. The APOE E4 allele reduced APOE expression in patients with different APOE genotypes. There was no association between PSEN1, PICALM, ABCA7, and SNCA gene polymorphisms and expression. Our study suggests that gene expression analysis has diagnostic value for NDDs and provides a liquid biopsy alternative to current diagnostic methods.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Polimorfismo Genético , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Apolipoproteínas E/genética , Perfilación de la Expresión GénicaRESUMEN
DNA methylation remains an under-recognized diagnostic biomarker for several diseases, including neurodegenerative disorders. In this study, we examined differences in global DNA methylation (5mC) levels in serum samples from patients during the initial- and the follow-up visits. Each patient underwent a blood analysis and neuropsychological assessments. The analysis of 5mC levels revealed two categories of patients; Group A who, during the follow-up, had increased 5mC levels, and Group B who had decreased 5mC levels. Patients with low Fe-, folate-, and vitamin B12- levels during the initial visit showed increased levels of 5mC after treatment when assessed during the follow-up. During the follow-up, 5mC levels in Group A patients increased after treatment for hypovitaminosis with the nutraceutical compounds Animon Complex and MineraXin Plus. 5mC levels were maintained during the follow-up in Group A patients treated for neurological disorders with the bioproducts AtreMorine and NeoBrainine. There was a positive correlation between 5mC levels and MMSE scores, and an inverse correlation between 5mC and ADAS-Cog scores. This expected correlation was observed in Group A patients only. Our study appears to indicate that 5mC has a diagnostic value as a biomarker across different pathologies.
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Metilación de ADN , Enfermedades del Sistema Nervioso , Humanos , Biomarcadores , Ácido FólicoRESUMEN
Anxiety and depression coexist with cognitive impairment in Alzheimer's disease along with other concomitant disorders (>60%), which require multipurpose treatments. Polypharmaceutical regimens cause drug-drug interactions and adverse drug reactions, potentially avoidable in number and severity with the implementation of pharmacogenetic procedures. The accumulation of defective variants (>30 genes per patient in more than 50% of cases) in pharmagenes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) influences the therapeutic response to antidementia, antidepressant and anxiolytic drugs in polyvalent regimens. APOE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, COMT, MAOB, CHAT, GSTP1, NAT2, SLC30A8, SLCO1B1, ADRA2A, ADRB2, BCHE, GABRA1, HMGCR, HTR2C, IFNL3, NBEA, UGT1A1, ABCB1, ABCC2, ABCG2, SLC6A2, SLC6A3, SLC6A4, MTHFR and OPRM1 variants affect anxiety and depression in Alzheimer's disease.
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Enfermedad de Alzheimer , Arilamina N-Acetiltransferasa , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Farmacogenética/métodos , Depresión/tratamiento farmacológico , Depresión/genética , Citocromo P-450 CYP2D6/genética , Ansiedad/tratamiento farmacológico , Ansiedad/genética , Transportador 1 de Anión Orgánico Específico del Hígado , Proteínas Portadoras , Proteínas del Tejido Nervioso , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Alzheimer's disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related (NOS3 and COX-2) gene expression in 3-4-month-old mice only, global (5mC)- and de novo DNA methylation (DNMT3a), HDAC3 expression and HDAC activity in 3-4-month-old mice; and SIRT1 expression and acetylated histone H3 protein levels in 8-9-month-old mice. Mass spectrometric analysis of Nosustrophine extracts revealed the presence of adenosylhomocysteinase, an enzyme implicated in DNA methylation, and nicotinamide phosphoribosyltransferase, which produces the NAD+ precursor, enhancing SIRT1 activity. Our findings show that Nosustrophine exerts substantial epigenetic effects against AD-related neurodegeneration and establishes Nosustrophine as a novel nutraceutical bioproduct with epigenetic properties (epinutraceutical) that may be therapeutically effective for prevention and early treatment for AD-related neurodegeneration.
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Alzheimer's disease (AD) is a priority health problem in developed countries with a high cost to society. Approximately 20% of direct costs are associated with pharmacological treatment. Over 90% of patients require multifactorial treatments, with risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) for the treatment of concomitant diseases such as hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60-90%), neuropsychiatric disorders (60-90%), and cancer (10%).For the past decades, pharmacological studies in search of potential treatments for AD focused on the following categories: neurotransmitter enhancers (11.38%), multitarget drugs (2.45%), anti-amyloid agents (13.30%), anti-tau agents (2.03%), natural products and derivatives (25.58%), novel synthetic drugs (8.13%), novel targets (5.66%), repository drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and other compounds (<1%).Pharmacogenetic studies have shown that the therapeutic response to drugs in AD is genotype-specific in close association with the gene clusters that constitute the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes) under the regulatory control of epigenetic mechanisms (DNA methylation, histone/chromatin remodeling, microRNA regulation). Most AD patients (>60%) are carriers of over ten pathogenic genes. The genes that most frequently (>50%) accumulate pathogenic variants in the same AD case are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.7059), and PSEN1 (77.19%). There is also an accumulation of 15 to 26 defective pharmagenes in approximately 85% of AD patients. About 50% of AD patients are carriers of at least 20 mutant pharmagenes, and over 80% are deficient metabolizers for the most common drugs, which are metabolized via the CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 enzymes.The implementation of pharmacogenetics can help optimize drug development and the limited therapeutic resources available to treat AD, and personalize the use of anti-dementia drugs in combination with other medications for the treatment of concomitant disorders.
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Enfermedad de Alzheimer , Farmacogenética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Inhibidores de la Colinesterasa , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/uso terapéutico , Utilización de Medicamentos , HumanosRESUMEN
Alzheimer's disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized therapeutic regimens to reduce adverse drug reactions (ADRs), drug−drug interactions (DDIs), and unnecessary costs. Men and women show substantial differences in their AD-related phenotypes. Genomic, epigenetic, neuroimaging, and biochemical biomarkers are useful for predictive and differential diagnosis. The most frequent concomitant diseases include hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60−90%), neuropsychiatric disorders (60−90%), and cancer (10%). Over 90% of AD patients require multifactorial treatments with risk of ADRs and DDIs. The implementation of pharmacogenetics in clinical practice can help optimize the limited therapeutic resources available to treat AD and personalize the use of anti-dementia drugs, in combination with other medications, for the treatment of concomitant disorders.
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Alzheimer's Disease (AD) is a major health problem worldwide. The lack of efficacy of existing therapies for AD is because of diagnosis at late stages of the disease, limited knowledge of biomarkers, and molecular mechanisms of AD pathology, as well as conventional drugs that are focused on symptomatic rather than mechanistic features of the disease. The connection between epigenetics and AD, however, may be useful for the development of novel therapeutics or diagnostic biomarkers for AD. The aim of this study was to investigate a pathogenic role for epigenetics and other biomarkers in the male APP/BIN1/COPS5 triple-transgenic (3xTg) mouse model of AD. In the APP/BIN1/COPS5 3xTg-AD mouse hippocampus, sirtuin expression and activity decreased, HDAC3 expression and activity increased, PSEN1 mRNA levels were unchanged, PSEN2 and APOE expression was reduced, and levels of the pro-inflammatory marker IL-6 increased; levels of pro-inflammatory COX-2 and TNFα and apoptotic (NOS3) markers increased slightly, but these were non-significant. In fixed mouse-brain slices, immunoreactivity for CD11b and ß-amyloid immunostaining increased. APP/BIN1/COPS5 3xTg-AD mice are a suitable model for evaluating epigenetic changes in AD, the discovery of new epigenetic-related biomarkers for AD diagnosis, and new epidrugs for the treatment of this neurodegenerative disease.
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Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Complejo del Señalosoma COP9/genética , Epigénesis Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Péptido Hidrolasas/genética , Proteínas Supresoras de Tumor/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteínas E/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Histona Desacetilasas/genética , Humanos , Masculino , Ratones , Ratones Transgénicos , Presenilina-1/genética , Presenilina-2/genética , Sirtuinas/genéticaRESUMEN
Novel and effective chemotherapeutic agents are needed to improve cancer treatment. Epidrugs are currently used for cancer therapy but also exhibit toxicity. Targeting the epigenetic apparatus with bioproducts may aid cancer prevention and treatment. To determine whether the lipoprotein marine extract AntiGan shows epigenetic and antitumor effects, cultured HepG2 (hepatocellular carcinoma) and HCT116 (colorectal carcinoma) cell lines were treated with AntiGan (10, 50, 100, and to 500 µg/mL) for 24 h, 48 h, and 72 h. AntiGan (10 µg/mL) reduced cell viability after 48 h and increased Bax expression; AntiGan (10 and 50 µg/mL) increased caspase-3 immunoreactivity in HepG2 and HCT116 cells. AntiGan (10 and 50 µg/mL) attenuated COX-2 and IL-17 expression in both cell lines. AntiGan (10 µg/mL) increased 5mC levels in both cell types and reduced DNMT1 and DNMT3a expression in these cells. AntiGan (10 and 50 µg/mL) promoted DNMT3a immunoreactivity and reduced SIRT1 mRNA expression in both cell types. In HCT116 cells treated with AntiGan (10 µg/mL), SIRT1 immunoreactivity localized to nuclei and the cytoplasm; AntiGan (50 µg/mL) increased cytoplasmic SIRT1 localization in HCT116 cells. AntiGan is a novel antitumoral bioproduct with epigenetic properties (epinutraceutical) for treating liver and colorectal cancer.
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Introduction: Alzheimer's disease models (ADMs) are currently used for drug development (DD). More than 20,000 molecules were screened for AD treatment over decades, with only one drug (Aducanumab)FDA-approved over the past 18 years. A revision of pathogenic concepts and ADMs are needed.Areas covered: The authors discuss herein preclinical models including: (i) in vitro models (cell lines, primary neuron cell cultures, iPSC-derived brain cells), (ii) ex vivo models, and (iii) in vivo models (artificial, transgenic, non-transgenic and induced).Expert opinion: The following types of ADMs have been reported: Mouse models (45.08%), Rat models (15.04%), Non-human Primate models (0.76%), Rabbit models (0.46%), Cat models (0.53%), Pig models (0.30%), Guinea pig models (0.15%), Octodon degu models (0.02%), Dog models (0.54%), Drosophila melanogaster models (1.79%), Zebrafish models (0.50%), Caenorhabditis elegans (1.21%), Cell culture models (3.31%), Cholinergic models (8.26%), Neurotoxic models (6.79%), Neuroinflammation models (6.92%), Neurovascular models (7.88%), and Microbiome models (0.45%).No single ADM faithfully reproduces all the pathogenic events in the human AD phenotype spectrum. ADMs should be different for (i) pathogenic studies vs basic DD, and (ii) preventive interventions vs symptomatic treatments. There cannot be an ideal ADM for DD, because AD is a spectrum of syndromes. DD can integrate pathogenic, mechanistic, metabolic, transporter and pleiotropic genes in a multisystem model.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Perros , Drosophila melanogaster , Descubrimiento de Drogas , Cobayas , Ratones , Conejos , Ratas , Pez CebraRESUMEN
Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. The accumulation of epigenetic alterations over the lifespan may contribute to neurodegeneration. The aim of the present study was to identify epigenetic biomarkers for improving diagnostic efficacy in patients with neurodegenerative diseases. We analyzed global DNA methylation, chromatin remodeling/histone modifications, sirtuin (SIRT) expression and activity, and the expression of several important neurodegeneration-related genes. DNA methylation, SIRT expression and activity and neuregulin 1 (NRG1), microtubule-associated protein tau (MAPT) and brain-derived neurotrophic factor (BDNF) expression were reduced in buffy coat samples from patients with neurodegenerative disorders. Our data suggest that these epigenetic biomarkers may be useful in clinical practical for the diagnosis, surveillance, and prognosis of disease activity in patients with neurodegenerative diseases.
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Metilación de ADN , Regulación hacia Abajo , Marcadores Genéticos , Enfermedades Neurodegenerativas/diagnóstico , Sirtuina 1/genética , Adulto , Anciano , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Casos y Controles , Ensamble y Desensamble de Cromatina , Diagnóstico Precoz , Epigénesis Genética , Femenino , Código de Histonas , Humanos , Masculino , Persona de Mediana Edad , Neurregulina-1/genética , Enfermedades Neurodegenerativas/genética , Proteínas tau/genéticaRESUMEN
The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression.
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DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.
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Trastornos Cerebrovasculares/etiología , Metilación de ADN , Epigénesis Genética , Trastornos Neurocognitivos/etiología , Animales , Biomarcadores , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ratones , Ratones Transgénicos , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/metabolismoRESUMEN
High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We describe herein the results of the first HMGB1/HMGB2 interactome approach to PCa. Libraries constructed from the PCa cell line, PC-3, and from patients' PCa primary tumor have been screened by the yeast 2-hybrid approach (Y2H) using HMGB1 and HMGB2 baits. Functional significance of this PCa HMGB interactome has been validated through expression and prognosis data available on public databases. Copy number alterations (CNA) affecting these newly described HMGB interactome components are more frequent in the most aggressive forms of PCa: those of neuroendocrine origin or castration-resistant PCa. Concordantly, adenocarcinoma PCa samples showing CNA in these genes are also associated with the worse prognosis. These findings open the way to their potential use as discriminatory biomarkers between high and low risk patients. Gene expression of a selected set of these interactome components has been analyzed by qPCR after HMGB1 and HMGB2 silencing. The data show that HMGB1 and HMGB2 control the expression of several of their interactome partners, which might contribute to the orchestrated action of these proteins in PCa.
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Colorectal cancer (CRC) is one of leading causes of mortality in western countries and novel treatment strategies are required. The medicinal application of mushrooms has been used in traditional medicine in many oriental countries. Polysaccharide-rich extracts obtained from certain medicinal mushroom species have shown antitumor effects in different experimental models. In the present study, we have developed polysaccharide-rich extracts from Trametes versicolor (TV) and Grifola frondosa (GF) fruit bodies. We aim to evaluate the anticancer effects of these polysaccharide-rich extracts in LoVo and HT-29 human colon cancer cells. The in vitro effects were determined by cytotoxicity assay, proliferation assay, wound healing assay and invasion assay. Moreover, the effect on anchorage independent-cell growth was also determined. Our results showed that TV and GF extracts did inhibit human colon cell proliferation and induce cytotoxicity. Furthermore, both fungal extracts significantly inhibited oncogenic potential, cell migration and invasion in colon cancer cells. In addition, extracts induce a more epithelial phenotype, observed by phase contrast images, together with an increase expression of the E-cadherin epithelial marker, detected by western-blotting analyses. Moreover, by using gelatin zymography assays, it was detected a decrease of MMP-2 enzyme activity, a crucial metalloproteinase important for the degradation of the extracellular matrix. Finally, the combination of the extracts with one the most clinical used agents for colorectal cancer, 5-fluorouracil, increases cell cytotoxicity. Taken together our results underscore a potential antitumor effect of polysaccharide-rich extracts obtained from TV and GF in human colon cancer cells lines. These finding may contribute to the reported health effects of fungal extracts.
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Adenocarcinoma/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Grifola , Trametes , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Productos Biológicos/farmacología , Cadherinas/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/uso terapéutico , Células HT29 , Humanos , Metaloproteinasa 2 de la Matriz/metabolismoRESUMEN
At early stages of carcinoma progression, epithelial cells undergo a program named epithelial-to-mesenchymal transition characterized by the loss of the major component of the adherens junctions, E-cadherin, which in consequence causes the disruption of cell-cell contacts. Hakai is an E3 ubiquitin-ligase that binds to E-cadherin in a phosphorylated-dependent manner and induces its degradation; thus modulating cell adhesions. Here, we show that Hakai expression is gradually increased in adenoma and in different TNM stages (I-IV) from colon adenocarcinomas compared to human colon healthy tissues. Moreover, we confirm that Hakai overexpression in epithelial cells drives transformation in cells, a mesenchymal and invasive phenotype, accompanied by the downregulation of E-cadherin and the upregulation of N-cadherin, and an increased proliferation and an oncogenic potential. More importantly, for the first time, we have studied the role of Hakai during cancer progression in vivo. We show that Hakai-transformed MDCK cells dramatically induce tumour growth and local invasion in nude mice and tumour cells exhibit a mesenchymal phenotype. Furthermore, we have detected the presence of micrometastasis in the lung mice, further confirming Hakai role during tumour metastasis in vivo. These results lead to the consideration of Hakai as a potential new therapeutic target to block tumour development and metastasis.