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1.
Cell ; 182(3): 672-684.e11, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32697969

RESUMEN

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.


Asunto(s)
Evolución Clonal/genética , Colitis/genética , Enfermedades Inflamatorias del Intestino/genética , Tasa de Mutación , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Evolución Clonal/inmunología , Colitis/metabolismo , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Proteínas de Unión al ADN/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Humanos , Mutación INDEL , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Filogenia , Mutación Puntual , Receptores de Superficie Celular/genética , Ribonucleasas/genética , Receptores Toll-Like/genética , Factores de Transcripción/genética , Secuenciación Completa del Genoma
2.
Genet Med ; 26(6): 101104, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38411040

RESUMEN

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.


Asunto(s)
Proteínas Hierro-Azufre , Pez Cebra , Animales , Humanos , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Masculino , Femenino , Fenotipo , Fibroblastos/metabolismo , Fibroblastos/patología , Citosol/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Microcefalia/genética , Microcefalia/patología , Lactante , Metalochaperonas
3.
FASEB J ; 35(4): e21456, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33724555

RESUMEN

Nicotinamide adenine dinucleotide (NAD+ ) homeostasis is constantly compromised due to degradation by NAD+ -dependent enzymes. NAD+ replenishment by supplementation with the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD+ pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD+ precursor for the first time. We show that NMNH increases NAD+ levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD+ surge in whole blood, which is accompanied by increased NAD+ levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD+ precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD+ precursors and establish NMNH as a member of the new family of reduced NAD+ precursors.


Asunto(s)
NAD/metabolismo , Mononucleótido de Nicotinamida/metabolismo , Animales , Línea Celular , Supervivencia Celular , Células Epiteliales/efectos de los fármacos , Homeostasis , Humanos , Túbulos Renales , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , NAD/genética , Mononucleótido de Nicotinamida/química , Daño por Reperfusión
4.
Pediatr Blood Cancer ; 69(1): e29352, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34532970

RESUMEN

BACKGROUND: The Electronic Surviving Cancer Competently Intervention Program (eSCCIP), a psychosocial eHealth intervention for parents and caregivers of children with cancer (parents), was delivered in a community-based psychosocial oncology center. Primary endpoints were intervention acceptability, feasibility, and accessibility, with a secondary exploratory focus on psychosocial outcomes. PROCEDURE: Oncology therapists in a psychosocial oncology center were trained in eSCCIP delivery. Participants were eligible for participation if they were the primary caregiver of a child with cancer between the ages 0 and 17, could read and write in English, and had reliable internet access to complete eSCCIP. Surveys were administered electronically at baseline and post intervention to evaluate study endpoints. Effect sizes (Cohen's d) were computed for exploratory psychosocial outcomes. Nineteen parents completed the intervention. RESULTS: Parents rated eSCCIP as highly acceptable, feasible, and accessible. A large clinical effect was detected for acute distress (d = 0.79). Moderate clinical effects were reported for overall posttraumatic stress disorder (PTSD) symptoms (d = 0.37), negative mood/cognitions (d = 0.59), and symptoms of anxiety (d = 0.48). CONCLUSIONS: Results indicate that eSCCIP is an acceptable, feasible, and accessible psychosocial intervention for parents. Exploratory analyses suggest that participation in eSCCIP may contribute to decreases in acute distress, symptoms of anxiety, and symptoms of PTSD.


Asunto(s)
Cuidadores , Neoplasias , Padres , Intervención Psicosocial , Telemedicina , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Neoplasias/terapia
5.
PLoS Genet ; 15(3): e1007633, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30845140

RESUMEN

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan, and early adulthood is important for its salutary effects. Moreover, supplementation of glycine ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, which also feeds into the methionine cycle. RNA-sequencing reveals a similar transcriptional landscape in serine- and glycine-supplemented worms both demarked by widespread gene repression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle.


Asunto(s)
Caenorhabditis elegans/metabolismo , Glicina/metabolismo , Longevidad/fisiología , Metionina/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Dieta , Genes de Helminto , Glicina/administración & dosificación , Longevidad/efectos de los fármacos , Longevidad/genética , Redes y Vías Metabólicas/genética , Mutación , Interferencia de ARN , Serina/administración & dosificación , Serina/metabolismo , Transcriptoma/efectos de los fármacos
8.
Nature ; 477(7364): 289-94, 2011 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-21921910

RESUMEN

We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.


Asunto(s)
Regulación de la Expresión Génica/genética , Variación Genética/genética , Genoma/genética , Ratones Endogámicos/genética , Ratones/genética , Fenotipo , Alelos , Animales , Animales de Laboratorio/genética , Genómica , Ratones/clasificación , Ratones Endogámicos C57BL/genética , Filogenia , Sitios de Carácter Cuantitativo/genética
9.
Bioessays ; 37(8): 909-20, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26115037

RESUMEN

In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Experimentales/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Genes Relacionados con las Neoplasias , Humanos , Terapia Molecular Dirigida , Neoplasias Experimentales/tratamiento farmacológico , Especificidad de la Especie , Ensayos Antitumor por Modelo de Xenoinjerto
10.
EMBO J ; 31(11): 2486-97, 2012 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-22510880

RESUMEN

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression.


Asunto(s)
Homeostasis/fisiología , Intestinos/fisiología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Células Madre/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas de Transporte Vesicular/fisiología , Animales , Proteínas Portadoras/análisis , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Proteínas de Unión al ADN/análisis , Femenino , Eliminación de Gen , Humanos , Intestinos/citología , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Oxidorreductasas , Pronóstico , Receptores Citoplasmáticos y Nucleares/genética , Células Madre/citología , Factores de Transcripción/análisis , Proteínas Supresoras de Tumor/fisiología , Ubiquitinación/genética , Ubiquitinación/fisiología , Proteínas de Transporte Vesicular/genética
11.
PLoS Genet ; 8(11): e1003022, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23166506

RESUMEN

Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm) embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.


Asunto(s)
Centriolos , Enanismo , Desarrollo Embrionario/genética , Microcefalia , Proteínas Asociadas a Microtúbulos/genética , Animales , Apoptosis , Centriolos/genética , Centriolos/metabolismo , Daño del ADN , Enanismo/genética , Enanismo/fisiopatología , Facies , Inestabilidad Genómica , Ratones , Ratones Transgénicos , Microcefalia/genética , Microcefalia/fisiopatología , Proteínas Asociadas a Microtúbulos/deficiencia , Proteínas Asociadas a Microtúbulos/metabolismo , Mitosis/genética , Mutación , Transducción de Señal/genética , Huso Acromático/genética
12.
Gastroenterology ; 144(5): 1055-65, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23376645

RESUMEN

BACKGROUND & AIMS: Phosphatidylinositide 3-kinase (PI3K) is deregulated in many human tumor types, including primary liver malignancies. The kinase v-akt murine thymoma viral oncogene homolog 1 (Akt) and mammalian target of rapamycin complex (mTORC1) are effectors of PI3K that promote cell growth and survival, but their individual roles in tumorigenesis are not well defined. METHODS: In livers of albumin (Alb)-Cre mice, we selectively deleted tuberous sclerosis (Tsc)1, a negative regulator of Ras homolog enriched in brain and mTORC1, along with Phosphatase and tensin homolog (Pten), a negative regulator of PI3K. Tumor tissues were characterized by histologic and biochemical analyses. RESULTS: The Tsc1fl/fl;AlbCre, Ptenfl/fl;AlbCre, and Tsc1fl/fl;Ptenfl/fl;AlbCre mice developed liver tumors that differed in size, number, and histologic features. Livers of Tsc1fl/fl;AlbCre mice did not develop steatosis; tumors arose later than in the other strains of mice and were predominantly hepatocellular carcinomas. Livers of the Ptenfl/fl;AlbCre mice developed steatosis and most of the tumors that formed were intrahepatic cholangiocarcinomas. Livers of Tsc1fl/fl;Ptenfl/fl;AlbCre formed large numbers of tumors, of mixed histologies, with the earliest onset of any strain, indicating that loss of Tsc1 and Pten have synergistic effects on tumorigenesis. In these mice, the combination of rapamycin and MK2206 was more effective in reducing liver cell proliferation and inducing cell death than either reagent alone. Tumor differentiation correlated with Akt and mTORC1 activities; the ratio of Akt:mTORC1 activity was high throughout the course of intrahepatic cholangiocarcinomas development and low during hepatocellular carcinoma development. Compared with surrounding nontumor liver tissue, tumors from all 3 strains had increased activities of Akt, mTORC1, and mitogen-activated protein kinase and overexpressed fibroblast growth factor receptor 1. Inhibition of fibroblast growth factor receptor 1 in Tsc1-null mice suppressed Akt and mitogen-activated protein kinase activities in tumor cells. CONCLUSIONS: Based on analyses of knockout mice, mTORC1 and Akt have different yet synergistic effects during the development of liver tumors in mice.


Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas Experimentales/genética , Complejos Multiproteicos/genética , Mutación , Proteínas Proto-Oncogénicas c-akt/genética , ARN Neoplásico/genética , Serina-Treonina Quinasas TOR/genética , Animales , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Complejos Multiproteicos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas
13.
Blood ; 119(6): 1370-9, 2012 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-22184403

RESUMEN

Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysm1 in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages.


Asunto(s)
Diferenciación Celular/genética , Endopeptidasas/genética , Hematopoyesis/genética , Linfocitos/metabolismo , Animales , Recuento de Células Sanguíneas , Western Blotting , Endopeptidasas/metabolismo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Genotipo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Histonas/metabolismo , Linfocitos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores , Proteína p53 Supresora de Tumor/metabolismo , Proteasas Ubiquitina-Específicas
14.
Biochim Biophys Acta Mol Basis Dis ; 1870(2): 166978, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38061598

RESUMEN

Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.


Asunto(s)
Microglía , Enfermedades Neurodegenerativas , Humanos , Encéfalo/metabolismo , Inmunidad Innata , Microglía/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Fagocitosis/genética , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/metabolismo , Fosfolipasa C gamma/farmacología
15.
iScience ; 27(6): 109949, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38799567

RESUMEN

As the global aging population rises, finding effective interventions to improve aging health is crucial. Drug repurposing, utilizing existing drugs for new purposes, presents a promising strategy for rapid implementation. We explored naltrexone from the Library of Integrated Network-based Cellular Signatures (LINCS) based on several selection criteria. Low-dose naltrexone (LDN) has gained attention for treating various diseases, yet its impact on longevity remains underexplored. Our study on C. elegans demonstrated that a low dose, but not high dose, of naltrexone extended the healthspan and lifespan. This effect was mediated through SKN-1 (NRF2 in mammals) signaling, influencing innate immune gene expression and upregulating oxidative stress responses. With LDN's low side effects profile, our findings underscore its potential as a geroprotector, suggesting further exploration for promoting healthy aging in humans is warranted.

16.
BMJ Open ; 14(4): e073639, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38631839

RESUMEN

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Colitis Ulcerosa/terapia , Enfermedad de Crohn/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Medicina de Precisión , Estudios Prospectivos , Calidad de Vida
17.
Proc Natl Acad Sci U S A ; 107(34): 15145-50, 2010 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-20696900

RESUMEN

In 100 primary colorectal carcinomas, we demonstrate by array comparative genomic hybridization (aCGH) that 33% show DNA copy number (DCN) loss involving PARK2, the gene encoding PARKIN, the E3 ubiquitin ligase whose deficiency is responsible for a form of autosomal recessive juvenile parkinsonism. PARK2 is located on chromosome 6 (at 6q25-27), a chromosome with one of the lowest overall frequencies of DNA copy number alterations recorded in colorectal cancers. The PARK2 deletions are mostly focal (31% approximately 0.5 Mb on average), heterozygous, and show maximum incidence in exons 3 and 4. As PARK2 lies within FRA6E, a large common fragile site, it has been argued that the observed DCN losses in PARK2 in cancer may represent merely the result of enforced replication of locally vulnerable DNA. However, we show that deficiency in expression of PARK2 is significantly associated with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Evidence of some PARK2 mutations and promoter hypermethylation is described. PARK2 overexpression inhibits cell proliferation in vitro. Moreover, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity. We conclude that PARK2 is a tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Eliminación de Gen , Dosificación de Gen , Genes APC , Ubiquitina-Proteína Ligasas/genética , Poliposis Adenomatosa del Colon/etiología , Poliposis Adenomatosa del Colon/metabolismo , Poliposis Adenomatosa del Colon/patología , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular , Cromosomas Humanos Par 6/genética , Cocarcinogénesis , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Metilación de ADN , Cartilla de ADN/genética , ADN de Neoplasias/química , ADN de Neoplasias/genética , Genes Supresores de Tumor , Heterocigoto , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Modelos Moleculares , Mutación , Cariotipificación Espectral , Ubiquitina-Proteína Ligasas/química
18.
Ageing Res Rev ; 92: 102132, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37984625

RESUMEN

Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way to rapidly reduce age-related disease incidence in society. Several recent studies have found that a class of drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed as treatments for cancers and human immunodeficiency virus (HIV) infection, could be repurposed to slow the aging process. Interestingly, these studies propose complementary mechanisms that target multiple hallmarks of aging. At the molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting the hallmark of aging of 'Genomic Instability'. At the organellar level, NRTIs inhibit mitochondrial translation, activate ATF-4, suppress cytosolic translation, and extend lifespan in worms in a manner related to the 'Loss of Proteostasis' hallmark of aging. Meanwhile, at the cellular level, NRTIs inhibit the P2X7-mediated activation of the inflammasome, reducing inflammation and improving the hallmark of aging of 'Altered Intercellular Communication'. Future development of NRTIs for human aging health will need to balance out toxic side effects with the beneficial effects, which may occur in part through hormesis.


Asunto(s)
Infecciones por VIH , Inhibidores de la Transcriptasa Inversa , Humanos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Nucleósidos/farmacología , Nucleósidos/uso terapéutico , Reposicionamiento de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Envejecimiento
19.
Cell Rep ; 42(1): 111928, 2023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36640360

RESUMEN

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.


Asunto(s)
Infecciones por VIH , Zidovudina , Animales , Humanos , Zidovudina/farmacología , Zidovudina/uso terapéutico , Longevidad , Factor de Transcripción Activador 4 , Caenorhabditis elegans/fisiología , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Retroviridae , Infecciones por VIH/tratamiento farmacológico
20.
Nat Commun ; 14(1): 2779, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-37188705

RESUMEN

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.


Asunto(s)
Envejecimiento , Antidepresivos , Harmina , Mitocondrias , Mitofagia , Monoaminooxidasa , Receptores de GABA-A , Harmina/análogos & derivados , Harmina/farmacología , Antidepresivos/farmacología , Mitocondrias/efectos de los fármacos , Mitofagia/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Quinasas de la Proteína-Quinasa Activada por el AMP/metabolismo , Músculo Esquelético/efectos de los fármacos , Hígado/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Resistencia a la Insulina , Intolerancia a la Glucosa/metabolismo , Estado Prediabético/metabolismo , Monoaminooxidasa/metabolismo , Receptores de GABA-A/metabolismo , Longevidad/efectos de los fármacos , Caenorhabditis elegans , Drosophila melanogaster , Fragilidad/prevención & control , Condicionamiento Físico Animal , Modelos Animales , Masculino , Femenino , Animales , Ratones , Hígado Graso/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos
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