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1.
Circulation ; 149(22): 1729-1748, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38487879

RESUMO

BACKGROUND: Myocardial infarction (MI) and heart failure are associated with an increased incidence of cancer. However, the mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cell-derived sEVs (cMSC-sEVs), contribute to the link between post-MI left ventricular dysfunction (LVD) and cancer. METHODS: We purified and characterized sEVs from post-MI hearts and cultured cMSCs. Then, we analyzed cMSC-EV cargo and proneoplastic effects on several lines of cancer cells, macrophages, and endothelial cells. Next, we modeled heterotopic and orthotopic lung and breast cancer tumors in mice with post-MI LVD. We transferred cMSC-sEVs to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth. RESULTS: Post-MI hearts, particularly cMSCs, produced more sEVs with proneoplastic cargo than nonfailing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from post-MI hearts. The proneoplastic effects of cMSC-sEVs varied with different types of cancer, with lung and colon cancers being more affected than melanoma and breast cancer cell lines. Post-MI cMSC-sEVs also activated resting macrophages into proangiogenic and protumorigenic states in vitro. At 28-day follow-up, mice with post-MI LVD developed larger heterotopic and orthotopic lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from post-MI hearts accelerated the growth of heterotopic and orthotopic lung tumors, and biodistribution analysis revealed accumulating cMSC-sEVs in tumor cells along with accelerated tumor cell proliferation. sEV depletion reduced the tumor-promoting effects of MI, and adoptive transfer of cMSC-sEVs from post-MI hearts partially restored these effects. Finally, spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI LVD. CONCLUSIONS: Cardiac sEVs, specifically cMSC-sEVs from post-MI hearts, carry multiple protumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Treatment with spironolactone significantly reduces accelerated tumor growth after MI. Our results provide new insight into the mechanism connecting post-MI LVD to cancer and propose a translational option to mitigate this deadly association.


Assuntos
Vesículas Extracelulares , Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Vesículas Extracelulares/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/etiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Camundongos , Humanos , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino , Proliferação de Células/efeitos dos fármacos
2.
Gut Microbes ; 16(1): 2309682, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38324278

RESUMO

Spinal cord injury (SCI) is a devastating event that significantly changes daily function and quality of life and is linked to bowel and bladder dysfunction and frequent antibiotic treatment. We aimed to study the composition of the gut microbiome in individuals with SCI during the initial sub-acute rehabilitation process and during the chronic phase of the injury. This study included 100 fecal samples from 63 participants (Median age 40 years, 94% males): 13 cases with SCI in the sub-acute phase with 50 longitudinal samples, 18 cases with chronic SCI, and 32 age and gender-matched controls. We show, using complementary methods, that the time from the injury was a dominant factor linked with gut microbiome composition. Surprisingly, we demonstrated a lack of gut microbial recovery during rehabilitation during the sub-acute phase, with further deviation from the non-SCI control group in the chronic ambulatory SCI group. To generalize the results, we were able to show significant similarity of the signal when comparing to a previous cohort with SCI, to subjects from the American Gut Project who reported low physical activity, and to subjects from another population-based cohort who reported less normal stool consistency. Restoration of the microbiome composition may be another desirable measure for SCI recovery in the future, but further research is needed to test whether such restoration is associated with improved neurological outcomes and quality of life.


Assuntos
Microbioma Gastrointestinal , Microbiota , Traumatismos da Medula Espinal , Masculino , Humanos , Adulto , Feminino , Qualidade de Vida , Exercício Físico
3.
J Crohns Colitis ; 17(6): 960-971, 2023 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-36655602

RESUMO

BACKGROUND AND AIMS: Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined. METHODS: Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions. RESULTS: GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn's disease [CD] ileum and UC rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to a more severe UC form, and to a less favourable UC course. The GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in coeliac disease that is induced in UC, CD and coeliac disease, in contrast to GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with a reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in a reduction of metabolites linked to aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1-deficient cells rescued mitochondrial respiration. CONCLUSIONS: GATA6-AS1 levels are reduced in UC, CD and coeliac disease, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.


Assuntos
Doença Celíaca , Colite Ulcerativa , Doença de Crohn , Humanos , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Células CACO-2 , Mucosa Intestinal/metabolismo , Doença de Crohn/metabolismo , Reto , Inflamação/metabolismo , Mitocôndrias/metabolismo , Fator de Transcrição GATA6/metabolismo
4.
Int J Cancer ; 152(4): 781-793, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36214786

RESUMO

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Adulto , Genes BRCA2 , Mutação , Proteômica , Salpingo-Ooforectomia , Proteína BRCA1/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovariectomia , Mutação em Linhagem Germinativa , Neoplasias da Mama/genética , Predisposição Genética para Doença
5.
NPJ Biofilms Microbiomes ; 8(1): 2, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017536

RESUMO

The human gut microbiome develops during the first years of life, followed by a relatively stable adult microbiome. Day care attendance is a drastic change that exposes children to a large group of peers in a diverse environment for prolonged periods, at this critical time of microbial development, and therefore has the potential to affect microbial composition. We characterize the effect of day care on the gut microbial development throughout a single school year in 61 children from 4 different day care facilities, and in additional 24 age-matched home care children (n = 268 samples, median age of entering the study was 12 months). We show that day care attendance is a significant and impactful factor in shaping the microbial composition of the growing child, the specific daycare facility and class influence the gut microbiome, and each child becomes more similar to others in their day care. Furthermore, in comparison to home care children, day care children have a different gut microbial composition, with enrichment of taxa more frequently observed in older populations. Our results provide evidence that daycare may be an external factor that contributes to gut microbiome maturation and make-up in early childhood.


Assuntos
Microbioma Gastrointestinal , Microbiota , Adulto , Idoso , Criança , Pré-Escolar , Hospital Dia , Humanos , Lactente
6.
Sci Rep ; 11(1): 8922, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33903709

RESUMO

The coronavirus disease 2019 (COVID-19) has rapidly spread around the world, impacting the lives of many individuals. Growing evidence suggests that the nasopharyngeal and respiratory tract microbiome are influenced by various health and disease conditions, including the presence and the severity of different viral disease. To evaluate the potential interactions between Severe Acute Respiratory Syndrome Corona 2 (SARS-CoV-2) and the nasopharyngeal microbiome. Microbial composition of nasopharyngeal swab samples submitted to the clinical microbiology lab for suspected SARS-CoV-2 infections was assessed using 16S amplicon sequencing. The study included a total of 55 nasopharyngeal samples from 33 subjects, with longitudinal sampling available for 12 out of the 33 subjects. 21 of the 33 subjects had at least one positive COVID-19 PCR results as determined by the clinical microbiology lab. Inter-personal variation was the strongest factor explaining > 75% of the microbial variation, irrespective of the SARS-CoV-2 status. No significant effect of SARS-CoV-2 on the nasopharyngeal microbial community was observed using multiple analysis methods. These results indicate that unlike some other viruses, for which an effect on the microbial composition was noted, SARS-CoV-2 does not have a strong effect on the nasopharynx microbial habitants.


Assuntos
COVID-19/microbiologia , Microbiota , Nasofaringe/microbiologia , SARS-CoV-2/fisiologia , Adulto , Idoso , COVID-19/virologia , Feminino , Humanos , Masculino , Microbiota/genética , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética
7.
Front Immunol ; 10: 1672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379863

RESUMO

The alpha subunit of IL-7 receptor (IL7R7α) is critical for the differentiation of T cells, specifically for the development and maintenance of γδT cells. Mutations in IL7RA are associated with Severe Combined Immunodeficiency (SCID). Infants with IL7RA deficiency can be identified through newborn screening program. We aimed at defining the immunological and genetic parameters that are directly affected by the IL7RA mutation on the immune system of five unrelated patients which were identified by our newborn screening program for SCID. The patients were found to have a novel identical homozygote mutation in IL7RA (n.c.120 C>G; p.F40L). Both surface expression of IL7Rα and functionality of IL-7 signaling were impaired in patients compared to controls. Structural modeling demonstrated instability of the protein structure due to the mutation. Lastly the TRG immune repertoire of the patients showed reduced diversity, increased clonality and differential CDR3 characteristics. Interestingly, the patients displayed significant different clinical outcome with two displaying severe clinical picture of immunodeficiency and three had spontaneous recovery. Our data supports that the presented IL7RA mutation affects the IL-7 signaling and shaping of the TRG repertoire, reinforcing the role of IL7RA in the immune system, while non-genetic factors may exist that attribute to the ultimate clinical presentation and disease progression.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Mutação/genética , Mutação/imunologia , Feminino , Humanos , Sistema Imunitário/imunologia , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T
8.
Nucleic Acids Res ; 47(14): 7633-7647, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31147702

RESUMO

The parasite Trypanosoma brucei, the causative agent of sleeping sickness, cycles between an insect and a mammalian host. Here, we investigated the presence of pseudouridines (Ψs) on the spliceosomal small nuclear RNAs (snRNAs), which may enable growth at the very different temperatures characterizing the two hosts. To this end, we performed the first high-throughput mapping of spliceosomal snRNA Ψs by small RNA Ψ-seq. The analysis revealed 42 Ψs on T. brucei snRNAs, which is the highest number reported so far. We show that a trypanosome protein analogous to human protein WDR79, is essential for guiding Ψ on snRNAs but not on rRNAs. snoRNA species implicated in snRNA pseudouridylation were identified by a genome-wide approach based on ligation of RNAs following in vivo UV cross-linking. snRNA Ψs are guided by single hairpin snoRNAs, also implicated in rRNA modification. Depletion of such guiding snoRNA by RNAi compromised the guided modification on snRNA and reduced parasite growth at elevated temperatures. We further demonstrate that Ψ strengthens U4/U6 RNA-RNA and U2B"/U2A' proteins-U2 snRNA interaction at elevated temperatures. The existence of single hairpin RNAs that modify both the spliceosome and ribosome RNAs is unique for these parasites, and may be related to their ability to cycle between their two hosts that differ in temperature.


Assuntos
Proteínas de Protozoários/metabolismo , Pseudouridina/metabolismo , RNA Nuclear Pequeno/metabolismo , RNA Nucleolar Pequeno/metabolismo , Spliceossomos/metabolismo , Trypanosoma brucei brucei/metabolismo , Animais , Sequência de Bases , Humanos , Ligação Proteica , Proteínas de Protozoários/genética , Pseudouridina/genética , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA Nuclear Pequeno/genética , RNA Nucleolar Pequeno/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Spliceossomos/genética , Trypanosoma brucei brucei/genética
9.
Am J Gastroenterol ; 114(7): 1142-1151, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30741738

RESUMO

OBJECTIVES: Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. METHODS: We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. RESULTS: Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3-42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. DISCUSSION: Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , Progressão da Doença , Disbiose/complicações , Microbioma Gastrointestinal/fisiologia , Monitorização Fisiológica/métodos , Adulto , Estudos de Casos e Controles , Doença de Crohn/terapia , Feminino , Seguimentos , Humanos , Mucosa Intestinal/microbiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo
10.
J Vis Exp ; (133)2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29608151

RESUMO

The human intestinal microbiome plays a central role in protecting cells from injury, in processing energy and nutrients, and in promoting immunity. Deviations from what is considered a healthy microbiota composition (dysbiosis) may impair vital functions leading to pathologic conditions. Recent and ongoing research efforts have been directed toward the characterization of associations between microbial composition and human health and disease. Advances in high-throughput sequencing technologies enable characterization of the gut microbial composition. These methods include 16S rRNA-amplicon sequencing and shotgun sequencing. 16S rRNA-amplicon sequencing is used to profile taxonomical composition, while shotgun sequencing provides additional information about gene predictions and functional annotation. An advantage in using a targeted sequencing method of the 16S rRNA gene variable region is its substantially lower cost compared to shotgun sequencing. Sequence differences in the 16S rRNA gene are used as a microbial fingerprint to identify and quantify different taxa within an individual sample. Major international efforts have enlisted standards for 16S rRNA-amplicon sequencing. However, several studies report a common source of variation caused by batch effect. To minimize this effect, uniformed protocols for sample collection, processing, and sequencing must be implemented. This protocol proposes the integration of broadly used protocols starting from fecal sample collection to data analyses. This protocol includes a column-free, direct-PCR approach that enables simultaneous handling and DNA extraction of large numbers of fecal samples, along with PCR amplification of the V4 region. In addition, the protocol describes the analysis pipeline and provides a script using the latest version of QIIME (QIIME 2 version 2017.7.0 and DADA2). This step-by-step protocol is aimed to guide those interested in initiating the use of 16S rRNA-amplicon sequencing in a robust, reproductive, easy to use, detailed way.


Assuntos
Fezes/microbiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA Ribossômico 16S/genética , Humanos
11.
Nat Commun ; 8(1): 1440, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29129909

RESUMO

Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double-stranded RNAs. Here we determine, by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double-stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes. The duplexes destabilized by editing are composed of vastly complementary inverted Alus found in untranslated regions of genes performing vital biological processes, including housekeeping functions and type-I interferon responses. They are predominantly cytoplasmic and generally demonstrate higher ribosomal occupancy. Our findings imply that the editing effect on RNA secondary structure is context dependent and underline the intricate regulatory role of ADAR1 on global RNA secondary structure.


Assuntos
Adenosina Desaminase/genética , Conformação de Ácido Nucleico , Edição de RNA/genética , RNA de Cadeia Dupla/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Adenosina/metabolismo , Composição de Bases/genética , Linhagem Celular Tumoral , Desaminação , Células Hep G2 , Humanos , Inosina/metabolismo , Biossíntese de Proteínas/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Transcriptoma/fisiologia
12.
Sci Rep ; 7(1): 1088, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28439072

RESUMO

Hospitalized patients are at increased risk for acquiring healthcare-associated infections (HAIs) and inadequate nutrition. The human intestinal microbiota plays vital functions in nutrient supply and protection from pathogens, yet characterization of the microbiota of hospitalized patients is lacking. We used 16S rRNA amplicon sequencing to characterize the global pattern of microbial composition of fecal samples from 196 hospitalized patients with suspected infectious diarrhea in comparison to healthy, non-hospitalized subjects (n = 881), and to traditional culture results. We show that hospitalized patients have a significant rise in α-diversity (richness within sample) from birth to <4 years of age, which continues up to the second decade of life. Additionally, we noted a profoundly significant increase in taxa from Proteobacteria phylum in comparison to healthy subjects. Finally, although more than 60% of hospitalized samples had a greater than 10% abundance of Proteobacteria, there were only 19/196 (10%) positive cultures for Campylobacter, Salmonella, or Shigella entero-pathogens in traditional culturing methods. As hospitalized patients have increased risk for HAIs and inadequate nutrition, our data support the consideration of nutritional and/or microbial modification in this population.


Assuntos
Bactérias/classificação , Diarreia/microbiologia , Disbiose , Fezes/microbiologia , Microbiota , Adolescente , Adulto , Idoso , Bactérias/genética , Criança , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Adulto Jovem
13.
Brain ; 140(3): 568-581, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28364549

RESUMO

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Encefalopatias/genética , Encefalopatias/patologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/mortalidade , Células Cultivadas , Pré-Escolar , Consanguinidade , Saúde da Família , Feminino , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Estudos de Associação Genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Consumo de Oxigênio/genética , Transporte Proteico/genética , Transfecção
14.
Neoplasia ; 18(2): 90-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26936395

RESUMO

In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.


Assuntos
Carcinogênese/genética , Citidina Desaminase/biossíntese , Inflamação/genética , Neoplasias Ovarianas/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Citidina Desaminase/genética , Dano ao DNA/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/complicações , Inflamação/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Ovulação/genética , Ovulação/metabolismo
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