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1.
Biochem Biophys Res Commun ; 579: 141-145, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34600299

RESUMO

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and general malaise may continue long after the infection has ended in recovered patients, suggesting that SARS-CoV-2 infection has profound consequences in the host cells. Here we report that SARS-CoV-2 infection can trigger a DNA damage response (DDR) in African green monkey kidney cells (Vero E6). We observed a transcriptional upregulation of the Ataxia telangiectasia and Rad3 related protein (ATR) in infected cells. In addition, we observed enhanced phosphorylation of CHK1, a downstream effector of the ATR DNA damage response, as well as H2AX. Strikingly, SARS-CoV-2 infection lowered the expression of TRF2 shelterin-protein complex, and reduced telomere lengths in infected Vero E6 cells. Thus, our observations suggest SARS-CoV-2 may have pathological consequences to host cells beyond evoking an immunopathogenic immune response.


Assuntos
COVID-19/genética , Dano ao DNA , Interações Hospedeiro-Patógeno/genética , SARS-CoV-2/patogenicidade , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinase 1 do Ponto de Checagem/metabolismo , Chlorocebus aethiops , Histonas/genética , Fosforilação , Telômero , Células Vero
2.
Transl Psychiatry ; 11(1): 519, 2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34628468

RESUMO

Methamphetamine (METH) use, most prevalent in young adults, has been associated with high rates of morbidity and mortality. The relationship between METH use and accelerated biological aging, which can be measured using leukocyte telomere length (LTL), remains unclear. We examined whether young adult METH users have shorter LTL and explored the relationship between characteristics of METH use and LTL by using Mendelian randomization (MR) analysis. We compared the LTL for 187 METH users and 159 healthy individuals aged between 25 and 34 years and examined the relationship of LTL with METH use variables (onset age, duration, and maximum frequency of METH use) by using regression analyses. In addition, 2-stage-least-squares (2SLS) MR was also performed to possibly avoid uncontrolled confounding between characteristics of METH use and LTL. We found METH users had significantly shorter LTL compared to controls. Multivariate regression analysis showed METH use was negatively associated with LTL (ß = -0.36, P < .001). Among METH users, duration of METH use was negatively associated with LTL after adjustment (ß = -0.002, P = .01). We identified a single nucleotide polymorphism (SNP) rs6585206 genome-wide associated with duration of METH use. This SNP was used as an instrumental variable to avoid uncontrolled confounding for the relationship between the use duration and LTL shortening. In conclusion, we show that young adult METH users may have shorter LTL compared with controls and longer duration of METH use was significantly associated with telomere shortening. These observations suggest that METH use may accelerate biological senescence.


Assuntos
Metanfetamina , Telômero , Adulto , Envelhecimento , Humanos , Leucócitos , Metanfetamina/efeitos adversos , Telômero/genética , Encurtamento do Telômero , Adulto Jovem
3.
Mol Biol (Mosk) ; 55(5): 772-795, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34671004

RESUMO

Cell metabolism depends, to a large extent, on correct regulation of gene expression. One of the mechanisms of regulation is the formation of nucleic acid secondary structures, among which guanine quadruplexes (G-quadruplexes, or G4) are of particular importance. G-quadruplexes are dynamic structures whose stability is determined by their size, ionic composition, and the nature of the nucleic acids forming them. They are regulated by various protein factors. Guanine quadruplexes play an important role in the regulation of many processes occurring in DNA and RNA, from maintaining telomere homeostasis to determining the ribosome landing site on mRNA. Therefore, these structures are considered a promising target for antitumor therapy, and their detailed study is important to modern biology. This review is focused on the structure and thermodynamic properties of G-quadruplexes together with their interaction with some nuclear proteins.


Assuntos
Quadruplex G , DNA , RNA , Telômero/genética , Termodinâmica
4.
Orphanet J Rare Dis ; 16(1): 395, 2021 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565437

RESUMO

BACKGROUND: Telomere biology disorders (TBD) such as dyskeratosis congenita (DKC) lead to progressive multi-organ failure as impaired telomere maintenance disturbs cellular proliferative capacity. A wide range of hepatic manifestations from asymptomatic liver enzyme elevation to overt liver fibrosis/cirrhosis can be observed in TBD patients. However, the incidence of hepatic involvement remains unknown. Non-invasive transient elastography (TE) predicts early fibrosis by measuring liver stiffness and may uncover subclinical liver damage in TBD patients. METHODS: Liver screening procedures of nine TBD patients from the Aachen TBD Registry are being presented retrospectively. Following clinical suspicion, TBD was diagnosed using flow-FISH with telomere length (TL) below the 1% percentile and confirmed by next-generation sequencing (NGS) detecting pathogenic mutations in telomere maintenance genes TERC or TERT. RESULTS: In all patients, TBD was first diagnosed in adulthood. Patients showed normal to slightly elevated liver function test parameters. Hepatic ultrasound revealed inhomogeneous parenchyma in seven (77.7%) and increased liver echogenicity in four patients (44.4%). Median liver stiffness was 10.7 kilopascal (kPa) (interquartile range 8.4, 15.7 kPa). Using 7.1 kPa as cut-off, 88.8% of patients were classified as moderate fibrosis to cirrhosis. CONCLUSION: Subclinical chronic liver involvement is frequent in patients with adult-onset TBD. TE could have a valuable role in the routine work-up of patients with telomere disorders including DKC for early detection of patients at risk for liver function impairment.


Assuntos
Disceratose Congênita , Técnicas de Imagem por Elasticidade , Adulto , Biologia , Disceratose Congênita/genética , Humanos , Fígado/diagnóstico por imagem , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/genética , Sistema de Registros , Estudos Retrospectivos , Telômero/genética
5.
Analyst ; 146(19): 5866-5872, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570847

RESUMO

DNA-tuned dye assemblies have received considerable attention toward developing various devices. Owing to easy conformation implementation, G-quadruplexes (G4s) have been extensively used as initiators to grow dye assemblies with controllable chiralities. However, programmed chirality regulation of dye assemblies for a given G4 sequence has not been realized in a straightforward manner. In this work, we replaced a middle guanine in the G-tracts of a human telomeric G4 with an apurinic site (AP site) to meet the programmed dye assemblies. Although all of the AP site replacements altered the G4 conformation from the hybrid to the antiparallel folding, the handedness of pinacyanol (PIN) assemblies grown on the AP site-containing G4 was programmably regulated. The G4 with the AP site at the 5'-most G-tract grew right-handed assemblies, while that with the AP site at the 3'-most G-tract grew left-handed assemblies. The handedness of assemblies almost totally mirrored each other within 450-700 nm. Interestingly, we found that the AP site provided a specific binding site for guanosine and guanine, and this binding event sensitively broke the chiral assemblies. Thus, dye assembly-based sensors can be easily established based on the chiral responses with a high selectivity and sensitivity. Our work first demonstrates the AP site programmed chirality regulation of G4-grown dye assemblies and will find wide application in chiral devices.


Assuntos
Quadruplex G , DNA , Guanina , Guanosina , Humanos , Telômero
6.
J Assoc Physicians India ; 69(9): 11-12, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34585887

RESUMO

INTRODUCTION: Although metabolic surgery has been shown to offer beneficial primary outcome results in obese individuals / obese Type 2 diabetes mellitus (T2DM) patients, there is paucity of information on the underlying mechanisms. In the recent years, estimations of non-invasive molecular parameters viz., telomere length and mtDNA copy number (mtDNAcn) assume significance as robust biomarkers. However, there is lack of evidence about this especially, in the Indian context. To assess the changes in the telomere length and mtDNAcn levels after metabolic surgery in obese Asian Indians with dysglycemia along with routine measurements of anthropometry, glycemic/lipidimic parameters and inflammatory markers. METHODS: This study is a prospective one-year follow-up study of 16 obese individuals with dysglycemia who underwent metabolic surgery at a tertiary diabetes centre in South India. Telomere length, mtDNAcn, serum adiponectin, glycated haemoglobin and high- sensitivity C-reactive protein (hs-CRP) levels were analysed before surgery and at 6 and 12 months after surgery. RESULTS: There was a significant reduction in weight (p<0.001), BMI (p<0.001), waist circumference (p<0.001), fasting and postprandial glucose (p<0.05), HbA1c (p<0.001), triglycerides (p<0.05), hs CRP (p<0.05) and increase in serum adiponectin (p<0.05) at 6 and 12 months post-surgery compared to the preoperative status. There was a significant reduction in mtDNAcn (p<0.001) and a significant increase in telomere length (p<0.001) at 6 and 12 months post metabolic surgery. CONCLUSION: We report an increase in telomere length and decrease in circulatory mtDNA copy number levels at 6 and 12 months post metabolic surgery in obese individuals with T2DM in India.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , DNA Mitocondrial/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Seguimentos , Humanos , Obesidade/complicações , Obesidade/genética , Estudos Prospectivos , Telômero/genética
7.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502212

RESUMO

Age is a major risk factor for severe outcome of the 2019 coronavirus disease (COVID-19). In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. We investigated various DNA methylation datasets of blood samples with epigenetic aging signatures and performed targeted bisulfite amplicon sequencing. Overall, epigenetic clocks closely correlated with the chronological age of patients, either with or without acute respiratory distress syndrome. Furthermore, lymphocytes did not reveal significantly accelerated telomere attrition. Thus, these biomarkers cannot reliably predict higher risk for severe COVID-19 infection in elderly patients.


Assuntos
Envelhecimento/genética , COVID-19/patologia , Epigênese Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/isolamento & purificação , Telômero/metabolismo , Encurtamento do Telômero
8.
Elife ; 102021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34545807

RESUMO

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether, we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.


Assuntos
DNA Viral/genética , Genoma Viral , Herpesvirus Humano 6/genética , Telômero/genética , Integração Viral , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Saliva/virologia
9.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576030

RESUMO

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere-CHIP-atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.


Assuntos
Aterosclerose/genética , Doenças Cardiovasculares/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Proteínas Repressoras/genética , Envelhecimento/genética , Envelhecimento/patologia , Aterosclerose/patologia , Doenças Cardiovasculares/patologia , Evolução Clonal/genética , Hematopoiese Clonal/genética , Humanos , Mutação/genética , Telômero/genética
10.
DNA Cell Biol ; 40(10): 1298-1307, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34591601

RESUMO

Alternative lengthening of telomeres (ALT) is a homologous recombination-based telomere maintenance mechanism activated in 10-15% of human cancers. Although significant progress has been made, the key regulators of the ALT pathway and its role in cancer development remain elusive. Bioinformatics methods were used to predict novel telomere-associated proteins (TAPs) by analysis of large-scale ChIP-Seq data. Immunostaining and fluorescence in situ hybridization experiments were applied to detect the subcellular location of target genes and telomeres. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to examine the expression of targeting genes. Overall survival (OS) analyses were used to evaluate the relationship between gene expression and survival time; immunohistochemistry was used to detect the distribution of target genes in liver cancer tissues. We found that nuclear factor related to kappaB binding protein (NFRKB), a metazoan-specific subunit of the INO80 complex, can associate with telomeres in human ALT cells. Loss of NFRKB induces dysfunction of telomeres and less PML bodies in U2OS cells. In addition, NFRKB is low/moderately expressed in cytoplasm of normal hepatocytes but heavily accumulating in the nucleus of liver cancer cells. Finally, the high expression of NFRKB is associated with short OS time and poor prognosis. NFRKB is a TAP and protects telomeres from DNA damage in ALT cells. It is highly expressed in hepatocellular carcinoma (HCC) cells and predicts a poor prognosis. NFRKB may be a promising prognostic biomarker for the treatment of HCC in the future.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Células K562 , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Células MCF-7 , Ligação Proteica , Telômero/metabolismo
11.
Nanoscale ; 13(32): 13795-13808, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34477654

RESUMO

Light-activated functional materials capable of remote control over duplex and G-quadruplex (G4) nucleic acids formation at the cellular level are still very rare. Herein, we report on the photoinduced macrocyclisation of a helicenoid quinoline derivative of binaphthol that selectively provides easy access to an unprecedented class of extended heteroaromatic structures with remarkable photophysical and DNA/RNA binding properties. Thus, while the native bisquinoline precursor shows no DNA binding activity, the new in situ photochemically generated probe features high association constants to DNA and RNA G4s. The latter inhibits DNA synthesis by selectively stabilizing G4 structures associated with oncogenic promoters and telomere repeat units. Finally, the light sensitive compound is capable of in cellulo photoconversion, localizes primarily in the G4-rich sites of cancer cells, competes with a well-known G4 binder and shows a clear nuclear co-localization with the quadruplex specific antibody BG4. This work provides a benchmark for the future design and development of a brand-new generation of light-activated target-selective G4-binders.


Assuntos
Corantes Fluorescentes , Quadruplex G , DNA , Ligantes , Telômero
12.
Nat Commun ; 12(1): 5514, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535663

RESUMO

Human shelterin components POT1 and TPP1 form a stable heterodimer that protects telomere ends from ATR-dependent DNA damage responses and regulates telomerase-dependent telomere extension. Mice possess two functionally distinct POT1 proteins. POT1a represses ATR/CHK1 DNA damage responses and the alternative non-homologous end-joining DNA repair pathway while POT1b regulates C-strand resection and recruits the CTC1-STN1-TEN1 (CST) complex to telomeres to mediate C-strand fill-in synthesis. Whether POT1a and POT1b are involved in regulating the length of the telomeric G-strand is unclear. Here we demonstrate that POT1b, independent of its CST function, enhances recruitment of telomerase to telomeres through three amino acids in its TPP1 interacting C-terminus. POT1b thus coordinates the synthesis of both telomeric G- and C-strands. In contrast, POT1a negatively regulates telomere length by inhibiting telomerase recruitment to telomeres. The identification of unique amino acids between POT1a and POT1b helps us understand mechanistically how human POT1 switches between end protective functions and promoting telomerase recruitment.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Telomerase/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Telômero/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Análise Mutacional de DNA , Camundongos , Ligação Proteica , Rad51 Recombinase/metabolismo , Sarcoma/patologia
13.
BMC Genomics ; 22(1): 688, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551706

RESUMO

BACKGROUND: Eukaryotic organisms, like the model yeast S. cerevisiae, have linear chromosomes that facilitate organization and protection of nuclear DNA. A recent work described a stepwise break/repair method that enabled fusion of the 16 chromosomes of S. cerevisiae into a single large chromosome. Construction of this strain resulted in the removal of 30 of 32 telomeres, over 300 kb of subtelomeric DNA, and 107 subtelomeric ORFs. Despite these changes, characterization of the single chromosome strain uncovered modest phenotypes compared to a reference strain. RESULTS: This study further characterized the single chromosome strain and found that it exhibited a longer lag phase, increased doubling time, and lower final biomass concentration compared with a reference strain when grown on YPD. These phenotypes were amplified when ethanol was added to the medium or used as the sole carbon source. RNAseq analysis showed poor induction of genes involved in diauxic shift, ethanol metabolism, and fatty-acid ß-oxidation during growth on ethanol compared to the reference strain. Enzyme-constrained metabolic modeling identified decreased flux through the enzymes that are encoded by these poorly induced genes as a likely cause of diminished biomass accumulation. The diminished growth on ethanol for the single chromosome strain was rescued by nicotinamide, an inhibitor of sirtuin family deacetylases, which have been shown to silence gene expression in heterochromatic regions. CONCLUSIONS: Our results indicate that sirtuin-mediated silencing in the single chromosome strain interferes with growth on non-fermentable carbon sources. We propose that the removal of subtelomeric DNA that would otherwise be bound by sirtuins leads to silencing at other loci in the single chromosome strain. Further, we hypothesize that the poorly induced genes in the single chromosome strain during ethanol growth could be silenced by sirtuins in wildtype S. cerevisiae during growth on glucose.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Tolerância a Medicamentos , Etanol , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Telômero/genética
14.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576063

RESUMO

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.


Assuntos
Dano ao DNA , Telômero/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Reparo do DNA , Humanos , Processamento de Proteína Pós-Traducional
15.
Cytogenet Genome Res ; 161(6-7): 297-304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34433164

RESUMO

Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD+ depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD+ and mitophagy may shed light on potential therapeutic strategies for the WS patients.


Assuntos
Envelhecimento/genética , Dano ao DNA , Mitocôndrias/genética , Mitofagia/genética , Células-Tronco/metabolismo , Síndrome de Werner/genética , Animais , Senescência Celular/genética , Humanos , Mitocôndrias/metabolismo , Telômero/genética , Telômero/metabolismo , Síndrome de Werner/metabolismo , Síndrome de Werner/patologia
16.
Environ Health ; 20(1): 99, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461906

RESUMO

BACKGROUND: Urban air pollution is involved in the progress of idiopathic pulmonary fibrosis (IPF). Its potential role on the devastating event of Acute Exacerbation of IPF (AE-IPF) needs to be clarified. This study examined the association between long-term personal air pollution exposure and AE- IPF risk taking into consideration inflammatory mediators and telomere length (TL). METHODS: All consecutive IPF-patients referred to our Hospital from October 2013-June 2019 were included. AE-IPF events were recorded and inflammatory mediators and TL measured. Long-term personal air pollution exposures were assigned to each patient retrospectively, for O3, NO2, PM2.5 [and PM10, based on geo-coded residential addresses. Logistic regression models assessed the association of air pollutants' levels with AE-IPF and inflammatory mediators adjusting for potential confounders. RESULTS: 118 IPF patients (mean age 72 ± 8.3 years) were analyzed. We detected positive significant associations between AE-IPF and a 10 µg/m3 increase in previous-year mean level of NO2 (OR = 1.52, 95%CI:1.15-2.0, p = 0.003), PM2.5 (OR = 2.21, 95%CI:1.16-4.20, p = 0.016) and PM10 (OR = 2.18, 95%CI:1.15-4.15, p = 0.017) independent of age, gender, smoking, lung function and antifibrotic treatment. Introduction of TL in all models of a subgroup of 36 patients did not change the direction of the observed associations. Finally, O3 was positively associated with %change of IL-4 (p = 0.014) whilst PM2.5, PM10 and NO2 were inversely associated with %changes of IL-4 (p = 0.003, p = 0.003, p = 0.032) and osteopontin (p = 0.013, p = 0.013, p = 0.085) respectively. CONCLUSIONS: Long-term personal exposure to increased concentrations of air pollutants is an independent risk factor of AE-IPF. Inflammatory mediators implicated in lung repair mechanisms are involved.


Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Fibrose Pulmonar Idiopática/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Citocinas/sangue , Progressão da Doença , Exposição Ambiental/análise , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Masculino , Pessoa de Meia-Idade , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Ozônio/efeitos adversos , Ozônio/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Fatores de Risco , Telômero
17.
Nutrients ; 13(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34444746

RESUMO

Elderly Costa Ricans have lower mortality rates compared to their counterparts from developed countries. Reasons for this survival advantage are not completely known. In the present study, we aimed to identify dietary factors associated with leukocyte telomere length (LTL), a marker of biologic aging, in the elderly population of Costa Rica. We conducted prospective analysis in 909 participants aged 60+ years from the Costa Rican Longevity and Healthy Aging Study (CRELES). We used a food frequency questionnaire to assess usual diet. We calculated dietary patterns using Principal Component Analysis (PCA). We used generalized linear models to examine the association of dietary patterns and food groups with leukocyte telomere length. We found two major dietary patterns explaining 9.15% and 7.18% of the total variation of food intake, respectively. The first dietary pattern, which represents a traditional Costa Rican rice and beans pattern, was more frequent in rural parts of the country and was positively associated with baseline LTL: ß (95% CI) = 42.0 base-pairs (bp) (9.9 bp, 74.1 bp) per one-unit increase of the traditional dietary pattern. In analysis of individual food groups, intake of grains was positively associated with baseline LTL: ß (95% CI) = 43.6 bp (13.9 bp, 73.3 bp) per one-serving/day increase of consumption of grains. Our results suggest that dietary factors, in particular a traditional food pattern, are associated with telomere length and may contribute to the extended longevity of elderly Costa Ricans.


Assuntos
Dieta , Leucócitos , Longevidade , Telômero , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Costa Rica , Fabaceae , Feminino , Alimentos , Envelhecimento Saudável , Humanos , Masculino
18.
Ann Epidemiol ; 63: 68-74, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34343614

RESUMO

PURPOSE: To examine whether there was an association of leucocyte telomere length (LTL) with all-cause, cardiovascular (CVD)- and cancer-specific mortality risks among U.S. adults; and whether these associations vary with race and ethnicity and age. METHODS: We conducted a retrospective cohort using data from the National Health and Nutrition Examination Survey, 1999 to 2002 and the 2015 Linked Mortality File on adults 25 years or older (n = 6,526 and 1,753 deaths). Cox proportional hazards regression was used to quantify the association of LTL with each outcome adjusting for baseline sociodemographic and health-related characteristics. We tested a three-way interaction for LTL, race and ethnicity, and age groups. RESULTS: After adjustment, the rate of dying for all-cause and CVD-specific mortality was at least 24% lower for a 1 kilobase increase in LTL. When compared with adults with the shortest telomere, the rates of dying were at least 17% lower for all-cause and CVD-specific mortality for those with longer telomere. For all-cause mortality, increase LTL was associated with lower rate of dying among non-Hispanic Blacks 45 years or older, and non-Hispanic Whites 65 years or older. CONCLUSIONS: We found that increase telomere length was associated with lower all-cause and CVD-specific mortality rates among U.S. adults. For all-cause mortality, this association varies within racial and ethnic groups across age groups.


Assuntos
Doenças Cardiovasculares , Grupos Étnicos , Adulto , Doenças Cardiovasculares/genética , Humanos , Inquéritos Nutricionais , Estudos Retrospectivos , Telômero , Estados Unidos/epidemiologia
19.
Matern Child Health J ; 25(11): 1798-1805, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34390428

RESUMO

OBJECTIVES: Despite the obstacles of limited education and employment opportunities-and the stress associated with immigration and pregnancy-Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB. METHODS: This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36 weeks gestation. PTB data was collected from the participant's medical record after delivery. RESULTS: TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p = 0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL. CONCLUSIONS FOR PRACTICE: This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.


Assuntos
Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Projetos Piloto , Gravidez , Gestantes , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Telômero , Encurtamento do Telômero
20.
Biomolecules ; 11(8)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439779

RESUMO

Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.


Assuntos
Genoma Humano , Proteína Proto-Oncogênica N-Myc/genética , Neoplasias do Sistema Nervoso/genética , Neuroblastoma/genética , Telomerase/genética , Telômero/química , Proteína Nuclear Ligada ao X/genética , Antineoplásicos/uso terapêutico , Criança , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , Metástase Neoplásica , Neoplasias do Sistema Nervoso/tratamento farmacológico , Neoplasias do Sistema Nervoso/mortalidade , Neoplasias do Sistema Nervoso/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Fatores de Risco , Transdução de Sinais , Análise de Sobrevida , Telomerase/metabolismo , Telômero/efeitos dos fármacos , Telômero/patologia , Homeostase do Telômero , Proteína Nuclear Ligada ao X/metabolismo
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