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Advances in Nutrition (Bethesda, Md.) Nov 2020Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered... (Meta-Analysis)
Meta-Analysis
Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.
Topics: Cross-Sectional Studies; Diet, Mediterranean; Humans; Prospective Studies; Telomere; Telomere Shortening
PubMed: 32730558
DOI: 10.1093/advances/nmaa079 -
International Journal of Molecular... Jul 2022Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or... (Review)
Review
Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or more of the defects in DNA repair pathways, particularly in homologous recombination (HR), which is strictly linked to mutations in breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2). The treatment of ovarian cancer remains a challenge, and the majority of patients with advanced-stage ovarian cancers experience relapse and require additional treatment despite initial therapy, including optimal cytoreductive surgery (CRS) and platinum-based chemotherapy. Targeted therapy at DNA repair genes has become a unique strategy to combat homologous recombination-deficient (HRD) cancers in recent years. Poly (ADP-ribose) polymerase (PARP), a family of proteins, plays an important role in DNA damage repair, genome stability, and apoptosis of cancer cells, especially in HRD cancers. PARP inhibitors (PARPi) have been reported to be highly effective and low-toxicity drugs that will tremendously benefit patients with HRD (i.e., BRCA 1/2 mutated) epithelial ovarian cancer (EOC) by blocking the DNA repair pathways and inducing apoptosis of cancer cells. PARP inhibitors compete with NAD at the catalytic domain (CAT) of PARP to block PARP catalytic activity and the formation of PAR polymers. These effects compromise the cellular ability to overcome DNA SSB damage. The process of HR, an essential error-free pathway to repair DNA DSBs during cell replication, will be blocked in the condition of BRCA 1/2 mutations. The PARP-associated HR pathway can also be partially interrupted by using PARP inhibitors. Grossly, PARP inhibitors have demonstrated some therapeutic benefits in many randomized phase II and III trials when combined with the standard CRS for advanced EOCs. However, similar to other chemotherapy agents, PARP inhibitors have different clinical indications and toxicity profiles and also face drug resistance, which has become a major challenge. In high-grade epithelial ovarian cancers, the cancer cells under hypoxia- or drug-induced stress have the capacity to become polyploidy giant cancer cells (PGCCs), which can survive the attack of chemotherapeutic agents and start endoreplication. These stem-like, self-renewing PGCCs generate mutations to alter the expression/function of kinases, p53, and stem cell markers, and diploid daughter cells can exhibit drug resistance and facilitate tumor growth and metastasis. In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation.
Topics: Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Clinical Trials, Phase II as Topic; Female; Genes, BRCA2; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Randomized Controlled Trials as Topic
PubMed: 35897700
DOI: 10.3390/ijms23158125 -
Diabetologia Feb 2018Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA... (Review)
Review
DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA levels: a systematic review and replication in a case-control sample of the Lifelines study.
AIMS/HYPOTHESIS
Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA levels. Here we present a systematic review of these studies and attempt to replicate the CpG sites (CpGs) with the most significant associations from these EWASs in a case-control sample of the Lifelines study.
METHODS
We performed a systematic literature search in PubMed and EMBASE for EWASs to test the association between DNA methylation and type 2 diabetes and/or glycaemic traits and reviewed the search results. For replication purposes we selected 100 unique CpGs identified in peripheral blood, pancreas, adipose tissue and liver from 15 EWASs, using study-specific Bonferroni-corrected significance thresholds. Methylation data (Illumina 450K array) in whole blood from 100 type 2 diabetic individuals and 100 control individuals from the Lifelines study were available. Multivariate linear models were used to examine the associations of the specific CpGs with type 2 diabetes and glycaemic traits.
RESULTS
From the 52 CpGs identified in blood and selected for replication, 15 CpGs showed nominally significant associations with type 2 diabetes in the Lifelines sample (p < 0.05). The results for five CpGs (in ABCG1, LOXL2, TXNIP, SLC1A5 and SREBF1) remained significant after a stringent multiple-testing correction (changes in methylation from -3% up to 3.6%, p < 0.0009). All associations were directionally consistent with the original EWAS results. None of the selected CpGs from the tissue-specific EWASs were replicated in our methylation data from whole blood. We were also unable to replicate any of the CpGs associated with HbA levels in the healthy control individuals of our sample, while two CpGs (in ABCG1 and CCDC57) for fasting glucose were replicated at a nominal significance level (p < 0.05).
CONCLUSIONS/INTERPRETATION
A number of differentially methylated CpGs reported to be associated with type 2 diabetes in the EWAS literature were replicated in blood and show promise for clinical use as disease biomarkers. However, more prospective studies are needed to support the robustness of these findings.
Topics: Blood Glucose; CpG Islands; DNA Methylation; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Fasting; Genome-Wide Association Study; Glycated Hemoglobin; Humans
PubMed: 29164275
DOI: 10.1007/s00125-017-4497-7 -
Advances in Nutrition (Bethesda, Md.) Nov 2023Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging.... (Review)
Review
Protective Effects of Micronutrient Supplements, Phytochemicals and Phytochemical-Rich Beverages and Foods Against DNA Damage in Humans: A Systematic Review of Randomized Controlled Trials and Prospective Studies.
Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging. Optimizing nutrient intake can minimize accrual of DNA damage. The objectives of this review are to: 1) assemble and systematically analyze high-level evidence for the effect of supplementation with micronutrients and phytochemicals on baseline levels of DNA damage in humans, and 2) use this knowledge to identify which of these essential micronutrients or nonessential phytochemicals promote DNA integrity in vivo in humans. We conducted systematic literature searches of the PubMed database to identify interventional, prospective, cross-sectional, or in vitro studies that explored the association between nutrients and established biomarkers of DNA damage associated with developmental and degenerative disease risk. Biomarkers included lymphocyte chromosome aberrations, lymphocyte and buccal cell micronuclei, DNA methylation, lymphocyte/leukocyte DNA strand breaks, DNA oxidation, telomere length, telomerase activity, and mitochondrial DNA mutations. Only randomized, controlled interventions and uncontrolled longitudinal intervention studies conducted in humans were selected for evaluation and data extraction. These studies were ranked for the quality of their study design. In all, 96 of the 124 articles identified reported studies that achieved a quality assessment score ≥ 5 (from a maximum score of 7) and were included in the final review. Based on these studies, nutrients associated with protective effects included vitamin A and its precursor β-carotene, vitamins C, E, B1, B12, folate, minerals selenium and zinc, and phytochemicals such as curcumin (with piperine), lycopene, and proanthocyanidins. These findings highlight the importance of nutrients involved in (i) DNA metabolism and repair (folate, vitamin B, and zinc) and (ii) prevention of oxidative stress and inflammation (vitamins A, C, E, lycopene, curcumin, proanthocyanidins, selenium, and zinc). Supplementation with certain micronutrients and their combinations may reduce DNA damage and promote cellular health by improving the maintenance of genome integrity.
Topics: Humans; Prospective Studies; Selenium; Lycopene; Cross-Sectional Studies; Curcumin; Proanthocyanidins; Randomized Controlled Trials as Topic; Vitamins; Vitamin A; Micronutrients; Folic Acid; Zinc; Beverages; Phytochemicals; DNA; DNA Damage; Biomarkers; Dietary Supplements
PubMed: 37573943
DOI: 10.1016/j.advnut.2023.08.004 -
BMC Genomics Mar 2022Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate...
BACKGROUND
Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.
METHODS
We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data.
RESULTS
We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts.
CONCLUSIONS
Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants' methylome.
Topics: Canada; DNA Methylation; Epigenome; Female; Fetal Blood; Genome-Wide Association Study; Humans; Infant, Newborn; Pregnancy
PubMed: 35305575
DOI: 10.1186/s12864-022-08451-6 -
Ageing Research Reviews Sep 2022The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to... (Meta-Analysis)
Meta-Analysis Review
The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to PRISMA 2020 guidelines, we performed a systematic review and meta-analysis using data from 27 observational studies in non-demented individuals. We used effect size and p-value based meta-analysis methods considering marked heterogeneity among studies. We found that the longer LTL was associated with higher brain volume (β = 0.43, 95%CI: 0.36-0.50%, p = 0.008, N = 1102) and with higher global cognition (β = 0.01; 95%CI: 0.00-0.02, p = 0.03, N = 19609) by effect size based meta-analysis and with brain volume, hippocampal volume, global cognition, cognitive domains of attention/speed as well as executive functions by p-value based meta-analysis. No significant association of LTL with brain white matter hyperintensities was detected. Furthermore, the evidence strongly suggests a subgroup-specific canonical effect of telomeres, notably in older individuals and females. In conclusion, we provide meta-analytic evidence on the beneficial effect of telomeres on brain structure as well as cognition and advocate for a beneficial subgroup-specific effect that warrants further attention.
Topics: Aged; Aging; Brain; Cognition; Female; Humans; Leukocytes; Telomere; Telomere Shortening
PubMed: 35777725
DOI: 10.1016/j.arr.2022.101679 -
Molecular Ecology Dec 2022Human-driven environmental changes are affecting wildlife across the globe. These challenges do not influence species or populations to the same extent and therefore a... (Meta-Analysis)
Meta-Analysis Review
Human-driven environmental changes are affecting wildlife across the globe. These challenges do not influence species or populations to the same extent and therefore a comprehensive evaluation of organismal health is needed to determine their ultimate impact. Evidence suggests that telomeres (the terminal chromosomal regions) are sensitive to environmental conditions and have been posited as a surrogate for animal health and fitness. Evaluation of their use in an applied ecological context is still scarce. Here, using information from molecular and occupational biomedical studies, we aim to provide ecologists and evolutionary biologists with an accessible synthesis of the links between human disturbances and telomere length. In addition, we perform a systematic review and meta-analysis on studies measuring telomere length in wild/wild-derived animals facing anthropogenic disturbances. Despite the relatively small number of studies to date, our meta-analysis revealed a significant small negative association between disturbances and telomere length (-0.092 [-0.153, -0.031]; n = 28; k = 159). Yet, our systematic review suggests that the use of telomeres as a biomarker to understand the anthropogenic impact on wildlife is limited. We propose some research avenues that will help to broadly evaluate their suitability: (i) further causal studies on the link between human disturbances and telomeres; (ii) investigating the organismal implications, in terms of fitness and performance, of a given telomere length in anthropogenically disturbed scenarios; and (iii) better understanding of the underlying mechanisms of telomere dynamics. Future studies in these facets will help to ultimately determine their role as markers of health and fitness in wildlife facing anthropogenic disturbances.
Topics: Animals; Humans; Animals, Wild; Telomere Shortening; Anthropogenic Effects; Telomere; Biological Evolution
PubMed: 35080073
DOI: 10.1111/mec.16370 -
International Journal of Biometeorology Nov 2022Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions.... (Review)
Review
Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions. A literature review was conducted to systematically investigate and assess the overall effect of heat stress and DNA damage following heat exposure. In this study, electronic databases including PubMed, Scopus, and Web of Science were searched to find relevant literature on DNA damage in different ambient temperatures. Outcomes included (1) measurement of DNA damage in heat exposure, (2) three different quantification methods (comet assay, 8-hydroxy-2-deoxyguanosine (8-OHdG), and γ-H2AX), and (3) protocols used for moderate (31) and high temperatures (42). The evidence shows that long exposure and very high temperature can induce an increase in DNA damage through aggregate in natural proteins, ROS generation, cell death, and reproductive damage in hot-humid and hot-dry climate conditions. A substantial increase in DNA damage occurs following acute heat stress exposure, especially in tropical and subtropical climate conditions. The results of this systematic literature review showed a positive association between thermal stress exposure and inhibition of repair of DNA damage.
Topics: Humans; DNA Damage; 8-Hydroxy-2'-Deoxyguanosine; Heat Stress Disorders; Heat-Shock Response; Hot Temperature
PubMed: 36178536
DOI: 10.1007/s00484-022-02351-w -
Acta Paediatrica (Oslo, Norway : 1992) Oct 2021This systematic review and meta-analysis aimed to assess the association between paediatric obesity and telomere length. (Meta-Analysis)
Meta-Analysis Review
AIM
This systematic review and meta-analysis aimed to assess the association between paediatric obesity and telomere length.
METHODS
We conducted a comprehensive literature search for original studies assessing the associations between obesity and telomere length in children. Fixed or random effects with inverse-variance meta-analysis were used to estimate the standardised mean difference (SMD) and its 95% confidence interval (95% CI) between overweight or obese and normal-weight children. Heterogeneity was assessed using the I statistic, and meta-regression analyses were used to evaluate the potential source of heterogeneity. Subgroup analysis was further conducted by sex.
RESULTS
A total of 11 studies were included. The meta-analysis showed that children who were overweight or obese had shorter telomere length than normal-weight children (SMD: -0.85; 95% CI: -1.42 to -0.28; p < 0.01). However, significant heterogeneity was present (I = 97%; p < 0.01). Study design, methods used for measuring telomere length, tissue types, mean age, and percentage of boys were not the source of heterogeneity revealed by meta-regression analysis. The inverse trend was significant only in boys, but not in girls.
CONCLUSION
There was a negative association between paediatric obesity and telomere length. Weight control in children might have beneficial effect on telomere length.
Topics: Child; Female; Humans; Male; Overweight; Pediatric Obesity; Research Design; Telomere; Telomere Shortening
PubMed: 34101251
DOI: 10.1111/apa.15971 -
Placenta Nov 2020Pre-eclampsia (PE) is the major cause of fetal and maternal mortality and can be classified according to gestational age of onset into early-onset (EOPE, <34 weeks of... (Meta-Analysis)
Meta-Analysis
Pre-eclampsia (PE) is the major cause of fetal and maternal mortality and can be classified according to gestational age of onset into early-onset (EOPE, <34 weeks of gestation) and late- (LOPE, ≥34 weeks of gestation). DNA methylation (DNAm) may help to understand the abnormal placentation in PE. Therefore, we performed a systematic review to assess the role of global DNAm on pathophysiology of PE, focused on fetal and maternal tissues of placenta from pregnant with PE, including EOPE and LOPE. We searched the databases EMBASE, Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Scielo and Google Scholar, and followed the MOOSE guidelines. Moreover, we performed pathway analysis with the overlapping genes from the included studies. Twelve out of 24 included studies in the qualitative analysis considered the classification into EOPE and LOPE. We did not found heterogeneity in the criteria used for diagnosis of PE, and a few studies evaluated whether confounding factors would influence placental DNAm. Fourteen out of 24 included studies showed hypomethylation in placental tissue from pregnant with PE compared to controls. The differences in DNAm are specific to genes or differentially methylated regions, and more evident in EOPE and preterm PE compared to controls, rather than LOPE and term PE. The overlapping genes from included studies revealed pathways relevant to pathophysiology of PE. Our findings highlighted the heterogeneous results of the included studies, mainly focused on North America and China. Replication studies in different populations should use the same placental tissues, techniques to assess DNAm and pipelines for bioinformatic analysis.
Topics: DNA Methylation; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy
PubMed: 32942147
DOI: 10.1016/j.placenta.2020.09.004