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1.
J Mol Graph Model ; 110: 108058, 2022 01.
Article in English | MEDLINE | ID: mdl-34736054

ABSTRACT

Stabilizing human telomere DNA G-quadruplex (G4) proves a promising anti-cancer strategy. Though plenty of G4 stabilizing molecules have been reported, little is known about their selective binding mechanism among various G4s. Recently, a designed monohydrazone derivative (compound 15) was reported to display specific preference in binding and stabilizing parallel human telomeric G4. To reveal the selective binding mechanism, a comparative theoretical investigation was performed on two monohydrazone derivatives (compounds 1 and 15) and three telomeric G4s showing parallel, hybrid-I, and hybrid-II conformations. Two probable binding modes, i.e. the end-stacking binding and the groove binding, were predicted by molecular dockings for each monohydrazone in its binding with the telomeric G4s. Further long-timescale molecular dynamics simulations reveal the conversion from the groove binding to the end-stacking binding for both compounds, indicating the preference of the end-stacking binding mode. Structural analysis together with binding free energy calculations show that the van der Waals interaction plays a leading role in ranking the binding affinity. By forming extensive van der Waals interactions, the parallel G4-15 binding complex shows the highest binding affinity, and the corresponding compound 15 exhibits the strongest stabilizing effect to the telomeric G4. These findings agree well with the experimental observations. Through characterizing the selective binding between monohydrazones and telomeric G4s at the atomic level, the current study provides support to the design of novel selective stabilizers targeting telomeric G4s.


Subject(s)
G-Quadruplexes , DNA , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Telomere
2.
Acta Trop ; 225: 106196, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34687640

ABSTRACT

Trichomoniasis is the most common nonviral sexually transmitted disease; it is caused by Trichomonas vaginalis and seriously threatens human reproductive health. Telomeres are specialised DNA-protein complexes at the ends of chromosomes that have a protective function. The aim of the present study was to identify and characterise the telomeric DNA of T. vaginalis-which has not been previously reported-by multiple molecular methods including sequencing, the Bal nuclease (BAL) 31 nuclease assay, fluorescence in situ hybridisation (FISH), and Southern blotting. We found numerous repeated units of TTTTAGGG in T. vaginalis genomic DNA digested with S1 nuclease in combination with XbaI restriction enzyme. The (TTTTAGGG)n tandem repeats were also highly sensitive to BAL 31 exonuclease digestion. We confirmed that the (TTTTAGGG)n repeats were located at the end of T. vaginalis chromosomes by FISH. Restriction enzyme digestion combined with Southern blotting using a digoxigenin-labelled (TTTTAGGG)5 probe showed that the T. vaginalis telomeric DNA length varied from 1.0 to 1.5 kb. This is the first report on the telomeric DNA sequence of T. vaginalis which includes the length and distribution on chromosomes; our findings lay a foundation for further study on telomere maintenance mechanisms in T. vaginalis.


Subject(s)
Trichomonas Infections , Trichomonas vaginalis , Base Sequence , DNA , Humans , Telomere/genetics , Trichomonas vaginalis/genetics
3.
Theriogenology ; 177: 151-156, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34700072

ABSTRACT

There are controversial reports on the restoration of eroded telomere length in offspring produced by somatic cell nuclear transfer (SCNT) in different animal species. To the best of our knowledge, no earlier studies report the telomere length in naturally produced or cloned animals in any of the camelid species. Therefore, the present study was conducted to estimate the telomere length in dromedary camels produced by SCNT, the donor cells, and their age-matched naturally produced counterparts by Terminal Restriction Fragment (TRF) length analysis and real-time Q PCR T/S ratio methods. Genomic DNA was extracted from venous blood collected from 6 cloned animals and their age-matched counterparts. Using the southern blot technique, digested DNA was blotted onto a positively charged nylon membrane, and its hybridization was carried out using telomere (TTAGGG)n specific, DIG-labeled hybridization probe (Roche Diagnostics, Germany) at 42 °C for 4 h. Stringent washes were carried out at the same temperature, followed by a chemiluminescence reaction. The signals were captured using the Azure Biosystems C600 gel documentation system. A TeloTool program from MATLAB software with a built-in probe intensity correction algorithm was used for TRF analysis. The experiment was replicated three times, and the data, presented as mean ± SEM, were analyzed using a two-sample t-test (MINITAB statistical software, Minitab ltd, CV3 2 TE, UK). No difference was found in the mean telomere length of cloned camels when compared to their naturally produced age-matched counterparts. However, the telomere length was more (P < 0.05) than that of the somatic cells used for producing the SCNT embryos. A moderate positive Pearson correlation coefficient (r = 0.6446) was observed between the telomere lengths estimated by TRF and Q PCR T/S ratio method. In conclusion, this is the first study wherein we are reporting telomere length in naturally produced and cloned dromedary camels produced by somatic cell nuclear transfer. We found that telomere lengths in cloned camels were similar to their age-matched naturally produced counterparts, suggesting that the camel cytoplast reprograms the somatic cell nucleus and restores the telomere length to its totipotency stage.


Subject(s)
Camelus , Cloning, Organism , Animals , Cloning, Organism/veterinary , Embryo Transfer/veterinary , Nuclear Transfer Techniques/veterinary , Telomere/genetics
4.
BMC Genomics ; 22(1): 830, 2021 Nov 17.
Article in English | MEDLINE | ID: mdl-34789157

ABSTRACT

BACKGROUND: Trichoderma is a genus of fungi in the family Hypocreaceae and includes species known to produce enzymes with commercial use. They are largely found in soil and terrestrial plants. Recently, Trichoderma simmonsii isolated from decaying bark and decorticated wood was newly identified in the Harzianum clade of Trichoderma. Due to a wide range of applications in agriculture and other industries, genomes of at least 12 Trichoderma spp. have been studied. Moreover, antifungal and enzymatic activities have been extensively characterized in Trichoderma spp. However, the genomic information and bioactivities of T. simmonsii from a particular marine-derived isolate remain largely unknown. While we screened for asparaginase-producing fungi, we observed that T. simmonsii GH-Sj1 strain isolated from edible kelp produced asparaginase. In this study, we report a draft genome of T. simmonsii GH-Sj1 using Illumina and Oxford Nanopore technologies. Furthermore, to facilitate biotechnological applications of this species, RNA-sequencing was performed to elucidate the transcriptional profile of T. simmonsii GH-Sj1 in response to asparaginase-rich conditions. RESULTS: We generated ~ 14 Gb of sequencing data assembled in a ~ 40 Mb genome. The T. simmonsii GH-Sj1 genome consisted of seven telomere-to-telomere scaffolds with no sequencing gaps, where the N50 length was 6.4 Mb. The total number of protein-coding genes was 13,120, constituting ~ 99% of the genome. The genome harbored 176 tRNAs, which encode a full set of 20 amino acids. In addition, it had an rRNA repeat region consisting of seven repeats of the 18S-ITS1-5.8S-ITS2-26S cluster. The T. simmonsii genome also harbored 7 putative asparaginase-encoding genes with potential medical applications. Using RNA-sequencing analysis, we found that 3 genes among the 7 putative genes were significantly upregulated under asparaginase-rich conditions. CONCLUSIONS: The genome and transcriptome of T. simmonsii GH-Sj1 established in the current work represent valuable resources for future comparative studies on fungal genomes and asparaginase production.


Subject(s)
Trichoderma , Asparaginase , Genome , Hypocreales , Telomere , Trichoderma/genetics
5.
Medicina (Kaunas) ; 57(11)2021 Nov 10.
Article in English | MEDLINE | ID: mdl-34833441

ABSTRACT

Background and Objectives: Telomeric zinc finger-associated protein (TZAP) is a telomere regulation protein, previously known as ZBTB48. It binds preferentially to elongated telomeres, competing with telomeric repeat factors 1 and 2. TZAP expression may be associated with carcinogenesis, however; this study has not yet been performed in lung cancer. In this study, we examined the clinicopathological and prognostic values of TZAP expression in non-small cell lung cancer (NSCLC). Materials and Methods: Data were collected from The Cancer Genome Atlas. The clinical and prognostic values of TZAP for NSCLC were examined in adenocarcinoma (AD) and squamous cell carcinoma (SCC). Results: TZAP expression significantly increased in NSCLC tissues compared with normal tissues. In AD, TZAP expression was lower in patients with higher T stage (p = 0.005), and was associated with lymph node stage in SCC (p = 0.005). Survival analysis showed shorter disease-free survival in AD patients with lower TZAP expression (p = 0.047). TZAP expression did not have other clinical or prognostic value for AD and SCC. Conclusions: TZAP expression is a potential prognostic marker for NSCLC, especially in patients with AD.


Subject(s)
Adenocarcinoma , Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , DNA-Binding Proteins , Humans , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neoplasm Staging , Prognosis , Telomere/pathology , Transcription Factors , Zinc Fingers/genetics
6.
Article in English | MEDLINE | ID: mdl-34769797

ABSTRACT

Metabolic and hormonal outcomes of polycystic ovary syndrome (PCOS) have implications on telomere biology and physical activity may prevent telomere erosion. We sought to observe the effects of continuous (CAT) and intermittent (IAT) aerobic training on telomere length, inflammatory biomarkers, and its correlation with metabolic, hormonal, and anthropometric parameters of PCOS. This randomized controlled clinical trial study included 87 PCOS randomly stratified according to body mass index (BMI) in CAT (n = 28), IAT (n = 29) and non-training control group (CG, n = 30). The exercises were carried out on a treadmill, three times per week for 16 weeks. The participants' anthropometric characteristics and biochemical and hormonal concentrations were measured before and after aerobic training or observation period, as the telomere length that was evaluated using quantitative real-time PCR. Four months of aerobic exercises (CAT or IAT) did not alter telomere length and inflammatory biomarkers in PCOS women. Obesity index as BMI and waist circumference (WC), and inflammatory biomarkers negatively affect telomeres. The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC (p = 0.045), hip circumference (p = 0.032), serum cholesterol (p ≤ 0.001), and low-density lipoprotein (p = 0.030). Whereas, the IAT decreased WC (p = 0.014), waist-to-hip ratio (p = 0.012), free androgen index (FAI) (p = 0.037). WC (p = 0.049) and body fat (p = 0.015) increased in the non-training group while total cholesterol was reduced (p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers.


Subject(s)
Insulin Resistance , Polycystic Ovary Syndrome , Body Mass Index , Exercise , Female , Humans , Obesity , Telomere , Testosterone
7.
PLoS One ; 16(10): e0258156, 2021.
Article in English | MEDLINE | ID: mdl-34624021

ABSTRACT

Telomeres are nucleoprotein complexes that protect the ends of eukaryotic linear chromosomes from degradation and fusions. Telomere dysfunction leads to cell growth arrest, oncogenesis, and premature aging. Telomeric RNAs have been found in all studied species; however, their functions and biogenesis are not clearly understood. We studied the mechanisms of development disorders observed upon overexpression of telomeric repeats in Drosophila. In somatic cells, overexpression of telomeric retrotransposon HeT-A is cytotoxic and leads to the accumulation of HeT-A Gag near centrosomes. We found that RNA and RNA-binding protein Gag encoded by the telomeric retrotransposon HeT-A interact with Polo and Cdk1 mitotic kinases, which are conserved regulators of centrosome biogenesis and cell cycle. The depletion of proteins Spindle E, Ccr4 or Ars2 resulting in HeT-A overexpression in the germline was accompanied by mislocalization of Polo as well as its abnormal stabilization during oogenesis and severe deregulation of centrosome biogenesis leading to maternal-effect embryonic lethality. These data suggest a mechanistic link between telomeric HeT-A ribonucleoproteins and cell cycle regulators that ensures the cell response to telomere dysfunction.


Subject(s)
Centrosome/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/embryology , Drosophila melanogaster/metabolism , Embryonic Development , Oogenesis , Telomere/metabolism , Animals , Cell Death , Centrioles/metabolism , Embryo, Nonmammalian/metabolism , Mitosis , Protein Binding , RNA/metabolism , Retroelements/genetics , Ribonucleoproteins/metabolism , Zygote/metabolism
8.
Biochem Biophys Res Commun ; 579: 141-145, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34600299

ABSTRACT

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.


Subject(s)
COVID-19/genetics , DNA Damage , Host-Pathogen Interactions/genetics , SARS-CoV-2/pathogenicity , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , Checkpoint Kinase 1/metabolism , Chlorocebus aethiops , Histones/genetics , Phosphorylation , Telomere , Vero Cells
9.
Transl Psychiatry ; 11(1): 519, 2021 10 09.
Article in English | MEDLINE | ID: mdl-34628468

ABSTRACT

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.


Subject(s)
Methamphetamine , Telomere , Adult , Aging , Humans , Leukocytes , Methamphetamine/adverse effects , Telomere/genetics , Telomere Shortening , Young Adult
10.
Biol Lett ; 17(10): 20210409, 2021 10.
Article in English | MEDLINE | ID: mdl-34665991

ABSTRACT

As telomere length (TL) often predicts survival and lifespan, there is considerable interest in the origins of inter-individual variation in TL. Cross-generational effects of parental age on offspring TL are thought to be a key source of variation, but the rarity of longitudinal studies that examine the telomeres of successive offspring born throughout the lives of parents leaves such effects poorly understood. Here, we exploit TL measures of successive offspring produced throughout the long breeding tenures of parents in wild white-browed sparrow weaver (Plocepasser mahali) societies, to isolate the effects of within-parent changes in age on offspring TLs. Our analyses reveal the first evidence to date of a positive within-parent effect of advancing age on offspring TL: as individual parents age, they produce offspring with longer telomeres (a modest effect that persists into offspring adulthood). We consider the potential for pre- and post-natal mechanisms to explain our findings. As telomere attrition predicts offspring survival to adulthood in this species, this positive parental age effect could impact parent and offspring fitness if it arose via differential telomere attrition during offspring development. Our findings support the view that cross-generational effects of parental age can be a source of inter-individual variation in TL.


Subject(s)
Sparrows , Telomere , Animals , Animals, Wild , Longevity , Telomere/genetics , Telomere Shortening
11.
Biol Lett ; 17(10): 20210398, 2021 10.
Article in English | MEDLINE | ID: mdl-34637637

ABSTRACT

In many animals, recent evidence indicates that the gut microbiome may be acquired during early development, with possible consequences on newborns' health. Thus, it has been hypothesized that a healthy microbiome protects telomeres and genomic integrity against cellular stress. However, the link between the early acquired microbiome and telomere dynamics has not hitherto been investigated. In birds, this link may also be potentially modulated by the transfer of maternal glucocorticoids, since these substances dysregulate microbiome composition during postnatal development. Here, we examined the effect of the interplay between the microbiome and stress hormones on the telomere length of yellow-legged gull hatchlings by using a field experiment in which we manipulated the corticosterone content in eggs. We found that the hatchling telomere length was related to microbiome composition, but this relationship was not affected by the corticosterone treatment. Hatchlings with a microbiome dominated by potential commensal bacteria (i.e. Catellicoccus and Cetobacterium) had larger telomeres, suggesting that an early establishment of the species-specific microbiome during development may have important consequences on offspring health and survival.


Subject(s)
Charadriiformes , Gastrointestinal Microbiome , Animals , Corticosterone , Telomere , Telomere Shortening
12.
Int J Mol Sci ; 22(19)2021 Sep 24.
Article in English | MEDLINE | ID: mdl-34638651

ABSTRACT

The telomeric transcriptome of Chironomus riparius has been involved in thermal stress response. One of the telomeric transcripts, the so-called CriTER-A variant, is highly overexpressed upon heat shock. On the other hand, its homologous variant CriTER-B, which is the most frequently encoded noncoding RNA in the telomeres of C. riparius, is only slightly affected by thermal stress. Interestingly, both transcripts show high sequence homology, but less is known about their folding and how this could influence their differential behaviour. Our study suggests that CriTER-A folds as two different conformers, whose relative proportion is influenced by temperature conditions. Meanwhile, the CriTER-B variant shows only one dominant conformer. Thus, a temperature-dependent conformational equilibrium can be established for CriTER-A, suggesting a putative functional role of the telomeric transcriptome in relation to thermal stress that could rely on the structure-function relationship of the CriTER-A transcripts.


Subject(s)
Chironomidae/genetics , RNA, Untranslated/genetics , Telomere/genetics , Transcriptome/genetics , Animals , Base Sequence , Heat-Shock Response/genetics , Hot Temperature
13.
Int J Mol Sci ; 22(19)2021 Sep 24.
Article in English | MEDLINE | ID: mdl-34638655

ABSTRACT

DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing RNA (TERRA), transcribed from telomeres, as potential pharmacological targets. Here, a virtual screening approach to identify a library of drug-like putative TERRA G4 binders, in tandem with circular dichroism melting assay to study their TERRA G4-stabilizing properties, led to the identification of a new hit compound. The affinity of this compound for TERRA RNA and some DNA G4s was analyzed through several biophysical techniques and its biological activity investigated in terms of antiproliferative effect, DNA damage response (DDR) activation, and TERRA RNA expression in high vs. low TERRA-expressing human cancer cells. The selected hit showed good affinity for TERRA G4 and no binding to double-stranded DNA. In addition, biological assays showed that this compound is endowed with a preferential cytotoxic effect on high TERRA-expressing cells, where it induces a DDR at telomeres, probably by displacing TERRA from telomeres. Our studies demonstrate that the identification of TERRA G4-targeting drugs with potential pharmacological effects is achievable, shedding light on new perspectives aimed at discovering new anticancer agents targeting these G4 structures.


Subject(s)
RNA/genetics , Telomere/genetics , Antineoplastic Agents/pharmacology , Binding Sites/drug effects , Binding Sites/genetics , DNA/genetics , DNA Damage/drug effects , DNA Damage/genetics , G-Quadruplexes/drug effects , Humans , Ligands , Neoplasms/drug therapy , Neoplasms/genetics , Structure-Activity Relationship , Telomere/drug effects
14.
Mol Biol (Mosk) ; 55(5): 772-795, 2021.
Article in Russian | MEDLINE | ID: mdl-34671004

ABSTRACT

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.


Subject(s)
G-Quadruplexes , DNA , RNA , Telomere/genetics , Thermodynamics
15.
Ann Oncol ; 32(12): 1608-1617, 2021 12.
Article in English | MEDLINE | ID: mdl-34690007

ABSTRACT

BACKGROUND: In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. MATERIALS AND METHODS: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. RESULTS: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). CONCLUSION: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy.


Subject(s)
Brain Neoplasms , Glioma , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Glioma/diagnosis , Glioma/genetics , Humans , Isocitrate Dehydrogenase/genetics , Liquid Biopsy , Telomere/genetics , X-linked Nuclear Protein/genetics
16.
Crit Rev Oncol Hematol ; 167: 103510, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34695574

ABSTRACT

In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk.


Subject(s)
Neoplasms , Telomere , DNA Copy Number Variations , DNA, Mitochondrial/genetics , Humans , Leukocytes/metabolism , Mitochondria/genetics , Neoplasms/epidemiology , Neoplasms/genetics , Neoplasms/metabolism , Telomere/genetics
17.
J Affect Disord ; 295: 1032-1039, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34706411

ABSTRACT

BACKGROUND: Shorter telomere length is a putative biomarker of accelerated aging and has been associated with affective disorders and mortality. Psychological factors and behaviors associated with telomere shortening are yet to be clarified. Here, we investigate the association between history of suicide attempts and telomere length in patients with affective disorders. METHODS: Leucocyte telomere length was determined by quantitative real-time Polymerase Chain Reaction (qPCR) in patients with affective disorders (n = 248) including bipolar disorders type I (n = 159), type II (n = 67), major depressive disorder (n = 22), and healthy controls (n = 401). Diagnosis, duration of illness, and age at onset were assessed using the Structural Clinical Interview for DSM-IV (SCID-I). Number of lifetime suicide attempts were based on self-reports. Effect size was calculated using Cohen's d. RESULTS: Telomere length was reduced in patients with affective disorders relative to healthy controls (d = 0.18, F = 5.26, p = 0.02). Among patients, a higher number of suicide attempts was associated with shorter telomere length (ß = -0.24, t = -3.83, CI = -0.44 to -0.14, p < 0.001), also when controlling for duration of illness and age at onset (ß = -.23, CI = -.42 to -.12, p = 0.001). Multiple suicide attempts were associated with telomere length reduction comparable to eight years lifespan, adjusted for demographic and clinical characteristics. CONCLUSIONS: While longitudinal data are needed to clarify the temporal course, previous suicide attempts and related distress may accelerate telomere shortening and aging in patients with affective disorders.


Subject(s)
Depressive Disorder, Major , Telomere , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/genetics , Humans , Mood Disorders/epidemiology , Mood Disorders/genetics , Suicide, Attempted , Telomere/genetics , Telomere Shortening/genetics
18.
Kidney Int ; 100(5): 980-983, 2021 11.
Article in English | MEDLINE | ID: mdl-34688387

ABSTRACT

Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park et al., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.


Subject(s)
Renal Insufficiency, Chronic , Telomere , Aging/genetics , Humans , Mendelian Randomization Analysis , Renal Insufficiency, Chronic/genetics , Telomere/genetics , Telomere Shortening
19.
Elife ; 102021 09 08.
Article in English | MEDLINE | ID: mdl-34494545

ABSTRACT

Background: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth. Methods: We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders. Results: In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score [95% CI 0.05, 0.42; FDR-corrected p-value = 0.01]). TL was not associated with other outcomes. Conclusions: Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first 2 years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories. Funding: Funded by the Bill and Melinda Gates Foundation. Clinical trial number: NCT01590095.


Subject(s)
Child Development , Telomere Homeostasis , Telomere/chemistry , Bangladesh , Child, Preschool , Cross-Sectional Studies , Female , Humans , Infant , Infant, Newborn , Male , Rural Population , Telomere/metabolism
20.
J Assoc Physicians India ; 69(9): 11-12, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34585887

ABSTRACT

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.


Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2 , DNA, Mitochondrial/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Follow-Up Studies , Humans , Obesity/complications , Obesity/genetics , Prospective Studies , Telomere/genetics
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