Cytoprotective effect on oxidative stress and inhibitory effect on cellular aging of Terminalia chebula fruit

The ethanol extract from the fruit of Terminalia chebula (Combretaceae) exhibited significant inhibitory activity on oxidative stress and the age-dependent shortening of the telomeric DNA length. In the peroxidation model using t-BuOOH, the T. chebula extract showed a notable cytoprotective effect on the HEK-N/F cells with 60.5 +/- 3.8% at a concentration of 50 microg/ml. In addition, the T. chebula extract exhibited a significant cytoprotective effect against UVB-induced oxidative damage. The life-span of the HEK-N/F cells was elongated by 40% as a result of the continuous administration of 3 microg/ml of the T. chebula extract compared to that of the control. These observations were attributed to the inhibitory effect of the T. chebula extract on the age-dependent shortening of the telomere, length as shown by the Southern blots of the terminal restriction fragments (TRFs) of DNA extracted from subculture passages.     

Telomerase activity,apoptosis and cell cycle progression in ataxia telangiectasia lymphocytes expressing TCL1

Individuals affected by ataxia telangiectasia (AT) have a marked susceptibility to cancer. Ataxia telangiectasia cells, in addition to defects in cell cycle checkpoints, show dysfunction of apoptosis and of telomeres, which are both thought to have a role in the progression of malignancy. In 1-5% of patients with AT, clonal expansion of T lymphocytes carrying t(14;14) chromosomal translocation, deregulating TCL1 gene(s), has been described. While it is known that these cells can progress with time to a frank leukaemia, the molecular pathway leading to tumorigenesis has not yet been fully investigated. In this study, we compared AT clonal cells, representing 88% of the entire T lymphocytes (AT94-1) and expressing TCL1 oncogene (ATM(-) TCL1(+)), cell cycle progression to T lymphocytes of AT patients without TCL1 expression (ATM(-) TCL1(-)) by analysing their spontaneous apoptosis rate, spontaneous telomerase activity and telomere instability. We show that in ATM(-) TCL1(+) lymphocytes, apoptosis rate and cell cycle progression are restored back to a rate comparable with that observed in normal lymphocytes while telomere dysfunction is maintained.     

Synergy Between 3′Azido-3′deoxythymidine and Paclitaxel in Human Pharynx FaDu Cells

Purpose. We recently demonstrated simultaneous targeting of telomere and telomerase as a novel cancer therapeutic approach, and that telomerase inhibitors such as 3azido-3deoxythymidine (AZT) significantly enhanced the antitumor activity of paclitaxel, which causes telomere erosion, in telomerase-positive human pharynx FaDu tumors in vitro and in vivo (1). The present study evaluated the synergy between AZT and paclitaxel to identify optimal combinations for future clinical evaluation. Methods. FaDu cells were incubated with or without AZT for 24 h and then treated with AZT with or without paclitaxel for an additional 48 h. Under these conditions, single agent paclitaxel produced a 60% maximum reduction of cell number (IC₅₀ was 7.3 nM), and single agent AZT produced a 97% reduction (IC₅₀ was 5.6 M). Synergy was evaluated using fixed-concentration and fixed-ratio methods, and data were analyzed by the combination index method. Results. The results indicate a concentration-dependent synergy between the two drugs; the synergy was higher for combinations containing greater paclitaxel-to-AZT concentration ratios and increased with the level of drug effect. For example, in combinations containing 1 M AZT, synergy was 1.3-fold at the 20% effect level and 3.1-fold at the 60% effect level. Because the major antitumor activity, determined by comparing the posttreatment cell number to the pretreatment cell number, was antiproliferation at the 20% effect level and cell kill at the 60% effect level, our results suggest that AZT mainly enhances the cell kill effect of paclitaxel. Conclusion. In summary, the present study demonstrates a synergistic interaction between paclitaxel and AZT and supports a combination using a low and nontoxic AZT dose in combination with a therapeutically active dose of paclitaxel.     

Androgen depletion activates telomerase in the prostate of the nonhuman primate, Macaca mulatta

BACKGROUND: The activity of telomerase, an enzyme that synthesizes telomeric repeats at the ends of chromosomes, is not detectable in normal human prostate. However, the majority of human prostate cancers exhibit telomerase activity. Since androgens play a major role in prostate tumorigenesis, we investigated the effect of androgen-depletion on the expression of telomerase activity in the prostate. METHODS: Adult male rhesus monkeys were either bilaterally castrated or subjected to sham surgery (n = 5 each). Approximately 6 weeks later, the animals were killed and the different regions of the prostate gland were removed and frozen immediately. Telomerase activity was assayed using the telomeric repeat amplification protocol. RESULTS: All five regions of the prostate from sham operated control animals failed to exhibit telomerase activity. In the castrated monkey, all regions of the prostate, except for the anterior lobe, expressed high levels of telomerase activity. CONCLUSIONS: Our results indicate that in monkeys, androgen-ablation leads to up-regulation of telomerase activity. The negative-regulation of telomerase activity by androgens is probably lost during prostate tumorigenesis.     

DNA structures common for chironomid telomeres terminating with complex repeats

Tandem repeats, 340 bp long, have been shown to terminate the chromosomes in Chironomus pallidivittatus and similar DNA may be used for this purpose by related insects. In view of the importance of Chironomus in telomere studies, representing in principle a third system after short repeats and Drosophila telomeric retrotransposons, we have investigated the related Chironomus dilutus, to learn what DNA structures are conserved at the chromosome ends. Interspersed subrepeats in the telomeric repeats, which contain a long palindrome, and a zone of about 100 bp of relatively constant subtelomeric DNA towards the junction to the telomeric DNA, are characteristic for C. dilutus as for previously investigated species. C. dilutus has similar subtelomeric DNA at all chromosome ends, but typical telomeric repeats in only seven of the pairs since the eighth telocentric pair contains centromere-specific repeats.     

检测端粒酶活性的PCR—ELISA方法的建立

建立一种更为敏感，特异的端粒酶检测方法。方法将分子生物学和免疫学方法有机地结合起来，建立ＰＣＲ－ＥＬＩＳＡ方法并检测多种肿瘤细胞株和部分组织中端粒酶活性。结论ＰＣＲ－ＥＬＩＳＡ方法检测端粒酶活性是一种简便，快速，无放射性污染的方法，适用于肿瘤早期诊断和普查。     

Study of abnormal length of chromosomal telomere in patients with lung cancer

Telomere is the tenonal sthetUxe of the chtDInosomes Of eukaryote and it consists of repeated seqUences ofoligonucledde wb rich G[IJ. In hUInan being, the avemp length of telomere is 8 -- 14 kb and its core sc.thence is 5' mGGG3I[2'3]. Telomere and its binding...Pmtein ~ntam the stability of .hmmosome.[']. odiousstudies reported that telomere length was obviously shortened in Patients with chIDnic myeloid leukenda and solidc~inomas such as colon c~inolna and ~ c~inomalsJ. There aught b…     

Telomere length and risk of Parkinson's disease

We investigated whether telomere length was associated with the risk of Parkinson's disease (PD) in a case‐control study (96 cases and 172 age‐matched controls) nested within the Health Professionals Follow‐up Study. Relative ratio of telomere repeat copy number to single‐gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12–0.90). Our results suggest that, contrary to telomere attrition observed in several aging‐related diseases, shorter telomeres are not associated with an increased risk of PD. © 2007 Movement Disorder Society     

Chronic Pain and Telomere Length in Community-Dwelling Adults: Findings From the 1999 to 2002 National Health and Nutrition Examination Survey

Chronic pain is a common condition associated with psychological distress, functional impairments, and age-associated comorbidity. Preliminary studies, on the basis of relatively small sample sizes, suggest that the combination of chronic pain and stress is associated with telomere shortening, a widely recognized marker of cellular aging. We sought to determine the cross-sectional association of chronic pain with telomere length in 7,816 community-dwelling adults ages 20 years and older who participated in the 1999 to 2002 National Health and Nutrition Examination Survey. Consistent with previous studies, leukocyte telomere length was assessed using the quantitative polymerase chain reaction method and compared with a DNA reference standard to compute a telomere to single copy gene ratio. Standardized, in-person interviews were used to identify chronic regional pain and chronic widespread pain in 784 (10.0%) and 266 (3.4%) participants, respectively. Older age, male sex, obesity, and less physical activity were associated with shorter telomere length (P?<.05 for all comparisons); however, there was no association of chronic pain with telomere length. The age-adjusted means (standard error) of telomere length telomere to single copy gene ratios were 1.04 (.02), 1.03 (.02), and 1.02 (.02) in participants with no chronic pain, chronic regional pain, and chronic widespread pain, respectively (P?=?.69). In addition, chronic pain did not modify the effects of age, sex, race/ethnicity, education, or psychological distress on telomere length. In summary, chronic regional and widespread pain were not associated with telomere length in this nationally representative study; however, we could not determine associations of pain duration and severity with telomere length because of limitations in pain assessment data.

Telomere length and brain aging: A systematic review and meta-analysis

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.