[The relationship of telomere and telomerase activity with outcome of aplastic anemia after immunosuppressive therapy].
Jiayin SongLiping KuangYang WangYonghua LiJiu-long WuHang ZhangLi LiYao-Chun WangZujun JiangYang Xiao
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To observe the changes of telomere length and telomerase activity in patients with aplastic anemia (AA), and relationship with immunosuppressive therapy (IST) efficacy, to explore the pathogenesis of AA and the role of telomere length in evaluating immunosuppressive therapy efficacy.71 cases of AA patients between September 2010 and March 2013 were enrolled into this study. 3 ml peripheral blood specimens from this cohort of patients were collected to test the telomere length in peripheral blood mononuclear cell (PBMNC) with flow-FISH and detect telomerase activity with TRAP-PCR-ELISA method.Telomere length and age showed negative correlation (b=-0.387, P=0.001) in normal control, NSAA and SAA + VSAA groups, telomere length became shorter with the growth of age, and normal control group telomere length decreased along with the age growth slightly greater than the other two groups (NSAA, SAA+VSAA). Besides the effect of age on telomere length, no significant difference was observed between NSAA and SAA+VSAA groups (P=0.573), and NSAA, SAA+VSAA (30.957 ± 4.502,29.510 ± 5.911)groups were significantly shorter than normal control group (51.086±10.844) (P<0.01). Telomere length in NR group (25.357±4.848)was significantly lower than normal control group (51.086 ± 10.844) (P=0.005), telomere length in CR(32.808 ± 4.685)/PR groups (30.334±4.464) compared with normal control group had no significant difference (P=0.517, P=0.254). Telomere length below 29.21% obviously decreased outcomes of IST. Telomerase activity had significant difference (χ²=20.385, P<0.01). The telomerase activity had no significant difference in terms of age and gender in three groups, multiple comparison found that telomerase activities in SAA + VSAA (0.324±0.178) (P<0.01), and NSAA (0.234±0.175) groups (P=0.002) were significantly higher than normal control group (0.107±0.083).Telomere length of PBMNC in AA patients was significantly shortened than normal control group with telomerase activity increased, and telomere shorted more apparently in NR group, these patients should adjust the treatment as early as possible. Telomeres could predict the curative effect of IST.Keywords:
Aplastic anemia
Telomeres shorten with successive cell divisions in normal somatic cells. Telomerase is a ribonucleoprotein enzyme associated with cellular proliferation and plays an important role in maintaining the stability of chromosomes and the length of DNA telomeres. Telomerase activity has been detected in tissues from many human tumors, but is not present in the majority of normal tissues. Thus, measurement of telomerase activity and telomere length may contribute to understanding the mechanism of tumorigenesis and provide useful diagnostic or prognostic information. The aim of this study was to investigate the telomerase activity and telomere length from patients with cutaneous T-cell lymphoma (CTCL).Eighteen skin-homing T-cell lines were established from skin biopsies and 10 peripheral blood mononuclear cells (PBMC) were isolated from patients with various stages of CTCL together with 22 PBMC from healthy donors. For each sample an identical amount of cellular protein was measured quantitatively for telomerase activity using the telomerase polymerase chain reaction-enzyme-linked immunosorbent assay based on the telomeric repeat amplification protocol method. Telomere length was assayed using a commercial kit.Eight of ten PBMC and 16 of 18 skin-homing T-cell lines from patients with CTCL showed moderate to strong telomerase activity. Freshly obtained PBMC from healthy donors showed weak levels of telomerase activity. A shorter telomere length was found in cell lines and PBMC from patients with CTCL compared with healthy controls. Four skin-homing T-cell lines going into growth crisis showed sharply reduced telomerase activity.The results of the current study indicate that both skin-homing T-cells and PBMC from CTCL have high telomerase activity and short telomere length. These changes are similar to the changes observed in the majority of malignant cells including other types of T-cell lymphoma. It is interesting to note that even in the very early stages of CTCL such as parapsoriasis (which is a clinically benign disease) the changes already are present, indicating that a significantly high level of telomerase activity frequently occurs in CTCL and may be an important event in tumorigenesis. Telomerase activity and telomere length are useful markers for CTCL risk assessment.
Cutaneous T-cell lymphoma
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Indian traditional medicine practices use defined rasayana preparations to improve the quality of life in aged individuals. Amalaki Rasayana is one such rasayana prepared from the fruits of Phyllanthus emblica and is popularly used to prevent or treat various age related health conditions. Telomerase activity in the cells maintains telomere length and is implicated in ageing and various diseases wherein the shortening of telomere during ageing is controlled chiefly by the telomerase activity.In the present study, we investigated telomerase activity and telomere length in the peripheral blood mononuclear cells of aged individuals administered with Amalaki Rasayana.Amalaki Rasayana was administered to healthy, aged (45-60 years) volunteers for 45 days after koshta shuddhi procedure. The telomerase activity and telomere length were analyzed on 0, 45th and 90th days of Amalaki Rasayana administration in peripheral blood mononuclear cells from these individuals and compared with age-matched placebo group and young volunteers (22-30 years). The data were compared between the groups.The results indicated an increase in telomerase activity with no discernible change in telomere length in the Amalaki administered participants. The comparison between young and aged participants revealed higher telomerase activity in young participants with no significant differences in telomere length.The data indicate that the maintenance of telomere length is facilitated by an increase in telomerase activity upon rasayana administration in aged individuals and Amalaki Rasayana may prevent the erosion of telomeres over a period of time in aged individuals to promote healthy ageing.
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Telomere shortening to a critical limit is associated with replicative senescence. This process is prevented by the enzyme telomerase. Oxidative stress and chronic inflammation are factors accelerating telomere loss. Chronic hemodialysis, typically accompanied by oxidative stress and inflammation, may be also associated with replicative senescence. To test this hypothesis, we determined telomere length and telomerase activity in peripheral blood mononuclear cells (PBMCs) in a cross-sectional study. Hemodialysis patients at the University Hospital Larissa and healthy controls were studied. Telomere length was determined by the TeloTAGGG Telomere Length Assay and telomerase activity by Telomerase PCR-ELISA (Roche Diagnostics GmbH, Mannheim, Germany). We enrolled 43 hemodialysis patients (17 females; age 65.0 ± 12.7 years) and 23 controls (six females; age 62.1 ± 15.7 years). Between the two groups, there was no difference in telomere length (6.95 ± 3.25 vs. 7.31 ± 1.96 kb; P = 0.244) or in telomerase activity (1.82 ± 2.91 vs. 2.71 ± 3.0; P = 0.085). Telomere length correlated inversely with vintage of hemodialysis (r = −0.332, P = 0.030). In hemodialysis patients, positive telomerase activity correlated with telomere length (r = 0.443, P = 0.030). Only age, and neither telomere length nor telomerase activity, was an independent survival predictor (hazard ratio 1.116, 95% confidence interval 1.009–1.234, P = 0.033). In this study, telomere length and telomerase activity in PBMCs are not altered in hemodialysis patients compared with healthy controls. Long duration of hemodialysis treatment is associated with telomere shortening and positive telomerase activity with an increased telomere length in PBMCs of hemodialysis patients. The underlying mechanism and clinical implications of our findings require further investigation.
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Telomerase is a reverse transcriptase that adds the telomeric sequence to the terminal of chromosomes, prevents shortening of telomere, and maintains the complete telomeric structure.1It has been recently reported that an increase in telomerase activity is associated with the activation of lymphocytes,2-7 and, in general, much attention has been paid to the role of telomerase in immunopathology. Katayama et al reported the telomerase activity in patients with systemic lupus erythematosus (SLE).8 They analysed 17 patients with SLE, and the telomerase activity in peripheral mononuclear cells was increased to 64.7%. Thus, in this study, we divided patients with SLE into treated and untreated groups, and measured the telomerase activity of peripheral mononuclear cells.
Thirteen patients with SLE (1 man, 12 women) with …
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Human genetics
Metabolic disease
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Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20-90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow-up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naïve cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naïve T-cell percentage and changes in health conditions.
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Aplastic anemia
Bone marrow failure
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We evaluated the clinical significance of the telomerase activity and telomere length of peripheral blood mononuclearcells (PBMC) in systemic lupus erythematosus (SLE). PBMC were isolated from 55 patients with SLE and the telomerase activity was measured by TRAP assay. The telomere length of PBMC was also measured in 30 of these subjects. As a control group, 45 healthy adults with no particular clinical history were studied. The results were compared with clinical data. In patients with active SLE, the telomerase activity of PBMC was significantly increased compared with the control group. In patients with inactive SLE, the PBMC telomerase activity was not different compared with the controls in their 20s, 30s and 40s, but it was significantly increased compared with the controls in their 50s. In SLE patients, the telomerase activity of PBMC was significantly correlatedwith modified SLEDAI. The telomere length of PBMC in younger SLE patients tended to be shorter than that in the controls, but no difference was observed in older patients. The correlation coefficient between the telomerase activity and telomere length of PBMC in SLE patients was not significant. Abnormalities in the telomeraseactivity and telomere length observedin SLE patients are consideredto be important findings for evaluation of the pathology of SLE.
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P134 Telomeres and telomerase are known to be important in chromosome function and cell proliferation. We investigated the effect of infection of HTLV-I on telomerase activity, telomere length and human telomerase RNA (hTR) of the peripheral blood mononuclear cells from donors infected with HTLV-I. Ten patients with ATL and 10 patients with HAM/TSP were examined. As controls, 11 asymptomatic controls were examined; 6 of these were infected with HTLV-I and the other 5 were not. The telomerase activity was assayed by a non-radioisotope quantitative system from a telomeric repeat amplification protocol (TRAP), and it was detected using a fluorescence-based TRAP method. We measured the telomere length as the terminal restriction fragment length. The amount of hTR was measured using the real-time PCR system. The telomerase activity was significantly increased in the samples from patients with acute type of ATL (n=4, mean ± SEM 206.24 ± 22.44 units/μg) compared with asymptomatic controls (11.29 ± 2.60) (p<0.01). It was also slightly increased in the other types of ATL (n=6, 29.06 ± 9.09) (p<0.05), but not in HAM/TSP (13.32 ± 3.49). Both telomere length and the amount of hTR showed no specific association with the type of diseases, although the decrease of telomere length was observed with aging (p<0.05). Infections with HTLV-I themselves cause no significant effect on the telomerase activity and telomere length, although telomerase may play an important role in the process of tumorigenesis of some types of ATL.
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Introduction: The telomeric DNA together with its associated proteins protects the chromosome ends from degradation or aberrant recombination. Telomerase and telomere are closely associated with development of cancers. In this study we aim to investigate the significance of telomerase activity (TA) and telomere length (TL) in patients with acute promyelocytic leukemia (APL). Methods: Peripheral blood samples were taken from 20 APL patients during the diagnosis and from 25 healthy normal individuals at different age ranges. Telomerase activity (TA) was assessed by TRAP- ELISA and PAGE procedures. Genomic DNA isolated from patient mononuclear cells was digested with Rsa1 and Hinf1 restriction enzymes; electrophoresis was performed in 0.8% agarose gels, and telomere length (TL) was determined by southern analysis using a Chemiluminescence-based assay. Results: As oppose to the normal individuals, telomerase activity was detected in peripheral blood mononuclear cells of all APL patients (P<0.001). Marked differences were observed in the sizes of the telomere length in the normal blood cells and APL leukemic cells. The leukemic cells of 18 of 20 (90%) patients with APL showed a significant reduction in the length of telomeric DNA, ranging from 2.3 to 6.7 kbp (median 3.5 kbp), while the telomere length in healthy normal individuals was 9.1 to 14.8 kbp (median 11.6 kbp) (P<0.000). In healthy individuals, the average TL was found to vary with age, and the rate of telomere shortening was age dependent. Conclusions: Telomere length shortening and Telomerase up-regulation are closely associated with acute promyelocytic leukemia; therefore, they may be used as potential markers for diagnostic, prognostic and for therapeutic intervention in APL patients.
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