Mechanism of telomerase in affecting biological characteristics of gastric cancer / 国际外科学杂志

Gastric cancer is one of the major diseases threatening human health, with a high incidence and a low early diagnostic rate. There are many bottlenecks encountered during its treatment. Consequently, improving the early diagnostic rate and exploring new therapeutic targets are currently urgent challenges that need to be addressed. Telomerase is undetectable in normal tissues, but it exhibits high specificity and sensitivity in most cancers and has a definite correlation with prognosis. It may serve as a serum tumor marker and prognostic indicator. Human telomerase reverse transcriptase (hTERT) gene polymorphism can regulate the susceptibility of people to gastric cancer, and affect the occurrence, development, proliferation and apoptosis of gastric cancer through its target gene. Substances such as resistin, visfatin, G-quadruplex and methylenedioxyaniline can affect the occurrence and development of gastric cancer by regulating telomerase expression. The mechanism by which hTERT regulates tumor invasion and metastasis is currently unclear, so elucidating its mechanism is of great significance.This paper will review the research progress of this mechanism in recent years.

Correlation analysis of serum POT1,TERT,8-OHdG,SOD expression levels and syndrome type of osteoporosis / 现代医院

Objective To analyze the distribution characteristics of traditional Chinese medicine(TCM)syndrome types in patients with osteoporosis and the distribution differences of clinical and serological indicators in TCM syndrome types.Meth-ods A total of 69 patients with osteoporosis were collected from the Third Affiliated Hospital of Guangzhou University of Chinese Medicine and Qifu Hospital Affiliated to Jinan University.The general information,bone mineral density T value,fasting periph-eral venous blood in the morning were collected.The expression of telomerase protective factor 1(POT1),telomerase reverse transcriptase(TERT),serum 8-hydroxy-2'-deoxyguanosine(8-OHdG)and superoxide dismutase 2(SOD2)were detected by ELISA.Finally,the above data were statistically analyzed.Results There were significant differences in body weight,height,bone mineral density,POT1,TERT,and 8-OHdG among the four syndromes(P＜0.05).In terms of correlation,the relation-ship between bone mineral density and each parameter in different syndrome types was explored.The bone mineral density of qi stagnation and blood stasis syndrome was positively correlated with SOD2 value.There is a positive correlation between bone min-eral density and 8-OHdG in patients with Yin deficiency of liver and kidney.TERT was positively correlated with qi stagnation and blood stasis syndrome.Liver and kidney Yin deficiency syndrome was positively correlated with weight and bone mineral den-sity,and negatively correlated with TERT value.Weight was negatively correlated with qi and blood stasis syndrome.Conclusion In TCM syndrome differentiation of osteoporosis,there were statistical differences in weight,height,bone mineral density,ser-um POT1,TERT and 8-OHdG among Qi-stagnation and blood stasis,spleen-kidney Yang deficiency,liver-kidney Yin deficiency and Qi-blood-peace syndrome.In different syndrome types,serum SOD2 and 8-OHdG were the influencing factors of bone miner-al density.Serum TERT and 8-OHdG are the main factors affecting the dialectical classification of osteoporosis.

hTERT gene methylation in circulating DNA, tumor, and surrounding tissue in breast cancer: a prospective study

ABSTRACT BACKGROUND: The human telomerase reverse transcriptase (hTERT) enzyme, encoded by the hTERT gene, synthesizes protective telomeric sequences on chromosomes and plays a fundamental role in cancer formation. Methylation of the hTERT gene has an upregulatory effect, increasing hTERT enzyme synthesis and allowing continuous tumor cell division. OBJECTIVE: In a group of patients with breast cancer, we aimed to analyze the methylation status of hTERT in the tumor, surrounding tissue, and circulating free deoxyribonucleic acid (cfDNA) of blood collected on the day of mastectomy and then approximately one year later. DESIGN AND SETTING: A prospective study was conducted at a university hospital in Rio de Janeiro, Brazil. METHODS: Samples were collected from 15 women with breast cancer on the day of mastectomy and approximately one year postoperatively. cfDNA was analyzed by sodium bisulfite conversion, followed by polymerase chain reaction, electrophoresis, and silver nitrate staining. RESULTS: Methylation of hTERT was detected in the tumors and surrounding tissues of all 15 patients. Five patients displayed hTERT methylation in the cfDNA from the blood of the first collection. Of the ten patients who returned for the second collection, three showed methylation. Two patients with methylation in the first collection did not display methylation in the second collection. One patient with no methylation in the first collection displayed methylation in the second collection, and one patient had a diminished level of methylation in the second collection. CONCLUSION: Only one-third of patients displayed methylation in their cfDNA, which may be related to the success of chemotherapy.

Lamin B1 regulates the growth of hepatocellular carcinoma cells by influencing telomerase activity / 生物工程学报

Lamin B1 (LMNB1) is highly expressed in liver cancer tissues, and its influence and mechanism on the proliferation of hepatocellular carcinoma cells were explored by knocking down the expression of the protein. In liver cancer cells, siRNAs were used to knock down LMNB1. Knockdown effects were detected by Western blotting. Changes in telomerase activity were detected by telomeric repeat amplification protocol assay (TRAP) experiments. Telomere length changes were detected by quantitative real-time polymerase chain reaction (qPCR). CCK8, cloning formation, transwell and wound healing were performed to detect changes in its growth, invasion and migration capabilities. The lentiviral system was used to construct HepG2 cells that steadily knocked down LMNB1. Then the changes of telomere length and telomerase activity were detected, and the cell aging status was detected by SA-β-gal senescence staining. The effects of tumorigenesis were detected by nude mouse subcutaneous tumorigenesis experiments, subsequent histification staining of tumors, SA-β-gal senescence staining, fluorescence in situ hybridization (FISH) for telomere analysis and other experiments. Finally, the method of biogenesis analysis was used to find the expression of LMNB1 in clinical liver cancer tissues, and its relationship with clinical stages and patient survival. Knockdown of LMNB1 in HepG2 and Hep3B cells significantly reduced telomerase activity, cell proliferation, migration and invasion abilities. Experiments in cells and tumor formation in nude mice had demonstrated that stable knockdown of LMNB1 reduced telomerase activity, shortened telomere length, senesced cells, reduced cell tumorigenicity and KI-67 expression. Bioinformatics analysis showed that LMNB1 was highly expressed in liver cancer tissues and correlated with tumor stage and patient survival. In conclusion, LMNB1 is overexpressed in liver cancer cells, and it is expected to become an indicator for evaluating the clinical prognosis of liver cancer patients and a target for precise treatment.

Effects and underlying mechanisms of telomerase reverse transcriptase in carcinogenesis and cancer progression / 肿瘤

As a limiting factor in telomerase activity,telomerase reverse transcriptase(TERT)controls cellular senescence and apoptosis by maintaining telomere length.TERT is not expressed or little expressed in most normal cells.However,the abnormal overexpression of TERT promotes the ability of tumor cells to replicate indefinitely.This review summarizes the regulatory mechanisms of TERT expression,including the main transcription factor families,single nucleotide polymorphism sites,and epigenetic modification changes such as DNA methylation,histone modification,and non-coding RNA.The role of these molecular mechanisms as well as significant TERT single-base variants and virus integration variants in the occurrence and development of cancer are reviewed.On this basis,its application in tumor diagnosis and prognosis is discussed.

Development and verification of multiplex fluorescence quantitative PCR (Taqman probe) for detection of telomerase activity / 中国生物制品学杂志

@#Objective To develop and verify a multiplex fluorescence quantitative PCR(Taqman probe) method for the detection of telomerase activity.Methods Specific reverse transcription primers,two pairs of quantitative primers and probes were designed for the CDS sequence of telomerase catalytic subunit telomerase reverse transcriptase(TERT).After optimization of the reverse transcription primers(specific reverse transcription primers and random primers) and quantitative primers(two pairs of quantitative primer probes used alone or in combination) in the reaction system,with the primer probe of internal reference gene GAPDH,multiplex fluorescence quantitative PCR was performed in a single tube.In addition,telomerase positive standard and negative standard were prepared with 293T and MRC-5 cells respectively,and the stability and precision of the method were verified.The telomerase activity in 19 normal mesenchymal cell samples and 32 breast cancer cell samples were detected by the developed method.Results The optimum reaction system was as follows:using cDNA synthesized with specific reverse transcription primers as the template,2 pairs of quantitative primer probes of TERT gene were mixed with internal reference gene GAPDH primer probes for multiplex fluorescence quantitative PCR reaction in a single tube.After optimization,the sensitivity and TERT fluorescence signal quantity of the system were greatly improved,and the ΔRn was enhanced by 3 times.The amplification curve of positive standard TERT gene was normal,and the ΔCt between TERT gene and GAPDH gene remained stable.The amplification curve of GAPDH gene in negative standard was normal,while there was no amplification curve of TERT gene.There was a little difference in ΔCt between TERT and GAPDH genes in the positive standard frozen and thawed for 3 and 5 times repeatedly and the positive standard without freezing and thawing,and the CVs of precision in intra-and inter-groups were all less than 1%.Telomerase activity was negative in 19 normal mesenchymal cell samples and positive in 32 breast cancer cell samples,and significant difference in Ct value of TERT gene between them was observed(t=4.236,P <0.001).Conclusion The developed multiplex fluorescence quantitative PCR(Taqman probe) method for the detection of telomerase activity has good stability and precision,which is expected to be used in early diagnosis and gene therapy of tumors.

Telomerase inhibitors TMPyP4 and thymoquinone decreased cell proliferation and induced cell death in the non-small cell lung cancer cell line LC-HK2, modifying the pattern of focal adhesion

G‐quadruplexes (G4) are structures formed at the ends of telomeres rich in guanines and stabilized by molecules that bind to specific sites. TMPyP4 and thymoquinone (TQ) are small molecules that bind to G4 and have drawn attention because of their role as telomerase inhibitors. The aim of this study was to evaluate the effects of telomerase inhibitors on cellular proliferation, senescence, and death. Two cell lines, LC‐HK2 (non-small cell lung cancer - NSCLC) and RPE‐1 (hTERT-immortalized), were treated with TMPyP4 (5 μM) and TQ (10 μM). Both inhibitors decreased telomerase activity. TMPyP4 increased the percentage of cells with membrane damage associated with cell death and decreased the frequency of cells in the S‐phase. TMPyP4 reduced cell adhesion ability and modified the pattern of focal adhesion. TQ acted in a concentration-dependent manner, increasing the frequency of senescent cells and inducing cell cycle arrest in G1 phase. Thus, the present results showed that TMPyP4 and TQ, although acting as telomerase inhibitors, had a broader effect on other signaling pathways and processes in cells, differing from each other. However, they act both on malignant and immortalized cells, and further studies are needed before their anti-cancer potential can be considered.

The effects of metformin, acetylsalicylic acid and ibuprofen on telomerase enzyme activity: inhibitory effect of ibuprofen

Abstract Telomerase enzyme is necessary for the elongation of telomeres while telomerase being critical for aging and cancer. Metformin, ibuprofen, and acetylsalicylic acid used in this research are drugs that millions of people already use and that many are likely to use in future. In this study, the effects of these drugs on telomerase activity of Mus musculus swiss albino mice in liver tissue were investigated and the telomerase activity was measured with a PCR-ELISA based kit. In the study a possible connection between telomerase enzyme activity and activities of antioxidant enzymes was also investigated by determining the activity of superoxide dismutase (SOD) and catalase enzymes. The data obtained show that metformin slightly decreased telomerase enzyme activity in low dose application; however, this change was not statistically significant. In ibuprofen application, there was a significant inhibitory effect when high doses were used; whereas, there was a slight inhibitory effect at low doses. In acetylsalicylic acid application, a slight activator effect was detected; it was not statistically significant, though. Metformin was observed to increase catalase and SOD activities in general while low and high doses of acetyl salicylic acid showed different effects. In addition, ibuprofen caused a statistically significant increase in liver SOD values. It is important to note that this study demonstrated a significant inhibitory effect of ibuprofen on telomerase enzyme activity in animal models..

Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado / Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were the only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Estratégias anti-aging baseadas em moléculas químicas naturais como potentes ativadores de telomerase / Anti-aging strategies based on natural chemical molecules as potent telomerase activators / Estrategias antienvejecimiento basadas en moléculas químicas naturales como potentes activadores de la telomerasa

Mesmo em tempos modernos, os grandes avanços tecnológicos não permitem de forma comprovada retardar o envelhecimento nos seres humanos. Neste sentido, uma das estratégias é o uso moléculas químicas naturais que possuem a ação de ativadores de telomerase, uma vez de que a telomerase é uma ribonucleoproteína transcriptase reversa que possui a função de alongar os telômeros e neutralizar a erosão normal dos telômeros. Neste contexto, este estudo de revisão dedicou-se a aprofundar o conhecimento sobre o uso de moléculas químicas naturais derivadas de plantas que possuem função de ativadores de telomerase para atividade anti-aging. Inúmeras moléculas têm sido propostas e, estudas os seus mecanismos com o intuito de desenvolver novas ferramentas para prevenir/retardar e tratar doenças relacionadas a idade e o envelhecimento. Adicionalmente, o uso de moléculas como ativadores da telomerase têm sido um meio de prolongar o encurtamento dos temoleros, como no caso, de moléculas isolada da erva Astragalus membranaceus (TA-65), curcumina, silbinina e alicina; ademais, outras moléculas de origem natural possuem atividade anti-aging comprovadas, conforme reportadas nesta revisão. Sendo assim, a procura por biomarcadores à base de compostos químicos naturais que estimulem a telomerase, a fim de prolongar a vida dos telômero e assim, retardar o processo de envelhecimento do organismo têm despertado o interesse de diversos pesquisadores ao redor do mundo.

Even in modern times, the great technological advances do not allow in a proven way to delay aging in humans. In this sense, one of the strategies is the use of natural chemical molecules that have telomerase activators, since telomerase is a ribonucleoprotein reverse transcriptase that has the function of lengthening telomeres and neutralizing the normal erosion of telomeres. In this context, this review study was dedicated to deepening the knowledge about the use of natural chemical molecules derived from plants that have telomerase activator function for anti-aging activity. Numerous molecules have been proposed and their mechanisms studied in order to develop new tools to prevent/delay and treat aging-related diseases. Additionally, the use of molecules as telomerase activators has been a means of prolonging the shortening of temolers, as in the case of molecules isolated from the herb Astragalus membranaceus (TA-65), curcumin, silbinin and allicin; in addition, other molecules of natural origin have proven anti-aging activity, as reported in this review. Therefore, the search for biomarkers based on natural chemical compounds that stimulate telomerase in order to prolong the life of telomeres and, thus delay the aging process of the organism has aroused the interest of several researchers around the world.

Aún en los tiempos modernos, los grandes avances tecnológicos no permiten de manera comprobada retrasar el envejecimiento en los humanos. En este sentido, una de las estrategias es el uso de moléculas químicas naturales que tengan activadores de la telomerasa, ya que la telomerasa es una ribonucleoproteína transcriptasa inversa que tiene la función de alargar los telómeros y neutralizar la erosión normal de los telómeros. En este contexto, este estudio de revisión se dedicó a profundizar en el conocimiento sobre el uso de moléculas químicas naturales derivadas de plantas que tienen función activadora de la telomerasa para la actividad antienvejecimiento. Se han propuesto numerosas moléculas y se han estudiado sus mecanismos para desarrollar nuevas herramientas para prevenir/retrasar y tratar enfermedades relacionadas con el envejecimiento. Adicionalmente, el uso de moléculas como activadores de la telomerasa ha sido un medio para prolongar el acortamiento de temolers, como es el caso de moléculas aisladas de la hierba Astragalus membranaceus (TA-65), curcumina, silbinina y alicina; además, otras moléculas de origen natural han demostrado actividad antienvejecimiento, como se reporta en esta revisión. Por ello, la búsqueda de biomarcadores basados en compuestos químicos naturales que estimulen la telomerasa para prolongar la vida de los telómeros y así retrasar el proceso de envejecimiento del organismo ha despertado el interés de varios investigadores a nivel mundial.

Clinical significance of telomerase reverse transcriptase promoter mutation in radioactive iodine refractory papillary thyroid cancer / 中华核医学与分子影像杂志

Objective:To evaluate the influence of telomerase reverse transcriptase (TERT) promoter mutation on radioiodine uptake status of radioactive iodine refractory papillary thyroid cancer (RAIR-PTC) and radioiodine therapy response by analyzing the mutation frequency of TERT promoter in RAIR-PTC.Methods:A total of 37 patients with RAIR-PTC (15 males, 22 females, age (49.8±16.1) years) and 40 PTC patients with effective radioiodine therapy (13 males, 27 females, age (39.8±10.9) years) between January 2005 and June 2020 in JiangYuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine were retrospectively analyzed. TERT promoter mutation and B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation of patients were observed. The differences across genotype patterns on radioiodine uptake status and therapy response were compared. The Fisher′s exact test and independent-sample t test were used for data analysis. Results:The incidence rate of TERT promoter mutation in the RAIR-PTC group was 40.54% (15/37, all C228T), which was significantly higher than that in the effective radioiodine therapy group (0, 0/40; P<0.001). No statistically significant difference was found for the mutation rate of BRAF V600E between the RAIR group (64.86%, 24/37) and the effective radioiodine therapy group (72.50%, 29/40; P=0.858). Patients with TERT promoter mutation were older ( t=3.76, P=0.001) and the non-intake rate of radioiodine in distant metastases of those patients was higher ( P=0.037). Furthermore, 2/3 of patients who received targeted therapies and 3/4 deaths had TERT promoter mutation. Among 35 patients with negative thyroglobulin antibody (TgAb), 11/14 of patients with TERT mutation had a rising stimulated thyroglobulin (sTg), while the percentage of the non-TERT mutation group was 57.1% (12/21; P=0.357). Conclusion:The TERT promoter mutation rate is significantly increased in RAIR-PTC patients and can serve as a prognostic predictor in RAIR.

Role of telomerase reverse transcriptase on cell apoptosis of neutrophils in rats with acute necrotizing pancreatitis / 中华胰腺病杂志

Objective:To investigate the effects of telomerase reverse transcriptase (TERT) on neutrophils apoptosis in rats with acute necrotizing pancreatitis (ANP).Methods:Twenty-four Sprague Dawley (SD) rats were randomly divided into three groups including control group, ANP (3h、6h) group and TERT inhibitor(BIBR1532)group using random number method with 6 in each group. ANP rats were induced by retrograde injection of 5% sodium taurocholate into the pancreaticcobiliary duct. After 3 and 6 hours, the fresh neutrophils were collected and isolated from peripheral blood of ANP rats. Rats were intraperitoneally injected with 2 mg/kg BIBR1532. After ANP modeling for 3 h, rats were killed and peripheral neutrophils were collected. Subsequently, the expression of TERT mRNA in neutrophils was tested by real-time quantitative PCR; the protein levels of TERT, BCL-xL and Bax were determined by Western blotting; neutrophil apoptosis was detected by flow cytometry; TNF-α and IL-6 were assayed by Elisa; the rat pancreatic tissue was pathologically examined.Results:In neutrophils from control group, ANP 3 h group, ANP 6 h group and BIBR1532 group, TERT mRNA was 1.03±0.26, 3.31±1.07, 5.21±0.78 and 1.95±0.49; TERT protein expression was 0.09±0.03, 0.43±0.12, 0.58±0.11 and 0.22±0.07; Bcl-xL protein expression was 0.19±0.05, 0.50±0.07, 0.85±0.04 and 0.40±0.11; Bax protein expression was 0.29±0.08, 0.23±0.03, 0.17±0.02 and 0.43±0.12; apoptosis rate was 10.03±0.74%, 7.99±0.27%, 6.65±0.36% and 22.98±2.86%. TERT mRNA and protein expression and Bcl-xL protein expression in ANP 3 h and 6 h group were higher than those in control group, but Bax preotein expression and apoptosis rate were lower than those in control group; TERT mRNA and protein expression and Bcl-xL protein expression in BIBR1532 group were lower than those in ANP 3 h group, but Bax protein expression and apoptosis rate in BIBR1532 group were higher than those in ANP 3 h group; and all the differences were statistically significant (all P value <0.05). The level of TNF-α was [(96.67±27.12)ng/L, (382.30±46.33)ng/L and (206.88±36.42)ng/L], IL-6 was [(43.34±14.50)ng/L, (134.21±16.13)ng/L and (88.06±13.05)ng/L in control, ANP 3 h and BIBR1532 group; those in ANP 3 h group were all higher than those in control group, but those in BIBR1532 group were lower than those in ANP 3 h group; all the differences were statistically significant (all P value <0.05). Compared with ANP group, the morphology of pancreatic tissue was obviously alleviated in BIBER1532 group. Conclusions:TERT expression is obviously increased in peripheral neutrophils in ANP rats, and apoptosis rate of neutrophils from ANP rats is greatly increased after TERT inhibitor treatment, demonstrating that TERT could inhibit the apoptosis of peripheral neutrophil in ANP rats.

Telomere length: biological marker of cellular vitality, aging, and health-disease process

SUMMARY The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.

Clinical Application and Challenges of Telomere and Telomerase Research in Lung Cancer / 中国肺癌杂志

Lung cancer is one of the malignant tumors with high incidence rate and high mortality worldwide. Telomere and telomerase are closely related to the occurrence and development of lung cancer. Although telomerase may not be the direct cause of carcinogenesis, it plays a key role in maintaining telomere length and tumor growth. The length of most tumors, including lung cancer, is shortened. The change of telomere length is related to the risk of lung cancer, and may become the therapeutic target and predictive index. Target drugs for telomere and telomerase signaling pathway are constantly being explored, and drugs represented by telomerase inhibitors are expected to be used in clinical treatment of lung cancer in the future. However, the research on telomere and telomerase is far from enough. The bypass mechanism of telomere length maintenance may be the direction of further research.
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Telomere length and telomerase: early biomarkers for environmental carcinogen exposure / 中国职业医学

Telomere is a DNA-protein complex located at the end of linear chromosome of eukaryotic cells, which has the function of stabilizing chromosome. The change of telomere length is closely related to the exposure to environmental carcinogens. The repair and elongation of telomere rely on the catalysis and mediation of telomerase. Exposure to typical environmental carcinogens polycyclic aromatic hydrocarbons(PAHs) can affect the change of telomere length by regulating the expression of telomere-related genes. Long-term exposure to PAHs can shorten the telomeres of peripheral blood leukocytes in a dose-response relationship. Telomere dysfunction is one of the important mechanisms of arsenic poisoning. The change of telomere length can be used as a biomarker of arsenic exposure. However, there are differences in the research results on the effect of arsenic exposure on telomere length, so the consistency of the effect of arsenic exposure on telomere length and the possible mechanism need to be further studied. Exposure to atmospheric fine particulate matter can attack genetic material by inducing oxidative stress and inflammatory response in the body, and then affect the telomere length of cells in vivo. Acute particulate matter exposure can increase telomere length in a short time(a few hours to a few days), and subsequent telomere shortening may be related to the inflammatory mechanism. Telomere length and telomerase activity can be used as biomarkers and play an important role in monitoring early carcinogenesis, diagnosis and prognosis assessment of cancers caused by environmental carcinogens.

Research progress on influencing factors of female telomere-telomerase system in critical period / 中国临床药理学与治疗学

The telomere/telomerase system, as a biological marker of aging, plays an important role in maintaining woman's health. The vulnerability of telomere-telomerase system is heightened in female during puberty, pregnancy and perimenopause period, which not only affect themselves, but also affect the healthy growth of offspring. Therefore, the purpose of this article is to provide basis for intervention time and method for delaying women aging due to the effects of estrogen levels, dietary, stress, movement, insulin resistance and sleep on the telomere/telomerase system during puberty, pregnancy and perimenopausal period.

Cost-Effective Trap qPCR Approach to Evaluate Telomerase Activity: an Important Tool for Aging, Cancer, and Chronic Disease Research

OBJECTIVES: Telomeres are a terminal "DNA cap" that prevent chromosomal fusion and degradation. However, aging is inherent to life, and so is the loss of terminal sequences. Telomerase is a specialized reverse transcriptase encoded by self-splicing introns that counteract chromosome erosion. Telomerase activity is observed during early embryonic development, but after the blastocyst stage, the expression of telomerase reduces. The consequences of either insufficient or unrestrained telomerase activity underscore the importance of ongoing studies aimed at elucidating the regulation of telomerase activity in humans. In the present study, we aimed to standardize a simplified telomerase repeat-amplification protocol (TRAP) assay to detect telomerase activity in unstimulated and PHA-stimulated mononuclear cells. METHODS and RESULTS: Our optimized qPCR-based can efficiently evaluate telomerase activity. Quantification of protein and DNA between unstimulated and PHA-stimulated peripheral blood mononuclear cells revealed cellular activation and cell-cycle entry. The assay also showed that relative telomerase activity is significantly different between these two conditions, supporting the applicability of the assay. Furthermore, our findings corroborated that telomerase activity decreases with age. CONCLUSIONS: Telomeres and telomerase are implicated in aging and development of chronic diseases and cancer; however, difficulty in accessing commercial kits to investigate these aspects is a critical constraint in health surveillance studies. Our optimized assay was successfully used to differentiate telomerase activity between unstimulated and stimulated cells, clearly showing the reactivation of telomerase upon cell activation. This assay is affordable, reproducible, and can be executed in resource-limited settings.

Acortamiento de telómeros en enfermedades neurodegenerativas: implicaciones terapéuticas / Telomere attrition in neurodegenerative disorders: therapeutic implications

Introducción: Varias enfermedades neurodegenerativas están asociadas a la ocurrencia de acortamiento de los telómeros, y los convierten en biomarcadores y dianas terapéuticas potenciales. Objetivo: Reflejar la relevancia del acortamiento de los telómeros para enfermedades neurodegenerativas, y destacar sus implicaciones Material y métodos: Se realizó una revisión bibliográfica durante los meses de septiembre de 2019 a enero de 2020. Fueron consultadas bases de datos de referencia, con el uso de descriptores y operadores booleanos. La estrategia de búsqueda avanzada para la selección de los artículos fue empleada, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias sólidas de asociación entre el acortamiento de los telómeros y las enfermedades de Alzheimer y Huntington, que sugieren un papel relevante de la biología de los telómeros en la fisiopatología de estas enfermedades. Las evidencias disponibles hasta el momento no permiten establecer la relevancia de la biología de los telómeros en la fisiopatología de la Enfermedad de Parkinson o de la esclerosis lateral amiotrófica. Se obtuvieron evidencias de la utilidad de terapias orientadas a la prevención del acortamiento de los telómeros para el tratamiento de enfermedades neurodegenerativas. Conclusiones: El acortamiento de los telómeros es de relevancia fisiopatológica y clínica para las enfermedades de Alzheimer y Huntington, mientras que existen evidencias insuficientes para establecer su importancia en la Enfermedad de Parkinson y la esclerosis lateral amiotrófica. El uso de estrategias para estimular la actividad de la telomerasa tiene potenciales aplicaciones terapéuticas en el contexto de enfermedades neurodegenerativas(AU)

Introduction: Several neurodegenerative disorders are associated with telomere attrition, turning telomeres into potential biomarkers and potential therapeutic targets. Objective: To assess the relevance of telomere attrition for neurodegenerative disorders, highlighting its therapeutic implications. Material and methods: A literature review was carried out from September 2019 to January 2020. Several databases were searched by using descriptors and Boolean operators. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence for an association between telomere attrition and Alzheimer and Huntington diseases was obtained, suggesting a potential importance of telomere biology in the physiopathology of these diseases. Current evidence does not allow establishing the relevance of telomere attrition in the physiopathology of Parkinson´s disease or Amyotrophic Lateral Sclerosis. Evidence was obtained for the usefulness of therapies for the prevention of telomere attrition in the treatment of neurodegenerative disorders. Conclusions: Telomere attrition has physiopathological and clinical relevance in Alzheimer´s and Huntington´s diseases, though current evidence is not enough to establish its role in Parkinson's disease and Amyotrophic Lateral Sclerosis. Strategies that enhance telomerase activity have therapeutic potential in the context of neurodegenerative disorders(AU)

Relationship between BRAF V600E, TERT promoter mutations and the clinicopathological features of papillary thyroid carcinoma / 中国肿瘤临床

Objective: To explore the relationship between TERT promoter mutations and BRAF V600E as well as their coexistence with the clinicopathological features of papillary thyroid cancer (PTC). Methods: A total of 728 patients enrolled in Shanxi Cancer Hospital from December 2014 to December 2016 with PTC were retrospectively analyzed. We reviewed and analyzed the clinical results, pathology records, ultrasound results, and BRAF V600E and TERT status. Results: BRAF V600E mutations were found in 42.3% (308 of 728) of patients, and TERT C228T and C250T promoter mutations were found in 10.7% (78 of 728) and 0.5% (4 of 728) of patients, respectively. The TERT promoter mutation was significantly associated with old age (P=0.034), extrathyroidal invasion (P=0.026), large tumor size (P=0.028), cervical lymph node metastasis (P=0.012), distant metastasis (P=0.001), advanced disease stages (P<0.001), histological type (P=0.003) and recurrence (P=0.002). The BRAF V600E mutation was significantly associated with extrathyroidal invasion (P= 0.001), large tumor size (P<0.001), Hashimoto thyroiditis (P<0.001), distant metastasis (P=0.010), advanced disease stages (P=0.009) and recurrence (P=0.001). The coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, such as old age (P=0.024), extrathyroidal invasion (P=0.022), Hashimoto thyroiditis (P=0.005), the cervical lymph node (P=0.018), and advanced disease stages (P=0.002). Conclusions: Our study demonstrates that BRAF V600E and TERT promoter mutations play a significant role in the aggressiveness of PTC, particularly when the two mutations coexist. The results reveal the significant role of these mutations in the treatment and prognosis prediction of PTC.

Serum hTERT Level as Sensitive Biomarker With Prognostic Implications in Breast, Lung, Gastric and Liver Cancers

@#Human telomerase reverse transcriptase (hTERT) plays an important role in telomere restitution and gene regulation. Evidences suggest that hTERT is linked with the risk and progression of several types of malignancies. Detection of hTERT mRNA levels, as one of tumor markers, may reflect the tumor burden and the clinical status of the patient. Present paper emphasizes the potency of hTERT mRNA detection in serum as a sensitive tumor biomarker in different types of cancer. Detection of serum hTERT mRNA levels has been found highly sensitive and specific for varied cancers. A number of reports reflect its superiority to other conventional tumor markers including alfa-fetoprotein, EGFR, lens culinaris agglutinin-reactive AFP and Des-gamma carboxy prothrombin. Serum hTERT has been found linked with the risk and progression of different cancer types. hTERT levels in combination with other tumor markers may be used to improve cancer detection, tumor size and level of cancer progression.