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Rev. Asoc. Méd. Argent ; 137(1): 4-10, mar. 2024.
Article in Spanish | LILACS | ID: biblio-1552830


Se exponen los hallazgos históricos y la importancia biológica de los telómeros en la vida celular y en los aspectos genéticos del ADN humano. (AU)

The discovery and the biological importance of the telomeres are exposed. (AU)

Humans , DNA/genetics , Telomere/physiology , Telomere/genetics , Telomerase/physiology , Telomerase/genetics , Aging/physiology , DNA/metabolism , Cellular Senescence , Telomerase/metabolism , DNA Replication/physiology , Telomere Shortening , Neoplasms/physiopathology
Cambios rev. méd ; 22 (2), 2023;22(2): 919, 16 octubre 2023. ilus, tabs
Article in Spanish | LILACS | ID: biblio-1516520


El envejecimiento y la longevidad son procesos que involucran una serie de factores genéticos, bioquímicos y ambientales. En esta revisión se tratan algunas cuestiones sobre estos dos procesos biológicos y epigenéticos. Se presentan los genes más importantes en estos procesos, así como se ejemplifican enfermedades que presentan un aceleramiento o falla en la longevidad y el envejecimiento. Se usa el análisis inteligente de datos para hallar interacciones de proteínas/genes que expliquen estos dos fenómenos biológicos.

Aging and longevity are processes that involve a series of genetic, biochemical and environmental factors. This review addresses some issues about these two biological and epigenetic processes. The most important genes in these processes are presented, as well as diseases that present an acceleration or failure in longevity and aging. Intelligent data analysis is used to find protein/gene interactions that explain these two biological phenomena.

Humans , Male , Female , Aged , Aged, 80 and over , Biological Phenomena , Aging , Cellular Senescence , Genes , Genetics , Longevity , Quality of Life , Life Expectancy , Apoptosis , Oxidative Stress , Telomerase , Aging, Premature , Ecuador , Immune System , Metabolism
Chinese Journal of Biotechnology ; (12): 1609-1620, 2023.
Article in Chinese | WPRIM | ID: wpr-981157


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.

Animals , Mice , Telomerase/metabolism , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Telomere Shortening , In Situ Hybridization, Fluorescence , Mice, Nude , Telomere/pathology , Carcinogenesis
Chinese Journal of Pathology ; (12): 153-159, 2023.
Article in Chinese | WPRIM | ID: wpr-970150


Objective: To investigate the pathological features and the clinicopathological significance of TERT detection in those tumors that were difficult to diagnosis. Methods: A total of 93 cases of fibroepithelial tumors without definite diagnosis were collected from the Affiliated Hospital of Qigndao University between 2013 and 2021. The clinical details such as patients' age and tumor size were collected. All slides were re-reviewed and the pathologic parameters, including stromal cellularity, stromal cell atypia, stromal cell mitoses, and stromal overgrowth were re-interpreted. Sanger sequencing was used to detect TERT promoter status, and immunohistochemistry was performed to detect TERT protein expression. The relationship between TERT promoter mutation as well as protein expression levels and the clinicopathological parameters were also analyzed. Results: The patients' ages ranged from 30 to 71 years (mean of 46 years); the tumor size ranged from 1.2 to 8.0 cm (mean 3.8 cm). These tumors showed the following morphologic features: leafy structures in the background of fibroadenoma, or moderately to severely abundant stromal cells. The interpretations of tumor border status were ambiguous in some cases. The incidence of TERT promoter mutation was high in patients of age≥50 years, tumor size≥4 cm, and stromal overgrowth at ×4 or ×10 objective, and these clinicopathologic features were in favor of diagnosis of phyllodes tumors. TERT protein expression levels was not associated with the above clinicopathologic parameters and its promoter mutation status. Conclusions: The diagnostic difficulty for the breast fibroepithelial tumors is due to the difficulty in recognition of the leafy structures or in those cases with abundant stromal cells. A comprehensive evaluation combined with morphologic characteristics and molecular parameters such as TERT promoter may be helpful for the correct diagnosis and better evaluating recurrence risk.

Humans , Adult , Middle Aged , Aged , Female , Neoplasms, Fibroepithelial/pathology , Phyllodes Tumor/genetics , Stromal Cells , Fibroadenoma/pathology , Breast Neoplasms/pathology , Mutation , Telomerase/genetics
Chinese Journal of Pathology ; (12): 1216-1222, 2023.
Article in Chinese | WPRIM | ID: wpr-1012396


Objective: To investigate the gene mutation of telomerase reverse transcriptase (TERT) promoter in inverted urothelial lesions of the bladder and its significance in differential diagnosis. Methods: From March 2016 to February 2022, a total of 32 patients with inverted urothelial lesions diagnosed in Department of Pathology at Qingdao Chengyang People's Hospital and 24 patients at the Affiliated Hospital of Qingdao University were collected, including 7 cases of florid glandular cystitis, 13 cases of inverted urothelial papilloma, 8 cases of inverted urothelial neoplasm with low malignant potential, 17 cases of low-grade non-invasive inverted urothelial carcinoma, 5 cases of high-grade non-invasive inverted urothelial carcinoma, and 6 cases of nested subtype of urothelial carcinoma were retrospectively analyzed for their clinical data and histopathological features. TERT promoter mutations were analyzed by Sanger sequencing in all the cases. Results: No mutations in the TERT promoter were found in the florid glandular cystitis and inverted urothelial papilloma. The mutation rates of the TERT promoter in inverted urothelial neoplasm with low malignant potential, low grade non-invasive inverter urothelial carcinoma, high grade non-invasive inverted urothelial carcinoma and nested subtype urothelial carcinoma were 1/8, 8/17, 2/5 and 6/6, respectively. There was no significant difference in the mutation rate of TERT promoter among inverted urothelial neoplasm with low malignant potential, low-grade non-invasive inverted urothelial carcinoma, and high-grade non-invasive inverted urothelial carcinoma (P>0.05). All 6 cases of nested subtype of urothelial carcinoma were found to harbor the mutation, which was significantly different from inverted urothelial neoplasm with low malignant potential and non-invasive inverted urothelial carcinoma (P<0.05). In terms of mutation pattern, 13/17 of TERT promoter mutations were C228T, 4/17 were C250T. Conclusions: The morphology combined with TERT promoter mutation detection is helpful for the differential diagnosis of bladder non-invasive inverted urothelial lesions.

Humans , Urinary Bladder Neoplasms/genetics , Carcinoma, Transitional Cell/pathology , Urinary Bladder/pathology , Diagnosis, Differential , Retrospective Studies , Mutation , Cystitis/genetics , Neoplasms, Glandular and Epithelial/diagnosis , Papilloma/diagnosis , Telomerase/genetics
Braz. J. Pharm. Sci. (Online) ; 59: e21233, 2023. tab, graf
Article in English | LILACS | ID: biblio-1429964


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..

Animals , Male , Female , Mice , Aspirin/adverse effects , Ibuprofen/adverse effects , Telomerase/analysis , Metformin/adverse effects , Catalase
Biomédica (Bogotá) ; 42(4): 574-590, oct.-dic. 2022. tab, graf
Article in Spanish | LILACS | ID: biblio-1420307


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.

Meningioma , Telomerase , Gain of Function Mutation
Arq. ciências saúde UNIPAR ; 26(3): 1229-1247, set-dez. 2022.
Article in Portuguese | LILACS | ID: biblio-1414495


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.

Biological Products , Aging/drug effects , Telomerase , DNA , Telomere , Astragalus propinquus , Curcuma/drug effects
Journal of Zhejiang University. Science. B ; (12): 158-163, 2022.
Article in English | WPRIM | ID: wpr-929047


At present, endometriosis remains a worldwide health burden, with the main symptoms of dysmenorrhea, chronic pelvic pain, and infertility, markedly reducing the quality of life (de Ziegler et al., 2010). Although there is no proof that the disease is associated with high mortality, this disorder can significantly contribute to the deterioration of women's general well-being (McPeak et al., 2018). The main current treatment for endometriosis is surgery to remove endometriotic lesions; however, the recurrence rate following surgical treatment is as high as 21.5% at two years and 40.0%‍-‍50.0% at five years post-surgery (Koga et al., 2015). To prevent recurrence, adjuvant treatment with drugs after surgery is recommended to prolong relapse-free intervals. However, it is inconvenient for patients to continuously use such medications in terms of adverse effects and cost (Turk, 2002).

Female , Humans , Endometriosis/pathology , Endometrium/pathology , Ki-67 Antigen/metabolism , Quality of Life , Recurrence , Telomerase/metabolism , Up-Regulation
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(3): 480-484, dez 20, 2021. fig
Article in Portuguese | LILACS | ID: biblio-1354354


Introdução: o gene TERT codifica a subunidade catalítica da telomerase responsável pelo alongamento dos telômeros no final dos cromossomos. Mutações na região promotora do gene TERT resultam em superexpressão da subunidade catalítica e promovem aumento da atividade da telomerase, fatos que levam ao aumento da incidência do câncer. No carcinoma anaplásico da tireoide, essas mutações são preditores de pior prognóstico e estão associadas a comportamento clínico agressivo, incluindo alta frequência de recidivas, metástases a distância e morte específica pela doença. Objetivo: relatar o caso de uma paciente idosa portadora de carcinoma anaplásico da tireoide, cujo teste de sequenciamento genético revelou a mutação do promotor TERT C228T. Caso clínico: mulher idosa, 66 anos, diagnosticada inicialmente com nódulo tireoidiano, o qual cresceu rapidamente em um curto período de tempo. Diante da suspeita de neoplasia maligna, a paciente foi submetida a tireoidectomia total, com realização de esvaziamento cervical. Os estudos anatomopatológico e imuno-histoquímico do tumor confirmaram o carcinoma. Estudos moleculares realizados a partir da tecnologia do sequenciamento de nova geração negaram a presença de fusões gênicas, porém detectaram a mutação TERT C228T. Discussão: a identificação da mutação no promotor TERT C288T reforça a hipótese de que mutações TERT são frequentes em tumores tireoidianos mais agressivos, como é o caso do carcinoma anaplásico da tireoide. Conclusão: os dados apresentados neste estudo reforçam a premissa de que mutações no promotor TERT são preditores de pior prognóstico e de comportamento clínico mais agressivo.

Introduction: the TERT gene encodes the catalytic telomerase subunit responsible for elongating telomeres at the end of chromosomes. Mutations in the promoter region of the TERT gene result in overexpression of the catalytic subunit and promote increased telomerase activity, facts that lead to an increased incidence of cancer. In anaplastic thyroid carcinoma, these mutations are predictors of worse prognosis and are associated with aggressive clinical behavior, including a high frequency of relapses, distant metastases, and diseasespecific death. Objective: to report the case of an elderly patient with anaplastic thyroid carcinoma, whose gene sequencing test revealed a TERT C228T promoter mutation. Case report: Elderly woman, 66 years old, initially diagnosed with a thyroid nodule, which grew rapidly in a short period of time. Given the suspicion of malignant neoplasm, the patient underwent total thyroidectomy, with neck dissection. The anatomopathological and immunohistochemical studies of the tumor confirmed the carcinoma. Molecular studies performed using next-generation sequencing technology denied the presence of gene fusions, but detected the TERT C228T mutation. Discussion: identification of the mutation in the TERT C288T promoter reinforces the hypothesis that TERT mutations are frequent in more aggressive thyroid tumors, such as anaplastic thyroid carcinoma. Conclusion: data presented in this study reinforce the premise that mutations in the TERT promoter are predictors of worse prognosis and more aggressive clinical behavior.

Humans , Female , Aged , Thyroidectomy , Telomerase , Thyroid Carcinoma, Anaplastic , Mutation , Genes
Arq. bras. neurocir ; 40(2): 186-189, 15/06/2021.
Article in English | LILACS | ID: biblio-1362256


The most common mixed glioma encountered in routine surgical practice is oligoastrocytoma (OA); however, its is currently considered a vanishing entity. The 2016 classification of the World Health Organization (WHO) discourages the diagnosis of tumors as mixed glioma. The recommendations are that diffuse gliomas, including those withmixed or ambiguous histological features, should be subjected tomolecular testing. Dual-genotype OAs are not yet a distinct entity or variant in the classification. We report a case ofmixed glioma: a pleomorphic xanthoastrocytoma (PXA)mixed with an oligodendroglioma. The immunohistochemistry (IHC) pattern of isocitrate dehydrogenase 1 (IDH1) negativity with retained nuclear expression of the alpha-thalassemia x-linked intellectual disability syndrome (ATRX) protein, and 1p19q co-deletion negativity in both the components enabled its identification as a mixed glioma rather than a collision tumor. To the best of our knowledge, the case herein presented is the fourth case of PXA with oligodendroglioma. Out of the other three reported cases, only one was of a collision tumor with a dual genotype, and the other two showed similar molecular signatures in both components. The present article discusses the histological, immunohistochemical and molecular features of the aforementioned case.

Humans , Male , Adult , Oligodendroglioma/surgery , Astrocytoma/surgery , Brain Neoplasms/therapy , Neoplasms, Multiple Primary/surgery , Oligodendroglioma/pathology , Oligodendroglioma/diagnostic imaging , Astrocytoma/pathology , Temporal Lobe/surgery , Aconitate Hydratase/genetics , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 19 , Chromosome Deletion , Telomerase/genetics , Craniotomy/methods
Clinics ; 76: e2432, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153954


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.

Humans , Female , Pregnancy , Telomerase/genetics , Telomerase/metabolism , Neoplasms , Aging , Leukocytes, Mononuclear/metabolism , Chronic Disease , Cost-Benefit Analysis
Braz. j. med. biol. res ; 54(11): e11352, 2021. tab, graf
Article in English | LILACS | ID: biblio-1339450


Diabetes mellitus is associated with neural and micro- and macrovascular complications. Therapeutic options for these complications are limited and the delivery of mesenchymal stem cells into lesions have been reported to improve the healing process. In this work, the effects of the administration of a lineage of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase (hBMSC-TERT) as a potential therapeutic tool for wound healing in diabetic rats were investigated. This is the first description of the use of these cells in diabetic wounds. Dorsal cutaneous lesions were made in streptozotocin-induced diabetic rats and hBMSC-TERT were subcutaneously administered around the lesions. The healing process was evaluated macroscopically, histologically, and by birefringence analysis. Diabetic wounded rats infused with hBMSC-TERT (DM-TERT group) and the non-diabetic wounded rats not infused with hBMSC-TERT (CW group) had very similar patterns of fibroblastic response and collagen proliferation indicating improvement of wound healing. The result obtained by birefringence analysis was in accordance with that obtained by the histological analysis. The results indicated that local administration of hBMSC-TERT in diabetic wounds improved the wound healing process and may become a therapeutic option for wounds in individuals with diabetes.

Humans , Animals , Rats , Telomerase , Diabetes Mellitus, Experimental , Mesenchymal Stem Cells , Wound Healing , Streptozocin
Journal of Experimental Hematology ; (6): 1056-1064, 2021.
Article in Chinese | WPRIM | ID: wpr-888518


OBJECTIVE@#To investigate the cytotoxic effect and its mechanism of the micromolecule compound on the leukemia cells.@*METHODS@#The cytotoxic effects of 28 Nilotinib derivatives on K562, KA, KG, HA and 32D cell lines were detected by MTT assays, and the compound Nilo 22 was screen out. Cell apoptosis and cell cycle on leukemia cells were detected by flow cytometry. The effect of compound screened out on leukemogenesis potential of MLL-AF9 leukemia mice GFP@*RESULTS@#Nilo 22 serves as the most outstanding candidate out of 28 Nilotinib derivatives, which impairs leukemia cell lines, but spares normal hematopoietic cell line. Comparing with Nilotinib, Nilo 22 could induce the apoptosis of GFP@*CONCLUSION@#Nilo 22 shows a significant cytotoxic effect on mice and human leukemia cells, especially for drug resistance cells. Nilo 22 is a promising anti-leukemia agent to solve the common clinical problems of drug resistance and relapse of leukemia.

Animals , Humans , Mice , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Leukemia , Myeloid-Lymphoid Leukemia Protein/genetics , Telomerase/metabolism , Telomere/metabolism
Homeopatia Méx ; 89(720): 12-17, ene.-mar. 2020.
Article in Spanish | HomeoIndex, LILACS | ID: biblio-1147377


El proceso de envejecimiento se produce por la disminución de las funciones fisiológicas y de la capacidad de adaptación del organismo, siendo influenciado por la genética y el estilo de vida. Actualmente, con los avances de la genética, el envejecimiento biológico se puede calcular por la longitud de los telómeros ('telomere lenght'). Los telómeros son regiones en los extremos de los cromosomas que juegan un papel en el mantenimiento y la integridad del ADN. Con el envejecimiento biológico, se produce el acortamiento de los telómeros, causando la senescencia celular. Numerosos estudios evidencian que telómeros más cortos están asociados a enfermedades crónicas, a vicios y a intoxicaciones. Por otro lado, hábitos de vida saludables propician el aumento de la longitud de los telómeros y el equilibrio de las diversas funciones celulares, previniendo enfermedades. Por lo tanto, los telómeros funcionan como un biomarcador de la vitalidad del organismo.(AU)

Aging , Chronic Disease , Telomere , Telomerase , Homeopathy
Arch. endocrinol. metab. (Online) ; 63(2): 107-112, Mar.-Apr. 2019. tab, graf
Article in English | LILACS | ID: biblio-1001216


ABSTRACT Objectives: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation. Subjects and methods: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations. Results: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation. Conclusions: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.

Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Young Adult , Thyroid Neoplasms/genetics , Thyroid Nodule/genetics , Telomerase/genetics , Proto-Oncogene Proteins B-raf/genetics , Thyroid Cancer, Papillary/genetics , Prognosis , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/pathology , DNA Mutational Analysis , Predictive Value of Tests , Age Factors , Promoter Regions, Genetic/genetics , Thyroid Nodule/diagnosis , Thyroid Nodule/pathology , Biopsy, Fine-Needle , Preoperative Period , Thyroid Cancer, Papillary/diagnosis , Thyroid Cancer, Papillary/pathology , Lymphatic Metastasis/diagnosis , Mutation/genetics , Neoplasm Staging
Clinical Psychopharmacology and Neuroscience ; : 343-363, 2019.
Article | WPRIM | ID: wpr-763558


Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell’s mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

Aged , Humans , Aging , Apoptosis , Biology , Bipolar Disorder , Brain , Cellular Senescence , Cell Division , Comprehension , Depressive Disorder, Major , Genomic Instability , Inflammation , Leukocytes , Monocytes , Mood Disorders , Mortality , Oxidative Stress , Schizophrenia , Telomerase , Telomere Shortening , Telomere
Nutrition Research and Practice ; : 58-63, 2019.
Article in English | WPRIM | ID: wpr-741693


BACKGROUND/OBJECTIVES: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model. MATERIALS/METHODS: CD133+CD44+ cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 µg/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt ). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt ). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR. RESULTS: Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 ± 0.13 at 0 µg/mL, 4.79 ± 0.12 at 10 µg/mL, 3.24 ± 0.08 at 20 µg/mL and 3.99 ± 0.09 at 40 µg/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 ± 0.04, 1.09 ± 0.01, 0.76 ± 0.08, and 0.88 ± 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner. CONCLUSIONS: In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.

Humans , Base Sequence , Cell Culture Techniques , Cell Cycle , Cell Line , Cell Survival , Colon , Colonic Neoplasms , DNA , Flow Cytometry , Juglans , Phenol , Polymerase Chain Reaction , Real-Time Polymerase Chain Reaction , Stem Cells , Telomerase , Telomere
Endocrinology and Metabolism ; : 11-22, 2019.
Article in English | WPRIM | ID: wpr-739224


The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting BRAF and RAS proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 (TP53) and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase (TERT) promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the BRAF(V600E)-driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of BRAF(V600E)-driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic BRAF(V600E)-driven thyroid cancers.

Animals , Mice , Carcinogenesis , Catalytic Domain , Mice, Transgenic , Negotiating , Proto-Oncogene Proteins B-raf , Proto-Oncogenes , Telomerase , Thyroid Gland , Thyroid Neoplasms