scholarly journals Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point

2019 ◽  
Vol 20 (13) ◽  
pp. 3186 ◽  
Author(s):  
Veverka ◽  
Janovič ◽  
Hofr
Keyword(s):  
Structural Information ◽  
Anticancer Therapy ◽  
Telomerase Activity ◽  
Future Research ◽  
Quantitative Biology ◽  
Telomeric Dna ◽  
Telomerase Inhibition ◽  
Promising Target ◽  
The Status ◽  
Associated Proteins

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies.

scholarly journals Towards structural characterization of H. polymorpha telomerase components

2014 ◽  
Vol 70 (a1) ◽  
pp. C816-C816
Author(s):  
Johanna Kallio ◽  
Elena Rodina ◽  
Maria Zvereva ◽  
Olga Petrova ◽  
Alexandr Malyavko ◽  
...  
Keyword(s):  
Cell Division ◽  
Structural Information ◽  
Hansenula Polymorpha ◽  
Embryonic Stem ◽  
Telomerase Activity ◽  
Premature Aging ◽  
Telomeric Dna ◽  
Terminal Domain ◽  
Protein Components

Telomeres are regions of non-coding DNA that cap the chromosomes, preventing the loss of coding DNA during cell division and contributing to chromosomal stability. In actively dividing cells, such as embryonic stem cells, the telomeres need to elongated by telomerase. The telomerase complex consist of the enzyme telomerase reverse transcriptase (TERT), telomerase RNA (TR) and additional proteins. TERT and TR are required for the telomerase activity in vitro. Telomerase is active in vast majority of the cancer cells ensuring continuous cell division and tumor growth. Syndromes leading to premature aging are often associated with short telomeres. Finding ways to regulate the telomerase activity would help to advance therapies for these conditions. However, the structural information available of the telomerase complex is very limited. We have chosen thermophilic yeast Hansenula polymorpha as a model system due to the stability of its proteins. The N-terminal domain of the TERT is essential for telomerase activity and possibly is involved in binding of TR, telomeric DNA and additional protein components of the telomerase complex. We have crystallised the N-terminal domain of H. polymorpha TERT and, in lack of a homologious structure, produced a seleno-methionine derivative of the protein. MAD data on N-terminal domain has been collected to resolution of 2.0 Å at the PETRA-III beamline P13 (EMBL/DESY) in Hamburg. We will discuss the structure-function relationship of the N-domain and the whole TERT component.

scholarly journals Telomerase as a therapeutic target.

1996 ◽  
Vol 43 (3) ◽  
pp. 531-538 ◽  
Author(s):  
L Huminiecki
Keyword(s):  
Bone Marrow ◽  
Therapeutic Target ◽  
Cancer Biology ◽  
Critical Length ◽  
Telomerase Activity ◽  
Telomeric Dna ◽  
Telomerase Inhibition ◽  
Normal Human ◽  
Peripheral Leukocytes ◽  
Biology Research

Ribonucleoprotein telomerase is an enzyme that elongates telomeric DNA. In cells without detectable telomerase activity telomeres shorten with every cell generation and reaching critical length is a signal for cell death. Normal human somatic cells express undetectable, or low (bone marrow and peripheral leukocytes), telomerase activity. Reactivation of telomerase (immortalization) is probably necessary during development of a fully malignant cancer. Consequently, telomerase was proposed to be a therapeutic target for the cancer therapy. Potential results (including side-effects) of telomerase inhibition are being considered. After all, telomerase inhibition can be useful not only in the therapy, but also in cancer biology research, elucidating ageing and immortalization phenomena.

scholarly journals Human Telomerase and Its Regulation

2002 ◽  
Vol 66 (3) ◽  
pp. 407-425 ◽  
Author(s):  
Yu-Sheng Cong ◽  
Woodring E. Wright ◽  
Jerry W. Shay
Keyword(s):  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Telomerase Activity ◽  
Cellular Aging ◽  
Telomeric Dna ◽  
Associated Proteins ◽  
Functional Complex ◽  
Length Regulation ◽  
Normal Human ◽  
Human Telomerase

SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

Telomerase Activity and Telomere Length in APL: May Be Proliferative and Prognostic Markers.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4236-4236 ◽  
Author(s):  
Seyed Hamidolah Ghaffari ◽  
Nilofar Shayan-Asl ◽  
Abdolhamid Jamialahmadi ◽  
Ardeshir Ghavamzadeh ◽  
Kamran Alimoghaddam
Keyword(s):  
Telomere Length ◽  
Prognostic Markers ◽  
Telomerase Activity ◽  
Size Difference ◽  
Activity Levels ◽  
Telomeric Dna ◽  
Pcr Assay ◽  
Peripheral Blood Mononuclear ◽  
Normal Individuals ◽  
Associated Proteins

Abstract Introduction: The telomeric DNA together with its associated proteins protects the chromosome ends from degradation or aberrant recombination. Telomerase and telomere are extensively investigated as potential diagnostic and prognostic markers in human tumors. 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: About 300 sequential peripheral blood mononuclear cell (PBMC) samples were collected from 40 patients with APL (32 newly diagnosed and 8 relapsed), at diagnosis, during and after therapy with Arsenic Trioxide. TA was assessed by TRAP-ELISA and -PAGE procedures. Terminal restriction fragment (TRF) length was determined by Southern blot analysis, using a Chemiluminescence-based assay. Quantification of PML-RARα/G6PDH transcripts was carried out by real-time PCR assay. Results: About 90% of the APL patients had a significant reduction in TRF length (median 3.5, ranged 2.3 to 6.7 kbp) relative to the age-matched control or to that at the time of CR (median 11.37; ranged 8.90 to 14.70 kbp) from the same patients (P<0.0001). A significance positive correlation between telomere length and PML-RARα expression was found in the APL patients (P=0.001). In all the APL patients, telomerase activity was elevated in comparison with normal individuals (P<0.001). The telomerase activity levels were significantly higher in patients with short TRF. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival. The levels of TA were even significantly higher and the TL size difference of leukemic from non-leukemic was significantly longer in relapsed patients than patients with the primary APL. Conclusion: Short telomere and high telomerase levels in the APL patients are mainly a consequence of extensive proliferative histories and they correlate with the disease progression. The shortened telomere length and the elevated telomerase activity may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, and who may not respond favourably to arsenic therapy.

scholarly journals The influence of compound itel1296 on telomerase activity and the growth of cancer cells

2011 ◽  
Vol 57 (5) ◽  
pp. 501-510 ◽  
Author(s):  
N.A. Kovalenko ◽  
D.D. Zhdanov ◽  
M.V. Bibikova ◽  
V.Y. Gotovtseva
Keyword(s):  
Cell Line ◽  
Fibroblast Cell ◽  
Telomerase Activity ◽  
Normal Fibroblast ◽  
Tumor Cell Lines ◽  
Sensitive Cell Line ◽  
Telomerase Inhibition ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Promising Target

Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19±0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0±0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line.

Moderating Role of Gender in the Relationship between Cognitive Errors and Anxiety among Adolescents

2020 ◽  
Vol 4 (1) ◽  
pp. 86-102
Author(s):  
Tasnim Rehna ◽  
Rubina Hanif ◽  
Muhammad Aqeel
Keyword(s):  
Mental Health Problems ◽  
Adolescent Psychopathology ◽  
Future Research ◽  
Cognitive Errors ◽  
Adolescent Anxiety ◽  
Study Results ◽  
The Status ◽  
Manifest Anxiety ◽  
The Relationship

Background: Widespread social paradigms on which the status variances are grounded in any society, gender plays pivotal role in manifestation of mental health problems (Rutter, 2007). A hefty volume of research has addressed the issue in adults nonetheless, little is vividly known about the role of gender in adolescent psychopathology. Sample: A sample of 240 adolescents (125 boys, 115 girls) aging 12-18 years was amassed from various secondary schools of Islamabad with the approval of the Federal Directorate of Education (FDE), relevant authorities of the schools and the adolescents themselves. Instruments: Taylor Manifest Anxiety Scale (Taylor & Spence, 1953) and Children’s Negative Cognitive Errors Questionnaire (CNCEQ) by Leitenberg et al., (1986) were applied in present study. Results: Multiple regression analysis revealed that cognitive errors jointly accounted for 78% of variance in predicting anxiety among adolescents. Findings also exhibited that gender significantly moderated the relationship between cognitive errors and adolescent anxiety. Implications of the findings are discoursed for future research and clinical practice.

Pharmacological Uses of the Plants Belonging to the Genus Commiphora

2020 ◽  
Vol 18 ◽  
Author(s):  
Subbiah Latha ◽  
Palanisamy Selvamani ◽  
Thangavelu Prabha
Keyword(s):  
Secondary Metabolites ◽  
Plant Species ◽  
Dna Cleavage ◽  
Structural Information ◽  
Chemical Constituents ◽  
Future Research ◽  
Pharmacological Properties ◽  
Chemical Structures ◽  
Indigenous Uses ◽  
Available Information

: Natural products have a unique place in the healthcare industry. The genus Commiphora emerged as a potential medicinal with huge benefits as evidenced through its use in various traditional and modern systems of medicine. Therefore, we aimed to prepare a concise review on the pharmacological activities and the indigenous uses of various plant species belonging to the genus Commiphora along with the structural information of various active botanical ingredients present in these plants based on the published literatures and scientific reports. To collect the various published literatures on Commiphora in various journals; to study and classify the available information on the pharmacological uses and chemical constituents; and to present the gathered information as a precise review to serve as a potential reference for future research. Pharmacological and phytochemical data on Commiphora plant species were collected from various journals, books, reference materials, websites including scientific databases, etc for compilation. This review article describes the various pharmacological properties of plants of Commiphora species viz., Anti-arthritic and anti-inflammatory, Anti-atherogenic, Antibacterial, Anti-coagulant, Anti-dicrocoeliasis, Anti-epileptic, Anti-fascioliasis, Anti-fungal, Anti-heterophyidiasis, Anti-hyper cholesterolemic, Anti-hyperlipidemic, Anti-hypothyroidism, Anti-obesity, Anti-osteoarthritic, Anti-osteoclastogenesis, Anti-oxidant, Anti-parasitic, Anti-pyretic, Anti-schistosomiasis, Anti-septic, Anti-thrombotic, Anti-ulcer, Cardioprotective, COX enzyme inhibitory, Cytotoxic /Anti-carcinogenic/Anti-cancer, DNA cleavage, Hypotensive, Inhibits lipid peroxidation, Inhibits NO and NO synthase production, Insecticidal, Local anesthetic, Molluscicidal, Smooth muscle relaxant, Tick repellent activities along with toxicity studies. Furthermore, the review also included various secondary metabolites isolated from various species of Commiphora genus along with their chemical structures serve as a ready resource for researchers. We conclude that the plant species belonging to the genus Commiphora possesses abundant pharmacological properties with a huge treasure of diverse secondary metabolites within themselves. This review indicates the necessity of further in-depth research, pre-clinical and clinical studies with Commiphora genus which may help to detect the unidentified potential of the Commiphora plant species.

scholarly journals Mapping domain characteristics influencing Analytics initiatives: The example of Supply Chain Analytics

2020 ◽  
Vol 13 (1) ◽  
pp. 56
Author(s):  
Tino Herden
Keyword(s):  
Supply Chain ◽  
Supply Chain Management ◽  
Success Factors ◽  
Research Collaboration ◽  
Future Research ◽  
Structured Interviews ◽  
Chain Management ◽  
Domain Specific ◽  
The Status ◽  
The Impact

Purpose: Analytics research is increasingly divided by the domains Analytics is applied to. Literature offers little understanding whether aspects such as success factors, barriers and management of Analytics must be investigated domain-specific, while the execution of Analytics initiatives is similar across domains and similar issues occur. This article investigates characteristics of the execution of Analytics initiatives that are distinct in domains and can guide future research collaboration and focus. The research was conducted on the example of Logistics and Supply Chain Management and the respective domain-specific Analytics subfield of Supply Chain Analytics. The field of Logistics and Supply Chain Management has been recognized as early adopter of Analytics but has retracted to a midfield position comparing different domains.Design/methodology/approach: This research uses Grounded Theory based on 12 semi-structured Interviews creating a map of domain characteristics based of the paradigm scheme of Strauss and Corbin.Findings: A total of 34 characteristics of Analytics initiatives that distinguish domains in the execution of initiatives were identified, which are mapped and explained. As a blueprint for further research, the domain-specifics of Logistics and Supply Chain Management are presented and discussed.Originality/value: The results of this research stimulates cross domain research on Analytics issues and prompt research on the identified characteristics with broader understanding of the impact on Analytics initiatives. The also describe the status-quo of Analytics. Further, results help managers control the environment of initiatives and design more successful initiatives.

scholarly journals Artificial intelligence in hospitals: providing a status quo of ethical considerations in academia to guide future research

AI & Society ◽  
2021 ◽  
Author(s):  
Milad Mirbabaie ◽  
Lennart Hofeditz ◽  
Nicholas R. J. Frick ◽  
Stefan Stieglitz
Keyword(s):  
Artificial Intelligence ◽  
Citation Network ◽  
Status Quo ◽  
Biomedical Ethics ◽  
Future Research ◽  
Ethical Considerations ◽  
Ethical Discourse ◽  
The Status ◽  
Clinical Environments ◽  
Research Questions

AbstractThe application of artificial intelligence (AI) in hospitals yields many advantages but also confronts healthcare with ethical questions and challenges. While various disciplines have conducted specific research on the ethical considerations of AI in hospitals, the literature still requires a holistic overview. By conducting a systematic discourse approach highlighted by expert interviews with healthcare specialists, we identified the status quo of interdisciplinary research in academia on ethical considerations and dimensions of AI in hospitals. We found 15 fundamental manuscripts by constructing a citation network for the ethical discourse, and we extracted actionable principles and their relationships. We provide an agenda to guide academia, framed under the principles of biomedical ethics. We provide an understanding of the current ethical discourse of AI in clinical environments, identify where further research is pressingly needed, and discuss additional research questions that should be addressed. We also guide practitioners to acknowledge AI-related benefits in hospitals and to understand the related ethical concerns.

scholarly journals Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 104
Author(s):  
Béla Kiss ◽  
István Laszlovszky ◽  
Balázs Krámos ◽  
András Visegrády ◽  
Amrita Bobok ◽  
...  
Keyword(s):  
Emotional Regulation ◽  
Drug Research ◽  
Treatment Options ◽  
Movement Control ◽  
Preclinical Research ◽  
High Affinity ◽  
Partial Agonists ◽  
Promising Target ◽  
The Status ◽  
Dopamine D3

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

Sign in / Sign up

Export Citation Format

Share Document