Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the ...diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.
COVID-19 caused by the SARS-CoV-2 outbreak quickly has turned into a pandemic. However, no specific antiviral agent is yet available. In this communication, we aimed to evaluate the significance of ...CD147 protein and the potential protective effect of melatonin that is mediated by this protein in COVID-19. CD147 is a glycoprotein that is responsible for the cytokine storm in the lungs through the mediation of viral invasion. Melatonin use previously was shown to reduce cardiac damage by blocking the CD147 activity. Hence, melatonin, a safe drug, may prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients. In conclusion, the use of melatonin, which is reduced in the elderly and immune-compromised patients, should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effect.
Role of Melatonin in Angiotensin and Aging Sehirli, Ahmet Ozer; Sayıner, Serkan; Chukwunyere, Ugochukwu ...
Molecules (Basel, Switzerland),
07/2021, Letnik:
26, Številka:
15
Journal Article
Recenzirano
Odprti dostop
The cellular utilization of oxygen leads to the generation of free radicals in organisms. The accumulation of these free radicals contributes significantly to aging and several age-related diseases. ...Angiotensin II can contribute to DNA damage through oxidative stress by activating the NAD(P)H oxidase pathway, which in turn results in the production of reactive oxygen species. This radical oxygen-containing molecule has been linked to aging and several age-related disorders, including renal damage. Considering the role of angiotensin in aging, melatonin might relieve angiotensin-II-induced stress by enhancing the mitochondrial calcium uptake 1 pathway, which is crucial in preventing the mitochondrial calcium overload that may trigger increased production of reactive oxygen species and oxidative stress. This review highlights the role and importance of melatonin together with angiotensin in aging and age-related diseases.
Background: Early detection of breast cancer alters the prognosis and tools that can predict the risk for breast cancer in women will have a significant impact on healthcare systems in low- and ...middle-income regions, such as North Cyprus. Objective: In this study, we developed a simple breast cancer risk model for the women of North Cyprus. Methods: Data from 655 women, consisting of 318 breast cancer cases and 337 hospital-based controls, was used to develop and internally validate the model, external validation was carried out using, 653 women consisting of 126 cases and 527 controls. Data were obtained from medical records and interviews after informed consent. Results: A model was derived that consisted of age ≥50 years and <50 years and the presence and absence of >1 first-degree relatives (FDR) with breast cancer. From internal and external validations the model’s AUCs were, 0.66 (95% CI = 0.62–0.70) and 0.69 (95% CI = 0.63–0.74) respectively. Conclusions: A unique model for risk prediction of breast cancer was developed to aid in identifying high-risk women from North Cyprus that can benefit from mammogram screening. Further study on a large scale that includes environmental risk factors is warranted.
The research work was designed to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of deferasirox (DFX). According to the solubility studies of DFX in different components, ...Peceol, Kolliphor EL, and Transcutol were selected as excipients. Pseudo-ternary phase diagrams were constructed, and then SNEDDS formation assessment studies and solubility of DFX in selected SNEDDSs formulations were performed. DFX loaded SNEDDS were prepared and characterized. The optimum DFX-SNEDDS formulations were developed. The relative safety of the optimized SNEDDS formulation was examined in a human immortalized myelogenous leukemia cell line, K562 cells, using the MTT cell viability test. Cytotoxicity studies revealed more cell viability (71.44%) of DFX loaded SNEDDS compared to pure DFX (3.99%) at 40 μM. The selected DFX-SNEDDS formulation was converted into S-SNEDDS by adsorbing into porous carriers, in order to study its dissolution behavior. The in vitro drug release studies indicated that DFX release (Q5%) from S-SNEDDS solidified with Neusilin UFL2 was significantly higher (93.6 ± 0.7% within 5 min) compared with the marketed product (81.65 ± 2.10%). The overall results indicated that the S-SNEDDS formulation of DFX could have the potential to enhance the solubility of DFX, which would in turn have the potential to improve its oral bioavailability as a safe novel delivery system.
The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the ...experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult mesenchymal stem cells (hMSC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of adult stem cells. The hTERT-transduced line, hMSC-TERT20 at population doubling level (PDL) 256 showed loss of contact inhibition, anchorage independence and formed tumours in 10/10 mice. hMSC-TERT4 showed loss of contact inhibition at PDL 95, but did not exhibit anchorage independence and did not form tumours in mice. Both lines had a normal karyotype but showed deletion of the Ink4a/ARF locus. At later passage, hMSC-TERT4 also acquired an activating mutation in KRAS. In hMSC-TERT20, expression of the cell cycle-associated gene, DBCCR1 was lost due to promoter hypermethylation. This epigenetic event correlated with acquisition of tumorigenicity. These data suggest that the adult hMSCs can be targets for neoplastic transformation and have implications for the development of novel anticancer therapeutics and for the use of hMSC in tissue engineering and transplantation protocols.
A gradual shortening of telomeres due to replication can be measured using the standard telomere restriction fragments (TRF) assay and other methods by measuring the mean length of all the telomeres ...in a cell. In contrast, stress-induced telomere shortening, which is believed to be just as important for causing cellular senescence, cannot be measured properly using these methods. Stress-induced telomere shortening caused by, e.g. oxidative damage happens in a stochastic manner leaving just a few single telomeres critically short. It is now possible to visualize these few ultra-short telomeres due to the advantages of the newly developed Universal single telomere length assay (STELA), and we therefore believe that this method should be considered the method of choice when measuring the length of telomeres after exposure to oxidative stress. In order to test our hypothesis, cultured human mesenchymal stem cells, either primary or hTERT immortalized, were exposed to sub-lethal doses of hydrogen peroxide, and the short term effect on telomere dynamics was monitored by Universal STELA and TRF measurements. Both telomere measures were then correlated with the percentage of senescent cells estimated by senescence-associated β-galactosidase staining. The exposure to acute oxidative stress resulted in an increased number of ultra-short telomeres, which correlated strongly with the percentage of senescent cells, whereas a correlation between mean telomere length and the percentage of senescent cells was absent. Based on the findings in the present study, it seems reasonable to conclude that Universal STELA is superior to TRF in detecting telomere damage caused by exposure to oxidative stress. The choice of method should therefore be considered carefully in studies examining stress-related telomere shortening as well as in the emerging field of lifestyle studies involving telomere length measurements.
Human bone marrow stromal cells (hMSCs) were stably transduced by a retroviral vector containing the gene for the catalytic subunit of human telomerase (hTERT). Transduced cells (hMSC-TERTs) had ...telomerase activity, and the mean telomere length was increased as compared with that of control cells. The transduced cells have now undergone more than 260 population doublings (PD) and continue to proliferate, whereas control cells underwent senescence-associated proliferation arrest after 26 PD. The cells maintained production of osteoblastic markers and differentiation potential during continuous subculturing, did not form tumors, and had a normal karyotype. When implanted subcutaneously in immunodeficient mice, the transduced cells formed more bone than did normal cells. These results suggest that ectopic expression of telomerase in hMSCs prevents senescence-associated impairment of osteoblast functions.
Human mesenchymal stem cells (hMSCs) are multipotent non-hematopoietic precursor cells with the ability to differentiate into several tissue types. The use of hMSCs has gained significant importance ...in cancer therapies as well as a large number of degenerative disease therapies due to their homing abilities. However, these cells may undergo spontaneous transformation leading to them bypassing naturally built-in cell controls that could lead to senescence and carcinogenesis. Therefore, although MSCs have great potential for cancer therapy, they also risk the development of cancer, which provides them with double-faced characteristics for both cancer development and therapy. The potential use of hMSCs in therapeutics from the aspect of in vitro expansion of hMSCs and telomere dynamic is discussed.
Tools that can predict breast cancer risk in women will have a significant impact on women and healthcare systems in low- and middle-income countries.
We compared the performances of the Breast and ...Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model, the International Breast Cancer Intervention Study (IBIS) model, and the Gail model in predicting breast cancer risk among women in Cyprus.
We recruited 655 women from Dr Burhan Nalbantoglu Devlet Hastanesi Hospital in Lefkosa: 318 had breast cancer and 337 did not have breast cancer (hospital-based controls). We collected retrospective data from the hospital's medical records and interviews with the women after informed consent. Data collected included: age, age at diagnosis, age at menarche, menopausal status, presence of benign breast disease, breast cancer in relatives, BRCA-1 and BRCA-2 mutations, history of hormone replacement therapy, and breast density. We calculated the 5-year risk of breast cancer and the risk values were used to plot receiver operating curves.
For the area under the curve (95% confidence interval, CI), sensitivity and specificity for the models were: BOADICEA 0.81 (95% CI: 0.77-0.84), 26.4% and 98.8%; IBIS 0.80 (95% CI: 0.77-0.84), 19.4% and 97.3%; and Gail 0.76 (95% CI: 0.73-0.80), 17.3% and 98.5%.
The breast cancer risk prediction models performed similarly although on closer appraisal, the BOADICEA and IBIS models performed slightly better. These models are simple, appropriate, cost-effective, and non-invasive tools for identifying high-risk women in low- and middle-income countries who could benefit from mammography screening.
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