Publications by authors named "Persefoni Fragkiadaki"

23 Publications

  • Page 1 of 1

Telomerase and telomeres in aging theory and chronographic aging theory (Review).

Mol Med Rep 2020 Sep 25;22(3):1679-1694. Epub 2020 Jun 25.

Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece.

The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.
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http://dx.doi.org/10.3892/mmr.2020.11274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411297PMC
September 2020

Telomere length and telomerase activity in osteoporosis and osteoarthritis.

Exp Ther Med 2020 Mar 24;19(3):1626-1632. Epub 2019 Dec 24.

Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece.

Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.
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http://dx.doi.org/10.3892/etm.2019.8370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027092PMC
March 2020

A novel approach regarding the anti-aging of facial skin through collagen reorganization.

Exp Ther Med 2020 Jan 27;19(1):717-721. Epub 2019 Nov 27.

Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece.

The needle shaping technique can be used to perform subcutaneous microtransplants, enabling the 'lifting' of the skin. This prospective cohort study aimed to examine the effects of needle shaping on facial skin tone, volume and histological structure. A total of 54 women underwent the needle shaping procedure performed by inserting a tiny acupuncture needle combined with mixed electrical currents. The overall treatment was completed within 4 sessions of 2 months apart, once every 15 days. Maintenance was ensured by 2 sessions (no longer than 15 days apart) every 6 months. Macroscopic skin appearance was evaluated by a specialized dermatologist and the satisfaction of the patients was assessed. The microscopic structure of the skin dermis was evaluated by optic and scanning electron microscopy. I-chrome staining demonstrated more compact dermis-collagen fibers which were larger and thicker as compared to the controls. Scanning electron microscopy demonstrated an increased dermis thickness as compared to pre-treatment. All patients that answered to the follow up reported satisfaction during assessment. The satisfaction of the patients was very good and excellent in 45% of cases. The results of the needle-shaping procedure are natural with no scaring or down time. Moreover, the result is lasting even for 1 year, depending always on the subject's lifestyle and general health condition.
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http://dx.doi.org/10.3892/etm.2019.8254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913239PMC
January 2020

Targeted Metabolomic Analysis of Serum Fatty Acids for the Prediction of Autoimmune Diseases.

Front Mol Biosci 2019 1;6:120. Epub 2019 Nov 1.

Department of Clinical Pharmacy, Faculty of Pharmacy, University of Medicine and Pharmacy, Craiova, Romania.

Autoimmune diseases (ADs) are rapidly increasing worldwide and accumulating data support a key role of disrupted metabolism in ADs. This study aimed to identify an improved combination of Total Fatty Acids (TFAs) biomarkers as a predictive factor for the presence of autoimmune diseases. A retrospective nested case-control study was conducted in 403 individuals. In the case group, 240 patients diagnosed with rheumatoid arthritis, thyroid disease, multiple sclerosis, vitiligo, psoriasis, inflammatory bowel disease, and other AD were included and compared to 163 healthy individuals. Targeted metabolomic analysis of serum TFAs was performed using GC-MS, and 28 variables were used as input for the predictive models. The primary analysis identified 12 variables that were statistically significantly different between the two groups, and metabolite-metabolite correlation analysis revealed 653 significant correlation coefficients with 90% level of significance ( < 0.05). Three predictive models were developed, namely (a) a logistic regression based on Principal Component Analysis (PCA), (b) a straightforward logistic regression model and (c) an Artificial Neural Network (ANN) model. PCA and straightforward logistic regression analysis, indicated reasonably well adequacy (74.7 and 78.9%, respectively). For the ANN, a model using two hidden layers and 11 variables was developed, resulting in 76.2% total predictive accuracy. The models identified important biomarkers: lauric acid (C12:0), myristic acid (C14:0), stearic acid (C18:0), lignoceric acid (C24:0), palmitic acid (C16:0) and heptadecanoic acid (C17:0) among saturated fatty acids, Cis-10-pentadecanoic acid (C15:1), Cis-11-eicosenoic acid (C20:1n9), and erucic acid (C22:1n9) among monounsaturated fatty acids and the Gamma-linolenic acid (C18:3n6) polyunsaturated fatty acid. The metabolic pathways of the candidate biomarkers are discussed in relation to ADs. The findings indicate that the metabolic profile of serum TFAs is associated with the presence of ADs and can be an adjunct tool for the early diagnosis of ADs.
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http://dx.doi.org/10.3389/fmolb.2019.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839420PMC
November 2019

Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives.

Mol Med Rep 2019 Oct 23;20(4):3701-3708. Epub 2019 Aug 23.

Department of Clinical Pharmacy, University of Medicine and Pharmacy, Faculty of Pharmacy, 200349 Craiova, Romania.

Telomere length, a marker of cellular aging, decreases with age and it has been associated with aging‑related diseases. Environmental factors, including diet and lifestyle factors, affect the rate of telomere shortening which can be reversed by telomerase. Telomerase activation by natural molecules has been suggested to be an anti‑aging modulator that can play a role in the treatment of aging‑related diseases. This study aimed to investigate the effect of natural compounds on telomerase activity in human peripheral blood mononuclear cells (PBMCs). The tested compounds included Centella asiatica extract formulation (08AGTLF), Astragalus extract formulation (Nutrient 4), TA‑65 (containing Astragalus membranaceus extract), oleanolic acid (OA), maslinic acid (MA), and 3 multi‑nutrient formulas (Nutrients 1, 2 and 3) at various concentrations. The mean absorbance values of telomerase activity measured following treatment with some of the above‑mentioned formulations were statistically significantly higher compared to those of the untreated cells. In particular, in order of importance with respect to telomerase activation from highest to lowest, 08AGTLF, OA, Nutrient 4, TA‑65, MA, Nutrient 3 and Nutrient 2, triggered statistically significant increase in telomerase activity compared to the untreated cells. 08AGTLF reached the highest levels of telomerase activity reported to date, at least to our knowledge, increasing telomerase activity by 8.8 folds compared to untreated cells, while Nutrient 4 and OA were also potent activators (4.3‑fold and 5.9‑fold increase, respectively). On the whole, this study indicates that the synergistic effect of nutrients and natural compounds can activate telomerase and produce more potent formulations. Human clinical studies using these formulations are required to evaluate their mode of action. This would reveal the health benefits of telomerase activation through natural molecules and would shed new light onto the treatment of aging‑related diseases.
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http://dx.doi.org/10.3892/mmr.2019.10614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755196PMC
October 2019

The association of female and male infertility with telomere length (Review).

Int J Mol Med 2019 Aug 31;44(2):375-389. Epub 2019 May 31.

Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece.

Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.
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http://dx.doi.org/10.3892/ijmm.2019.4225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605974PMC
August 2019

Association of nutraceutical supplements with longer telomere length.

Int J Mol Med 2019 Jul 10;44(1):218-226. Epub 2019 May 10.

Department of Clinical Pharmacy, University of Medicine and Pharmacy, Faculty of Pharmacy, Craiova 200349, Romania.

Telomeres are nucleotide tandem repeats located at the tip of eukaryotic chromosomes that maintain genomic integrity. The gradual shortening of telomeres leads to cellular senescence and apoptosis, a key mechanism of aging and age‑related chronic diseases. Epigenetic factors, such as nutrition, exercise and tobacco can affect the rate at which telomeres shorten and can modify the risk of developing chronic diseases. In this study, we evaluated the effects of a combination of nutraceutical supplements (NS) on telomere length (TL) in healthy volunteers with no medical history of any disease. Participants (n=47) were selected from healthy outpatients visiting a private clinic and were divided into the experimental group (n=16), that received the NS and the control group (n=31). We estimated the length of single telomeres in metaphase spread leukocytes, isolated from peripheral blood, using quantitative‑fluorescent in situ hybridization (Q‑FISH) analysis. The length of the whole telomere genome was significantly increased (P<0.05) for the mean, 1st quartile and median measurements in the experimental group. Similar findings were observed for short TL (20th percentile) (P<0.05) for the median and 3rd quartile measurements in the NS group, compared to the control group. The beneficial effects of the supplements on the length of short telomeres remained significant (P<0.05) following adjustment for age and sex. Telomeres were moderately longer in female patients compared to the male patients. On the whole, the findings of this study suggest that the administration of NS may be linked to sustaining the TL.
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http://dx.doi.org/10.3892/ijmm.2019.4191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559326PMC
July 2019

Developing BIOTEL: A Semi-Automated Spreadsheet for Estimating Telomere Length and Biological Age.

Front Genet 2019 19;10:84. Epub 2019 Feb 19.

Laboratory of Toxicology, Medical School, University of Crete, Heraklion, Greece.

Telomere length (TL) is causally related to aging and several age-related diseases. Specifically, the abundance of short telomeres and the rate of telomere shortening are strong determinants of cell homeostasis. Thus, tools for analyzing and manipulating TL data can vastly improve research focused on aging. Aim: In this study, we developed a semi-automated worksheet, BIOTEL, to generate individual and group TL statistics and provide a crude estimation of biological age. Data from the Telomere Length Database Project (TLDP) were implemented to the spreadsheet to produce TL statistics. 150 participants were included, and their age was from 21 to 82 years, and the sex distribution ratio was 52.3%: 47.7% (male: female). Initially, we analyzed the fluorescence intensities of telomeres that were measured on metaphase spread leukocytes using three-dimensional (3D) quantitative-fluorescent hybridization (Q-FISH) procedures (3D DNA FISH) with a (C3TA2)3 peptide nucleic acid (PNA) probe. Raw data of fluorescence intensities, demographic data and medical records from the participants were imported into the worksheet. Basic statistical analyses of TL data were provided through BIOTEL, including TL percentiles, specialized charts for TL distribution including the percentage of critically short telomeres (< 3,000 kilobases), individual telomere profiles, and graphs of biological age vs. chronological age. BIOTEL ver. 2.4 is a functional semi-automated worksheet that calculates a wide range of TL statistics, thus a useful tool with applications in research of telomeres and biological age estimation.
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http://dx.doi.org/10.3389/fgene.2019.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389611PMC
February 2019

Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults.

Int J Mol Med 2019 Jan 14;43(1):233-242. Epub 2018 Nov 14.

Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece.

Fatty acids (FAs) play critical roles in health and disease. The detection of FA imbalances through metabolomics can provide an overview of an individual's health status, particularly as regards chronic inflammatory disorders. In this study, we aimed to establish sensitive reference value ranges for targeted plasma FAs in a well‑defined population of healthy adults. Plasma samples were collected from 159 participants admitted as outpatients. A total of 24 FAs were analyzed using gas chromatography‑mass spectrometry, and physiological values and 95% reference intervals were calculated using an approximate method of analysis. The differences among the age groups for the relative levels of stearic acid (P=0.005), the omega‑6/omega‑3 ratio (P=0.027), the arachidonic acid/eicosapentaenoic acid ratio (P<0.001) and the linoleic acid‑produced dihomo‑gamma‑linolenic acid (P=0.046) were statistically significant. The majority of relative FA levels were higher in males than in females. The levels of myristic acid (P=0.0170) and docosahexaenoic acid (P=0.033) were significantly different between the sexes. The reference values for the FAs examined in this study represent a baseline for further studies examining the reproducibility of this methodology and sensitivities for nutrient deficiency detection and investigating the biochemical background of pathological conditions. The application of these values to clinical practice will allow for the discrimination between health and disease and contribute to early prevention and treatment.
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http://dx.doi.org/10.3892/ijmm.2018.3989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257830PMC
January 2019

Stanozolol administration combined with exercise leads to decreased telomerase activity possibly associated with liver aging.

Int J Mol Med 2018 Jul 26;42(1):405-413. Epub 2018 Apr 26.

Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey.

Anabolic agents are doping substances which are commonly used in sports. Stanozolol, a 17α‑alkylated derivative of testosterone, has a widespread use among athletes and bodybuilders. Several medical and behavioral adverse effects are associated with anabolic androgenic steroids (AAS) abuse, while the liver remains the most well recognized target organ. In the present study, the hepatic effects of stanozolol administration in rats at high doses resembling those used for doping purposes were investigated, in the presence or absence of exercise. Stanozolol and its metabolites, 16‑β‑hydroxystanozolol and 3'‑hydroxystanozolol, were detected in rat livers using liquid chromatography‑mass spectrometry (LC‑MS). Telomerase activity, which is involved in cellular aging and tumorigenesis, was detected by examining telomerase reverse transcriptase (TERT) and phosphatase and tensin homolog (PTEN) expression levels in the livers of stanozolol‑treated rats. Stanozolol induced telomerase activity at the molecular level in the liver tissue of rats and exercise reversed this induction, reflecting possible premature liver tissue aging. PTEN gene expression in the rat livers was practically unaffected either by exercise or by stanozolol administration.
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http://dx.doi.org/10.3892/ijmm.2018.3644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979936PMC
July 2018

The metabolism of imidacloprid by aldehyde oxidase contributes to its clastogenic effect in New Zealand rabbits.

Mutat Res Genet Toxicol Environ Mutagen 2018 May - Jun;829-830:26-32. Epub 2018 Mar 19.

Laboratory of Toxicology, Medical School, University of Crete, Voutes, 71409 Heraklion, Crete, Greece. Electronic address:

Imidacloprid (IMI) is a systemic, chloro-nicotinyl insecticide classified in Regulation N° 1272/2008 of the European Commision as "harmful if swallowed and very toxic to aquatic life, with long-lasting effects". IMI is metabolized in vitro both by aldehyde oxidase (AOX) (reduction) and by cytochrome P450s enzymes (CYPs). In the present study, the AOX inhibitor sodium tungstate dihydrate (ST) was used to elucidate the relative contribution of CYP 450 and AOX metabolic pathways on IMI metabolism, in male rabbits exposed to IMI for two months. To evaluate the inhibition effectiveness, various metabolite concentrations in the IMI and IMI + ST exposed groups were monitored. DNA damage was also evaluated in micronucleus (MN) and single cell electrophoresis (SCGC) assays in both groups, along with oxidative stress (OS) with the inflammatory status of the exposed animals, in order to clarify which metabolic pathway is more detrimental in this experimental setting. A significant increase in the frequency of binucleated cells with MN (BNMN, 105%) and micronuclei (MN, 142%) was observed after exposure to IMI (p < 0.001). The increase in the ST co-exposed animals was less pronounced (BNMN 75%, MN 95%). The Cytokinesis Block Proliferation Index (CBPI) showed no significant difference between controls and exposed animals at any time of exposure (p > 0.05), which indicates no cytotoxic effect. Similarly, comet results show that the IMI group exhibited the highest achieved tail intensity, which reached 70.7% over the control groups, whereas in the IMI + ST groups the increase remained at 48.5%. No differences were observed between all groups for oxidative-stress biomarkers. The results indicate that the AOX metabolic pathway plays a more important role in the systemic toxicity of IMI.
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http://dx.doi.org/10.1016/j.mrgentox.2018.03.002DOI Listing
June 2019

Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review).

Oncol Rep 2018 Jun 21;39(6):2455-2472. Epub 2018 Mar 21.

Laboratory of Anatomy‑Histology‑Embryology, Medical School, University of Crete, 71110 Heraklion, Greece.

Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy. In that way, they will be able to decrease both morbidity and mortality of their patients. In accordance with that, colon cancer research has described numerous biomarkers for diagnostic, prognostic and predictive purposes that either alone or as part of a panel would help improve patient's clinical management. This review aims to describe the most accepted biomarkers among those proposed for use in CRC divided based on the clinical specimen that is examined (tissue, faeces or blood) along with their restrictions. Lastly, new insight in CRC monitoring will be discussed presenting promising emerging biomarkers (telomerase activity, telomere length and micronuclei frequency).
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http://dx.doi.org/10.3892/or.2018.6330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983921PMC
June 2018

Application of metabolomics: Focus on the quantification of organic acids in healthy adults.

Int J Mol Med 2017 Jul 10;40(1):112-120. Epub 2017 May 10.

Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, Heraklion 71003, Greece.

Metabolomics, a 'budding' discipline, may accurately reflect a specific phenotype which is sensitive to genetic and epigenetic interactions. This rapidly evolving field in science has been proposed as a tool for the evaluation of the effects of epigenetic factors, such as nutrition, environment, drug and lifestyle on phenotype. Urine, being sterile, is easy to obtain and as it contains metabolized or non‑metabolized products, is a favored study material in the field of metabolomics. Urine organic acids (OAs) reflect the activity of main metabolic pathways and have been used to assess health status, nutritional status, vitamin deficiencies and response to xenobiotics. To date, a limited number of studies have been performed which actually define reference OA values in a healthy population and as reference range for epigenetic influences, and not as a reference to congenital metabolic diseases. The aim of the present study was thus the determination of reference values (RVs) for urine OA in a healthy adult population. Targeted metabolomics analysis of 22 OAs in the urine of 122 healthy adults by gas chromatography‑mass spectrometry, was conducted. Percentile distributions of the OA concentrations in urine, as a base for determining the RVs in the respective population sample, were used. No significant differences were detected between female and male individuals. These findings can facilitate the more sensitive determination of OAs in pathological conditions. Therefore, the findings of this study may contribute or add to the information already available on urine metabolite databases, and may thus promote the use of targeted metabolomics for the evaluation of OAs in a clinical setting and for pathophysiological evaluation. However, further studies with well‑defined patients groups exhibiting specific symptoms or diseases are warranted in order to discern between normal and pathological values.
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http://dx.doi.org/10.3892/ijmm.2017.2983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466383PMC
July 2017

Determination of DNA damage and telomerase activity in stanozolol-treated rats.

Exp Ther Med 2017 Feb 15;13(2):614-618. Epub 2016 Dec 15.

Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey.

Anabolic androgenic steroids (AAS) are performance-enhancing drugs commonly abused by atheletes. Stanozolol is a synthetic testosterone-derived anabolic steroid. Although it is well known that AAS have several side-effects, there are only few toxicological studies available on the toxic effects and mechanisms of action of stanozolol. The aim of this study was to investigate the genotoxic effects of stanozolol and to determine its effects on telomerase activity in Sprague-Dawley male rats. For this purpose, 34 male rats were divided into 5 groups as follows: i) the control group (n=5); ii) the propylene glycol (PG)-treated group (n=5); iii) the stanozolol-treated group (n=8); iv) the PG-treated group subjected to exercise (n=8); and v) the stanozolol-treated group subjected to exercise (n=8). PG is used as a solvent control in our study. Stanozolol (5 mg/kg) and PG (1 ml/kg) were injected subcutaneously 5 days/week for 28 days. After 28 days, the animals were sacrificed, and DNA damage evaluation (comet assay) and telomerase activity assays were then performed using peripheral blood mononuclear cells (PBMCs). Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS kit. The results of this study revealed that stanozolol treatment induced DNA damage, while exercise exerted a protective effect. Stanozolol treatment without exercise stimulation was associated with a significant increase in telomerase activity in the PBMCs.
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http://dx.doi.org/10.3892/etm.2016.3974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348646PMC
February 2017

Nephrotoxicity in rabbits after long-term nandrolone decanoate administration.

Toxicol Lett 2016 Sep 23;259:21-27. Epub 2016 Jun 23.

Center of Toxicology Science & Research, Medical School, University of Crete, Heraklion, Crete, Greece. Electronic address:

Among the various side effects of supra-physiological dose of anabolic androgenic steroids that are described, renal toxicity remains the least evaluated. The present study provides evidence that long-term administration of nandrolone decanoate could lead to alterations of renal function and structure in the experimental rabbit model. A pronounced increase in serum urea, creatinine, SGOT and SGPT is observed in the treated animals, with intramuscular administration being more detrimental. Histopathological evaluation of kidneys indicated hyperaemia, fibrosis and focal inflammation. Furthermore, the significantly increased telomerase activity found in the kidneys of the intramuscularly treated animals could possibly represent a counteracting survival mechanism. Oxidative stress markers that were influenced the most were TBARS, indicating lipid peroxidation, and GSH. An interesting finding in our study though, was that while intramuscular administration showed the highest biochemical derangement, oxidative stress markers provided mixed results between intramuscularly and subcutaneously treated rabbits. In conclusion, nephrotoxicity of nandrolone decanoate remains a multi-factorial, partly irreversible effect that involves augmented tissue oxidative status.
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http://dx.doi.org/10.1016/j.toxlet.2016.06.1122DOI Listing
September 2016

Long-term exposure to cypermethrin and piperonyl butoxide cause liver and kidney inflammation and induce genotoxicity in New Zealand white male rabbits.

Food Chem Toxicol 2016 Aug 16;94:250-9. Epub 2016 Jun 16.

Laboratory of Toxicology, Medical School, University of Crete, Voutes, 71409 Heraklion, Crete, Greece. Electronic address:

Cypermethrin (CY) is a frequently used class II pyrethroid pesticide, while piperonyl butoxide (PBO) plays a major role in the pesticide formulation of synthetic pyrethroids. Synthetic pyrethroids are metabolized in mammals via oxidation and ester hydrolysis. PBO can prevent the metabolism of CY and enhances its pesticide effect. While this potentiation effect reduces the amount of pesticide required to eliminate insects, it is not clear how this mixture affects mammals. In our in vivo experiment, New Zealand white male rabbits were exposed to low and high doses of CY, PBO, and their combinations, for 4 months. Genotoxicity and cytotoxicity were monitored by measuring binucleated cells with micronuclei (BNMN), micronuclei (MN) and the cytokinesis block proliferation index (CBPI) in lymphocytes. After two months of exposure, a statistically significant increase in the frequency of BNMN was observed for all exposed animals (p < 0.001) in a dose-dependent way. MN were significantly elevated compared to controls (p < 0.001), with high dose groups reaching a 442% increase when co-exposed. BNMN and MN continued to increase after four months. Histopathological examination of lesions showed damage involving inflammation, attaining lymphoplasmatocytic infiltration in the high dose groups. Both CY and PBO cause liver and kidney inflammation and induce genotoxicity.
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http://dx.doi.org/10.1016/j.fct.2016.06.016DOI Listing
August 2016

Telomerase activity in pregnancy complications (Review).

Mol Med Rep 2016 Jul 9;14(1):16-21. Epub 2016 May 9.

Center of Toxicology Science and Research, University of Crete, Heraklion 71003, Greece.

Telomeres are specific DNA regions positioned at the ends of chromosomes and composed of functional non-coding repeats. Upon cell division, the telomeres decrease in length by a preordained amount. When the telomeres become critically short, cells lose the ability to divide and enter a specific functioning mode designated as 'cellular senescence'. However, human tissues express an enzyme that deters the shrinking of the telomeres, the telomerase. Due to its ability to maintain telomere length, the telomerase slows down and possibly suspends the aging of the cells. In regard to this, solid evidence demonstrates that female human fertility decreases with increased maternal age and that various adverse factors, including alterations in telomerase activity, can contribute to age-associated infertility in women. The fact that telomerase activity is regulated in a time- and location-dependent manner in both embryo and placental tissues, highlights it potential importance to the successful completion of pregnancy. Since maternal age is a crucial determining factor for the success of in vitro and in vivo fertilization, numerous studies have focused on telomerase activity and its correlation with mammalian fertilization, as well as the following cleavage and pre-implantation developmental processes. Associations between telomerase activity and pregnancy complications have been previously observed. Our aim in this review was to summarize and critically discuss evidence correlating telomerase activity with pregnancy complications.
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http://dx.doi.org/10.3892/mmr.2016.5231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918539PMC
July 2016

Long-term exposure of rabbits to imidaclorpid as quantified in blood induces genotoxic effect.

Chemosphere 2016 Apr 5;149:108-13. Epub 2016 Feb 5.

Center of Toxicology Science & Research, Division of Morphology, Medical School, University of Crete, Voutes Campus, Heraklion, 71003, Crete, Greece. Electronic address:

The present in-vivo study focuses on the genotoxic effect of the neonicotinoid pesticide imidacloprid (IMI) in rabbits. The purpose of the study was to establish a possible relationship between exposure to the pesticide (dose and duration) and genotoxicity. Furthermore, an analytical method for the simultaneous determination of IMI and its major metabolite 6-chloronicotinic acid (6-ClNA) in blood was developed and validated. The isolation of the two analytes from blood was performed by liquid-liquid extraction with dichloromethane. Analysis was performed by Liquid Chromatography - Atmospheric Pressure Chemical Ionization - Mass Spectrometry (LC-APCI-MS). The method was applied on the determination of IMI and 6-ClNA in serum samples obtained from rabbits fed with the insecticide at two low doses. Furthermore, parameters of genotoxicity and cytotoxicity were evaluated by measuring binucleated cells with micronuclei (BNMN), micronuclei (MN) and the Cytokinesis Block Proliferation Index (CBPI), in lymphocytes of exposed rabbits. The results revealed a genotoxic effect of IMI for both exposed groups. There were statistically significant differences in the frequencies of BNMN and MN between control and exposed groups but there was no dose-dependence, neither time-dependence of the genotoxic effect for the administered doses. This is the first time that long term exposure to IMI in rabbits was studied for the determination of its genotoxic effect. The genotoxic effect of IMI as it is depicted by the current study is in accordance with previous studies.
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http://dx.doi.org/10.1016/j.chemosphere.2016.01.040DOI Listing
April 2016

Downgrading the systemic condition of rabbits after long term exposure to cypermethrin and piperonyl butoxide.

Life Sci 2016 Jan 12;145:114-20. Epub 2015 Dec 12.

Laboratory of Toxicology, Medical School, University of Crete, Voutes, 71409 Heraklion, Crete, Greece. Electronic address:

Aim: The aimof this study is to clarify the effect of cypermethrin (CY) on the oxidative stress (OS) and inflammation status of animals exposed to it and the synergistic role of piperonyl butoxide (PB0).

Main Methods: Markers of oxidative stress, such as total antioxidant activity (TAC), protein carbonyls, hemoglobin (Hb), reduced glutathione (GSH), thiobarbituric-acid reactive substances (TBARS), along with the telomerase activity in PBMCs (peripheral blood mononuclear cells) were analyzed.

Key Findings: Oxidative stress markers showed statistically significant differences between groups in TAC (p b 0.001), GSH (p = 0.018) and CAT activity (p = 0.029), which depended on dose and combined effect of both compounds. Telomerase activity also showed a statistically significant difference between all groups (F = 43.48, df=6, 14, p b 0.001)with cypermethrin, piperonyl butoxide and the co-exposed groups being significantly different fromthe control group (p b 0.05). Significance: The observed results for TBARS, GSH, Hb, TAC, Crbnls and CAT from our exposed groups showed altered levels compared to control groups that could be linked to doses and combined effects of each chemical substance (cypermethrin and piperonyl butoxide). Oxidative stress markers suggest that cypermethrin, piperonyl butoxide and the co-exposed groups, induce oxidative stress as well as induction of telomerase activity.
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http://dx.doi.org/10.1016/j.lfs.2015.12.026DOI Listing
January 2016

Downregulation of notch signaling pathway in late preterm and term placentas from pregnancies complicated by preeclampsia.

PLoS One 2015 11;10(5):e0126163. Epub 2015 May 11.

Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Crete, Greece.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3-5% of all pregnancies. The Notch signaling pathway plays an important role during placental development, activating several target genes. Defects in the Notch pathway have adverse effect on placentation. The aim of this study was to investigate the expression of receptors NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tissue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2 (NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p = 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical analysis revealed several significant associations: of NOTCH3 mRNA expression with smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p = 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregulation is associated with PE. Further studies are required in order to determine the role of these molecules in PE pathogenesis and to evaluate their potential use for the early detection and treatment of PE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126163PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427301PMC
February 2016

Dietary supplementation with tomato-juice in patients with metabolic syndrome: a suggestion to alleviate detrimental clinical factors.

Food Chem Toxicol 2014 Dec 3;74:9-13. Epub 2014 Sep 3.

Second Cardiology Department, Amalia Fleming General Hospital, 14 25th Martiou Str., 15127, Athens, Greece.

Lycopene, a carotenoid, is known for its antioxidant properties. Little is known, though, about the relationship of dietary tomato-juice intake and risks factors, like inflammation, insulin resistance and hyperlipidemia, implicated in metabolic syndrome. In the present study, we examined whether supplementation with tomato-juice has any implication on the risk status of patients with metabolic syndrome. A comparative study was conducted in 27 individuals diagnosed with metabolic syndrome. Fifteen of them were instructed to use commercially available tomato-juice as refreshment 4 times a week over a period of two months and twelve individuals served as the control group. Several parameters reflective of the metabolic syndrome were monitored both in the group supplemented with tomato juice and in the control group (ADMA for entdothelial function, TNF-α and IL-6 for inflammation, FIRI for insulin resistance). There was a significant improvement in the inflammation status and the endothelial dysfunction of the tomato-juice supplemented patients. At the same time, insulin resistance improved and a pronounced decrease in LDL was recorded, along with a slight increase in HDL. The results of the present study suggest an alleviating effect of tomato-juice with regard to risk factors associated with metabolic syndrome.
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http://dx.doi.org/10.1016/j.fct.2014.08.014DOI Listing
December 2014

Oxidative stress and myocardial dysfunction in young rabbits after short term anabolic steroids administration.

Food Chem Toxicol 2013 Nov 26;61:101-5. Epub 2013 Mar 26.

Paediatric Cardiology Unit, Department of Paediatrics, University Hospital Heraklion, Heraklion, Crete, Greece.

The present study focuses on the short term effects of repeated low level administration of turinabol and methanabol on cardiac function in young rabbits (4 months-old). The experimental scheme consisted of two oral administration periods, lasting 1 month each, interrupted by 1-month wash-out period. Serial echocardiographic evaluation at the end of all three experimental periods was performed in all animals. Oxidative stress markers have also been monitored at the end of each administration period. Treated animals originally showed significantly increased myocardial mass and systolic cardiac output, which normalized at the end of the wash out period. Re-administration led to increased cardiac output, at the cost though of a progressive myocardial mass reduction. A dose-dependent trend towards impaired longitudinal systolic, diastolic and global myocardial function was also observed. The adverse effects were more pronounced in the methanabol group. For both anabolic steroids studied, the low dose had no significant effects on oxidative stress markers monitored, while the high dose created a hostile oxidative environment. In conclusion, anabolic administration has been found to create a possible deleterious long term effect on the growth of the immature heart and should be strongly discouraged especially in young human subjects.
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http://dx.doi.org/10.1016/j.fct.2013.03.018DOI Listing
November 2013

Histopathological lesions, oxidative stress and genotoxic effects in liver and kidneys following long term exposure of rabbits to diazinon and propoxur.

Toxicology 2013 May 28;307:109-14. Epub 2012 Nov 28.

Section of Hazardous Substances, Mixtures and Articles, Directorate of Environment, General Chemical State Laboratory of Greece, Athens, Greece.

Purpose: The aim of the present study was to investigate the effects of diazinon and propoxur on liver and kidneys, following long term exposure of rabbits.

Methods: Ten New Zealand white female rabbits were used. The animals were divided into 5 groups, consisting of 2 animals each. Diazinon (groups 1 and 2) and propoxur (groups 3 and 4) were administered at 2 different doses, and group 5 served as the control group. Histopathological lesions in the liver and kidneys, oxidative stress and oxidative DNA damage were evaluated.

Results: Both pesticides induced focal inflammation and fibrosis in the liver and kidneys. The low dose of propoxur induced a significant increase in total antioxidant capacity (TAC), with no difference in reduced glutathione (GSH), while the high dose of propoxur induced an increase in GSH with no change in TAC. For diazinon-exposed animals, the opposite findings were observed. Both diazinon and propoxur induced a statistically significant oxidative DNA damage in the liver and kidneys and a subsequent increase in telomerase activity in these tissues, possibly as a counteracting mechanism. Furthermore, systemic inflammation, as depicted by the dose-dependent increase in telomerase activity in peripheral blood mononuclear cells (PBMCs), was observed in propoxur treated animals.

Conclusions: Histopathological lesions, oxidative stress and genotoxic effects were induced in liver and kidneys following long term exposure of rabbits to diazinon and propoxur.
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http://dx.doi.org/10.1016/j.tox.2012.11.002DOI Listing
May 2013