Publications by authors named "Aristides M Tsatsakis"

60 Publications

Biochemical adaptation of wild and cultivated soybean against toxicity of lead salts.

Environ Toxicol Pharmacol 2020 Oct 27;79:103429. Epub 2020 May 27.

Education and Scientific Center of Nanotechnology, Far Eastern Federal University, Vladivostok, 690950, Russia. Electronic address:

Agricultural production is becoming increasingly dependent on the environmental factors that alter soil properties, plant productivity, and product quality. Environment pollution caused by heavy metals because of human activities are among the most dangerous pollutants on the biosphere. Here, we have studied the biochemical adaptation of wild and cultivated soybeans to the simulated effects of lead nitrate and lead acetate. Lead in the form of acetate had a relevant toxic effect, as evidenced by a significant increase in the concentration of malonic dialdehyde in the treated samples relative to control samples. Catalase and peroxidase, possibly performing a signaling function, are involved in the adaptation to the toxicity of Pb salts. The studied Pb salts showed a predominant stimulating effect on the specific activity of acid phosphatases in cultivated soybean, while the ribonuclease activity changed in both Glycine species. Moreover, in wild soybean, it was mostly suppressive, except for the first day. We found that the electrophoretic spectra of acid phosphatases of soybean seedlings was highly stabile, while that of ribonucleases varied depending on the salt. On the seventh day of exposure, lead nitrate caused a decrease in the specific activity of the studied hydrolases of seedlings of cultivated and wild soybeans. A change in the number or electrophoretic mobility of multiple forms of enzymes during treatment with Pb salts was revealed, which indicates the adaptation of the plants at the molecular genetic level. These results imply that the observed enzymes can be used as sensitive indicators for predicting the effects of heavy metals on soybean.
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http://dx.doi.org/10.1016/j.etap.2020.103429DOI Listing
October 2020

Benomyl, a benzimidazole fungicide, induces oxidative stress and apoptosis in neural cells.

Toxicol Rep 2020 11;7:501-509. Epub 2020 Apr 11.

Department of Biochemistry and Biotechnology, University of Thessaly, Viopolis, Mezourlo, 41500, Larissa, Greece.

Fungicides are used in the agricultural sector against the harmful action of fungi, however they are potential toxic agents for the environment and the living organisms. Benomyl is a widely encountered benzimidazole fungicide that exerts its toxicity via inhibiting microtubule formation in the nervous system and the male reproductive and endocrine systems, whilst it is a known teratogen. Since toxic effects of benomyl and its molecular mechanisms are not fully understood, we aimed to detect its neurotoxic potential via evaluating cytotoxicity, oxidative stress and apoptosis in SH-SY5Y cell line. The cells were incubated with benomyl in a concentration range between 1 and 6 μM for 24 h. Our results indicated a concentration-dependent enhancement of reactive oxygen species measured through flow cytometry and DNA damage evaluated via the comet assay. Additionally, it induced apoptosis in all tested concentrations. According to the findings of the present study, benomyl is a xenobiotic, which it appears to exert its toxic action via a redox-related mechanism that, finally, induces cell apoptosis and death. We believe that this study will offer further insight in the toxicity mechanism of benomyl, although further studies are recommended in order to elucidate these mechanisms in the molecular level.
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http://dx.doi.org/10.1016/j.toxrep.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175046PMC
April 2020

A review of the alleged health hazards of monosodium glutamate.

Compr Rev Food Sci Food Saf 2019 Jul 8;18(4):1111-1134. Epub 2019 May 8.

Faculty of Pharmacy, "Carol Davila" Univ. of Medicine and Pharmacy, Traian Vuia 6, Bucharest, 020956, Romania.

Monosodium glutamate (MSG) is an umami substance widely used as flavor enhancer. Although it is generally recognized as being safe by food safety regulatory agencies, several studies have questioned its long-term safety. The purpose of this review was to survey the available literature on preclinical studies and clinical trials regarding the alleged adverse effects of MSG. Here, we aim to provide a comprehensive overview of the reported possible risks that may potentially arise following chronic exposure. Furthermore, we intend to critically evaluate the relevance of this data for dietary human intake. Preclinical studies have associated MSG administration with cardiotoxicity, hepatotoxicity, neurotoxicity, low-grade inflammation, metabolic disarray and premalignant alterations, along with behavioral changes. Moreover, links between MSG consumption and tumorigenesis, increased oxidative stress and apoptosis in thymocytes, as well as genotoxic effects in lymphocytes have been reported. However, in reviewing the available literature, we detected several methodological flaws, which led us to conclude that these studies have limited relevance for extrapolation to dietary human intakes of MSG risk exposure. Clinical trials have focused mainly on the effects of MSG on food intake and energy expenditure. Besides its well-known impact on food palatability, MSG enhances salivary secretion and interferes with carbohydrate metabolism, while the impact on satiety and post-meal recovery of hunger varied in relation to meal composition. Reports on MSG hypersensitivity, also known as 'Chinese restaurant syndrome', or links of its use to increased pain sensitivity and atopic dermatitis were found to have little supporting evidence. Based on the available literature, we conclude that further clinical and epidemiological studies are needed, with an appropriate design, accounting for both added and naturally occurring dietary MSG. Critical analysis of existing literature, establishes that many of the reported negative health effects of MSG have little relevance for chronic human exposure and are poorly informative as they are based on excessive dosing that does not meet with levels normally consumed in food products.
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http://dx.doi.org/10.1111/1541-4337.12448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952072PMC
July 2019

Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population.

J Mol Neurosci 2020 Mar 25;70(3):467-474. Epub 2019 Nov 25.

Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.

Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.
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http://dx.doi.org/10.1007/s12031-019-01439-0DOI Listing
March 2020

Transgenic crops for the agricultural improvement in Pakistan: a perspective of environmental stresses and the current status of genetically modified crops.

GM Crops Food 2020 3;11(1):1-29. Epub 2019 Nov 3.

Center of Agricultural Biochemistry and Biotechnology, University of Agriculture, Faisalabad, Pakistan.

Transgenic technologies have emerged as a powerful tool for crop improvement in terms of yield, quality, and quantity in many countries of the world. However, concerns also exist about the possible risks involved in transgenic crop cultivation. In this review, literature is analyzed to gauge the real intensity of the issues caused by environmental stresses in Pakistan. In addition, the research work on genetically modified organisms (GMOs) development and their performance is analyzed to serve as a guide for the scientists to help them select useful genes for crop transformation in Pakistan. The funding of GMOs research in Pakistan shows that it does not follow the global trend. We also present socio-economic impact of GM crops and political dimensions in the seed sector and the policies of the government. We envisage that this review provides guidelines for public and private sectors as well as the policy makers in Pakistan and in other countries that face similar environmental threats posed by the changing climate.
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http://dx.doi.org/10.1080/21645698.2019.1680078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158921PMC
February 2020

Addressing concerns over the fate of DNA derived from genetically modified food in the human body: A review.

Food Chem Toxicol 2019 Feb 21;124:423-430. Epub 2018 Dec 21.

Department of Biotechnology, Chonnam National University, Yeosu, Chonnam, 59626, Republic of Korea. Electronic address:

Global commercialization of GM food and feed has stimulated much debate over the fate of GM food-derived DNA in the body of the consumer and as to whether it poses any health risks. We reviewed the fate of DNA derived from GM food in the human body. During mechanical/chemical processing, integrity of DNA is compromised. Food-DNA can survive harsh processing and digestive conditions with fragments up to a few hundred bp detectable in the gastrointestinal tract. Compelling evidence supported the presence of food (also GM food) derived DNA in the blood and tissues of human/animal. There is limited evidence of food-born DNA integrating into the genome of the consumer and of horizontal transfer of GM crop DNA into gut-bacteria. We find no evidence that transgenes in GM crop-derived foods have a greater propensity for uptake and integration than the host DNA of the plant-food. We found no evidence of plant-food DNA function/expression following transfer to either the gut-bacteria or somatic cells. Strong evidence suggested that plant-food-miRNAs can survive digestion, enter the body and affect gene expression patterns. We envisage that this multi-dimensional review will address questions regarding the fate of GM food-derived DNA and gene-regulatory-RNA in the human body.
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http://dx.doi.org/10.1016/j.fct.2018.12.030DOI Listing
February 2019

Antimicrobial resistance in bacterial pathogens among hospitalised patients with severe invasive infections.

Exp Ther Med 2018 Dec 14;16(6):4499-4510. Epub 2018 Sep 14.

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

The most severe infections are invasive infections, due to the fact that the germs can accumulate in multiple sites and produce a body-wide infection known as sepsis. Septic shock has the highest mortality rate among non-traumatic medical conditions. In this study, we aimed to evaluate the incidence and prevalence of invasive infections in a hospital environment. Another second objective was to establish the aetiology of invasive infections in our hospital and the antibiotic resistance profile of the germs involved, which are both important for determining the therapeutic approach for the treatment of these infections. The study included 505 hospitalized patients from which we collected a total of 974 blood cultures. For the analysis of the blood cultures, we used an automated incubator. The bottles flagged as positive were subcultured on blood agar, and the grown colonies were identified using an identification system. Invasive infections had a prevalence rate of 27.72% in our hospital. From the 974 blood cultures, we isolated 170 bacterial strains: (SA; 63 strains, 37.06%), spp. (27 strains, 15.88%), coagulase-negative staphylococci (CoNS; 18 strains, 10.59%), spp. (17 strains, 10.00%), (12 strains, 7.06%), spp. (11 strains, 6.47%) and other bacterial species. The prevalence of methicillin-resistant SA (MRSA) in our study was 36.51% from the SA strains. The MRSA prevalence differed significantly according to age (37.50% in adults vs. 28.57% in children, P=0.047) and ICU admission (42.42% in ICU patients vs. 30.00% in non-ICU patients, P=0.018). We performed a multivariate analysis of the invasive infection risk which detected as significant predictors the admission into the cardiology ward and plastic surgery ward. On the whole, the findings of this study indicate that the high prevalence of Gram-positive cocci in blood cultures, mostly SA, with multidrug resistance has important consequences for the management of invasive infections.
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http://dx.doi.org/10.3892/etm.2018.6737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257814PMC
December 2018

Estimation of daily intake and risk assessment of organophosphorus pesticides based on biomonitoring data - The internal exposure approach.

Food Chem Toxicol 2019 Jan 22;123:57-71. Epub 2018 Oct 22.

Laboratory of Toxicology, Medical School, University of Crete, GR-71003, Heraklion, Crete, Greece. Electronic address:

Human exposure to pesticides can be estimated through different approaches. The approach adopted in this study is based on internal dose measures. Studies published during 2001 and 2017 were collected from PubMed and Scopus databases, filtered and organized. The intake of parent compounds is estimated based on the urinary excretion of different OP metabolites applying a mathematical model previously used for similar purposes. Once defined an Estimated Daily Intake (EDI), risk assessment is performed through comparison with specific guideline values and hazard index (HI) is calculated to assess cumulative health risk. The EDI was expressed as malathion, diazinon, parathion, phorate and dimethoate equivalents. Differences in exposure between pregnant women, general population, children and farmers are highlighted and exposures are presented by country and sampling year. Higher exposure to OPs was calculated for farmers, followed by children whereas pregnant women were less exposed. Median HQ values for children ranged between 0.016 and 0.618, for pregnant women 0.005-0.151, for general population 0.008-0.206 and for farmers 0.009-0.979. Combined exposure to dimethoate and phorate was the worst-case scenario. The annual distribution of the urinary DAPs showed that exposure to OPs since 1998 tends to be stable for both children and adults.
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http://dx.doi.org/10.1016/j.fct.2018.10.047DOI Listing
January 2019

Antioxidant effects of an olive oil total polyphenolic fraction from a Greek Olea europaea variety in different cell cultures.

Phytomedicine 2018 Aug 8;47:135-142. Epub 2018 May 8.

Department of Biochemistry and Biotechnology, University of Thessaly, Larissa 41500, Greece. Electronic address:

Background: Numerous studies have been carried out concerning the advantageous health effects, especially the antioxidant effects, of olive oil's (OO) individual biophenolic compounds, but none until now for its total phenolic fraction (TPF). Plenty of evidence, in research about nutrition and healthiness, points out that it is the complex mixture of nutritional polyphenols, more than each compound separate, which can synergistically act towards a health result.

Purpose: The aim of the present study was to examine the antioxidant properties of an extra virgin olive oil (EVOO) total polyphenolic fraction, from a Greek endemic variety of Olea europaea in cell lines.

Methods: EVOO from a Greek endemic variety was used for the extraction of a total polyphenolic fraction, using a green CPE‑based method. The redox status [in terms of ROS, GSH, TBARS, protein carbonyls] was assessed at a cellular level, particularly in EA.hy926 endothelial, HeLa, HepG2 hepatic cells and C2C12 myoblasts. Moreover, the levels of glutamate-cysteine ligase catalytic subunit (γ-GCLc) of GSH, one of the most important antioxidant enzymes, were assessed by western blot.

Results: According to the results, TPF improves the redox profile of all cell lines, mainly by increasing GSH and its catalytic subunit, while at low, not cytotoxic TPF concentrations there was a decrease in TBARS and carbonyls. Regarding ROS levels a reduction was observed only in the HepG2 cell line, contrary to the other cell lines, that there is no statistically significant difference.

Conclusion: The TPF appeared to protect cells from oxidative stress due to the strong antioxidant activity of its polyphenols. This could have interesting implications in development of new products based on this olive oil to provide protection and treatment against harmful effects of free radicals.
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http://dx.doi.org/10.1016/j.phymed.2018.04.054DOI Listing
August 2018

Oxidative Stress in Methylmercury-Induced Cell Toxicity.

Toxics 2018 Aug 9;6(3). Epub 2018 Aug 9.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Methylmercury (MeHg) is a hazardous environmental pollutant, which elicits significant toxicity in humans. The accumulation of MeHg through the daily consumption of large predatory fish poses potential health risks, and the central nervous system (CNS) is the primary target of toxicity. Despite well-described neurobehavioral effects (i.e., motor impairment), the mechanisms of MeHg-induced toxicity are not completely understood. However, several lines of evidence point out the oxidative stress as an important molecular mechanism in MeHg-induced intoxication. Indeed, MeHg is a soft electrophile that preferentially interacts with nucleophilic groups (mainly thiols and selenols) from proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress, which can produce damage by several interacting mechanisms, impairing the function of various molecules (i.e., proteins, lipids, and nucleic acids), potentially resulting in modulation of different cellular signal transduction pathways. This review summarizes the general aspects regarding the interaction between MeHg with regulators of the antioxidant response system that are rich in thiol and selenol groups such as glutathione (GSH), and the selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). A particular attention is directed towards the role of the PI3K/Akt signaling pathway and the nuclear transcription factor NF-E2-related factor 2 (Nrf2) in MeHg-induced redox imbalance.
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http://dx.doi.org/10.3390/toxics6030047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161175PMC
August 2018

Correction to: Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

J Mol Neurosci 2018 09;66(1):155

Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 157 71, Athens, Greece.

The original version of this article unfortunately contained mistakes in author group section.
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http://dx.doi.org/10.1007/s12031-018-1149-4DOI Listing
September 2018

Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

J Mol Neurosci 2018 07 29;65(3):367-376. Epub 2018 Jun 29.

Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 157 71, Athens, Greece.

Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.
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http://dx.doi.org/10.1007/s12031-018-1103-5DOI Listing
July 2018

Physiological and anthocyanin biosynthesis genes response induced by vanadium stress in mustard genotypes with distinct photosynthetic activity.

Environ Toxicol Pharmacol 2018 Sep 13;62:20-29. Epub 2018 Jun 13.

School of Life and Health Sciences, Aston University, Birmingham, United Kingdom. Electronic address:

The present study aimed to elucidate the photosynthetic performance, antioxidant enzyme activities, anthocyanin contents, anthocyanin biosynthetic gene expression, and vanadium uptake in mustard genotypes (purple and green) that differ in photosynthetic capacity under vanadium stress. The results indicated that vanadium significantly reduced photosynthetic activity in both genotypes. The activities of the antioxidant enzymes were increased significantly in response to vanadium in both genotypes, although the purple exhibited higher. The anthocyanin contents were also reduced under vanadium stress. The anthocyanin biosynthetic genes were highly expressed in the purple genotype, notably the genes TT8, F3H, and MYBL2 under vanadium stress. The results indicate that induction of TT8, F3H, and MYBL2 genes was associated with upregulation of the biosynthetic genes required for higher anthocyanin biosynthesis in purple compared with the green mustard. The roots accumulated higher vanadium than shoots in both mustard genotypes. The results indicate that the purple mustard had higher vanadium tolerance.
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http://dx.doi.org/10.1016/j.etap.2018.06.003DOI Listing
September 2018

Risk assessment of exposure to aflatoxin B1 and ochratoxin A through consumption of different Pistachio (Pistacia vera L.) cultivars collected from four geographical regions of Iran.

Environ Toxicol Pharmacol 2018 Jul 24;61:61-66. Epub 2018 May 24.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Iran is one of the main suppliers of pistachio for the European market accounting for over 90% of its demands; hence, efficient analytical methods are required for detection of mycotoxins contamination in pistachio kernels before exporting them. In this study, aflatoxin B1 (AFB1) and ochratoxin A (OTA) levels in five pistachio cultivars collected from four sites of Iran, were measured by HPLC. Based on the results, risk assessment for AFB1 and OTA residues was done. The highest mean concentrations of AFB1 and OTA were found in Ahmad-aghaei (4.33 and 2.19 ng/g, respectively) and Akbari (4.08 and 1.943 ng/g, respectively) cultivars from Rafsanjan, Iran. Even the highest concentrations of AFB1 and OTA in analyzed samples were lower than the corresponding maximum limits set by EU authorities. The hazard index (HI) value for consumers of Iranian pistachio is below one. It could be concluded that consumption of pistachio cultivated in these regions poses no health risk of mycotoxins exposure.
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http://dx.doi.org/10.1016/j.etap.2018.05.010DOI Listing
July 2018

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

Toxicity of plant extracts containing pyrrolizidine alkaloids using alternative invertebrate models.

Mol Med Rep 2018 Jun 26;17(6):7757-7763. Epub 2018 Mar 26.

Faculty of Pharmacy, University of Medicine and Pharmacy 'Carol Davila', 020956 Bucharest, Romania.

Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC‑MS method, using a retention time (TR)‑5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson 's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC‑MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans.
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http://dx.doi.org/10.3892/mmr.2018.8795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983973PMC
June 2018

Assessment of telomerase activity in leukocytes of type 2 diabetes mellitus patients having or not foot ulcer: Possible correlation with other clinical parameters.

Exp Ther Med 2018 Apr 25;15(4):3420-3424. Epub 2018 Jan 25.

Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece.

Telomerase is the enzyme that maintains telomere length by adding telomeric repeats after each cell division. Numerous metabolic factors such as obesity, insulin resistance or physical inactivity have been associated with shortened telomeres. In the present study, we assessed telomerase activity in diabetic patients having or not foot ulcer. A total of 90 adult patients with type 2 diabetes mellitus (T2DM) were studied. Patients were allocated into two groups according to the absence or presence of active foot ulcers as follows: Νon-ulcer group (N=58) and ulcer group (N=32). Our data revealed that the patients with diabetic ulcers had significantly greater waist circumference and neuropathy disability score, while exhibiting lower telomerase activity, indicating the possible existence of a common clinical profile among ulcer-bearing diabetic patients. Validation of our findings by extending the study in larger patient groups may contribute to the understanding of T2DM pathophysiology and its main clinical implications.
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http://dx.doi.org/10.3892/etm.2018.5798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876498PMC
April 2018

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

Effects of sheep/goat whey protein dietary supplementation on the redox status of rats.

Mol Med Rep 2018 Apr 20;17(4):5774-5781. Epub 2018 Feb 20.

Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece.

The purpose of the present study is to estimate the effects of sheep/goat whey protein dietary supplementation on the redox status of blood and tissues of rats. Twelve male Wistar rats were divided into the control group (standard commercial diet) and whey group [standard commercial diet + sheep/goat whey protein (1 g kg b.w/day)] (6 rats/group). The animals were maintainted on their respective diet for 28 days. At the end of the experimental period, reduced glutathione, catalase activity, total antioxidant capacity, thiobarbituric reactive substances, protein carbonyls and the decomposition rate of H2O2 were measured in blood and tissues of rats. According to the results, the rats fed with the sheep/goat whey protein exhibited improved antioxidant status and decreased free radical‑induced toxic effects on lipids and proteins. Specifically, in blood, GSH and CAT levels were significantly increased while TBARS and protein carbonyl levels were significantly decreased compared to the control group. Regarding the effects on tissues, it was observed that GSH levels were significantly increased in small intestine, quadriceps muscle, pancreas and lung tissue compared to the control group. The decomposition rate of H2O2 was significantly decreased in liver, brain and quadriceps muscle, but was significantly increased in spleen tissue compared to the control group. TBARS levels were significantly decreased in liver, brain, quadriceps muscle, pancreas, lung and spleen tissue compared to the control group. Finally, protein carbonyl levels were significantly decreased in brain, small intestine, kidney, pancreas and spleen tissue compared to the control group. Thus, the present findings show the beneficial effects of sheep/goat whey protein, a by‑product of cheese manufacturing, on the redox status in an in vivo model.
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http://dx.doi.org/10.3892/mmr.2018.8622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866020PMC
April 2018

Quercetin attenuates the hyperoxic lung injury in neonatal mice: Implications for Bronchopulmonary dysplasia (BPD).

Food Chem Toxicol 2018 Apr 9;114:23-33. Epub 2018 Feb 9.

Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Quercetin (QU) is one of the most common flavonoids that are present in a wide variety of fruits, vegetables, and beverages. This compound possesses potent anti-inflammatory and anti-oxidant properties. Supplemental oxygen is routinely administered to premature infants with pulmonary insufficiency. However, hyperoxia is one of the major risk factors for the development of bronchopulmonary dysplasia (BPD), which is also termed chronic lung disease in premature infants. Currently, no preventive approaches have been reported against BPD. The treatment of BPD is notably limited to oxygen administration, ventilatory support, and steroids. Since QU has been shown to be effective in reducing inflammation and oxidative stress in various disease models, we hypothesized that the postnatal QU treatment of newborn mice will protect against hyperoxic lung injury by the upregulation of the phase I (CYP1A/B) and/or phase II, NADPH quinone reductase enzymes. Newborn C57BL/6J mice within 24 h of birth with the nursing dams were exposed to either 21% O (air) and/or 85% O (hyperoxia) for 7 days. The mice were treated, intraperitoneally (i.p.) once every other day with quercetin, at a concentration of 20 mg/kg, or saline alone from postnatal day (PND) 2-6. The mice were sacrificed on day 7, and lung and liver tissues were collected. The expression levels of CYP1A1, CYP1B1, NQO1 proteins and mRNA as well as the levels of MDA-protein adducts were analyzed in lung and liver tissues. The findings indicated that QU attenuated hyperoxia-mediated lung injury by reducing inflammation and improving alveolarization with decreased number of neutrophil and macrophage infiltration. The attenuation of this lung injury correlated with the upregulation of CYP1A1/CYP1B1/NQO1 mRNA, proteins and the down regulation of NF-kB levels and MDA-protein adducts in lung and liver tissues. The present study demonstrated the potential therapeutic value of quercetin in the prevention and/or treatment of BPD.
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http://dx.doi.org/10.1016/j.fct.2018.02.026DOI Listing
April 2018

Anti-inflammatory effects of soyasapogenol I-αa via downregulation of the MAPK signaling pathway in LPS-induced RAW 264.7 macrophages.

Food Chem Toxicol 2018 Mar 31;113:211-217. Epub 2018 Jan 31.

Department of Biotechnology, Chonnam National University, Yeosu, Chonnam 59626, Republic of Korea. Electronic address:

The crude extract of soyasaponins was reported to possess anti-inflammatory activity. We determined the new purity group I saponin, I-αa and I-γa that was isolated from wild soybean (Glycine soja) in terms of its efficacy in protecting RAW 264.7 macrophages from lipopolysaccharide (LPS)-stimuli. Cells were treated with soyasaponin I-αa/I-γa (30-300 μΜ) and LPS (0.1 μg/mL) for 24 h. Soyasaponin I-αa inhibited nitric oxide (NO) production at 100 μg/mL, while soyasaponin I-γa demonstrated this effect at a higher concentration (200 μg/mL). The expression levels of iNOS and COX-2 enzymes were downregulated by both soyasaponins. Soyasaponin I-αa exerted its effect via the TNF-α and IL-1β cytokines. However, soyasaponin I-γa only inhibited the expression of TNF-α. The inflammatory effect of group I soyasaponin was mainly mediated via the phosphorylation of the p38 and JNK proteins. Collectively, these results suggested the potential anti-inflammatory effects of soyasaponins.
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http://dx.doi.org/10.1016/j.fct.2018.01.050DOI Listing
March 2018

Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review).

Int J Oncol 2018 Mar 29;52(3):637-655. Epub 2018 Jan 29.

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

Human papilloma viruses (HPV) are a small group of non‑enveloped viruses belonging to the Papillomaviridae family with strong similarities to polyoma viruses. The viral particles consist of a genome in the form of a circular double‑stranded DNA, encompassing eight open reading frames, as well as a non‑enveloped icosahedral capsid. HPV infection is considered the most common sexually transmitted disease in both sexes and is strongly implicated in the pathogenesis of different types of cancer. 'High‑risk' mucosal HPV types, predominantly types 16, 18, 31, 33 and 35, are associated with most cervical, penile, vulvar, vaginal, anal, oropharyngeal cancers and pre‑cancers. Screening for HPV is necessary for the prognosis and for determining treatment strategies for cancer. Novel HPV markers, including proteomic and genomic markers, as well as anti‑papillomavirus vaccines are currently available. The aim of this comprehensive review was to thoroughly present the updated information on virus development, cancer occurrence, treatment and prevention strategies, in an attempt to shed further light into the field, including novel research avenues.
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http://dx.doi.org/10.3892/ijo.2018.4256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807043PMC
March 2018

Update on radionuclide therapy in oncology.

Oncol Lett 2017 Dec 5;14(6):7011-7015. Epub 2017 Oct 5.

Departament of Toxicology, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, 020956 Bucharest, Romania.

Unstable isotopes and their capacity to emit ionizing radiation have been employed in clinical practice not only for diagnostic, but also for therapeutic purposes, with significant contribution in several fields of medicine and primarily in the management of oncologic patients. Their efficacy is associated with their ability to provide the targeted delivery of ionizing radiation for a determined duration. These compounds can be used for curative or palliative treatment, as well as for a diagnostic-therapeutic (theranostic) approach. This review summarises the most recent trends in radionuclide treatment for several malignancies, including prostate cancer, neuroendocrine tumours, and hematological and thyroid malignancies, in which radionuclide-based therapies have been employed with high effectiveness.
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http://dx.doi.org/10.3892/ol.2017.7141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754838PMC
December 2017

Endocrine Disruptors Leading to Obesity and Related Diseases.

Int J Environ Res Public Health 2017 10 24;14(10). Epub 2017 Oct 24.

Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Crete, Greece.

The review aims to comprehensively present the impact of exposure to endocrine disruptors (EDs) in relation to the clinical manifestation of obesity and related diseases, including diabetes mellitus, metabolic syndrome, cardiovascular diseases, carcinogenesis and infertility. EDs are strong participants in the obesity epidemic scenery by interfering with cellular morphological and biochemical processes; by inducing inflammatory responses; and by presenting transcriptional and oncogenic activity. Obesity and lipotoxicity enhancement occur through reprogramming and/or remodeling of germline epigenome by exposure to EDs. Specific population groups are vulnerable to ED exposure due to current dietary and environmental conditions. Obesity, morbidity and carcinogenicity induced by ED exposure are an evolving reality. Therefore, a new collective strategic approach is deemed essential, for the reappraisal of current global conditions pertaining to energy management.
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http://dx.doi.org/10.3390/ijerph14101282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664782PMC
October 2017

Staphylococcus aureus colonisation in patients from a primary regional hospital.

Mol Med Rep 2017 Dec 10;16(6):8771-8780. Epub 2017 Oct 10.

Department of Microbiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.

Staphylococcus aureus (SA or S. aureus) is a common pathogen that leads to local and systemic infections in communitarian and hospitalised patients. Staphylococcus colonizing nasal or pharyngeal sites can become virulent and cause severe infections. In this study, we collected 322 pharyngeal exudates and 142 nasal exudates from hospitalised and outpatients for screening purposes. The carriage rates in the pharynx were 27.06% for S. aureus, 11.55% for methicillin‑resistant S. aureus (MRSA) and 5.61% for methicillin‑oxacillin resistant S. aureus (MORSA). The carriage rates in the nose were 35.38% for S. aureus, 18.46% for MRSA and 13.85% for MORSA. The median multiple antibiotic resistance (MAR) index of SA was 33.33%. The MAR of MRSA was significantly higher than that of methicillin-susceptible strains (MSSA) (45.45% vs. 18.75%, P<0.0001) and the MAR of MORSA was 57.14%. Hierarchical clustering analysis revealed differences in the resistance of methicillin-sensitive, MRSA and MORSA strains. On the whole, our study demonstrates the pattern of distribution of nasal and pharyngeal colonisation with SA, MRSA and MORSA in adults vs. children, inpatients vs. outpatients, ICU patients vs. non‑ICU patients, and females vs. males, which can be used for adjusting the screening and decontamination protocols in a hospital. SA is a pervasive pathogen with constantly changing trends in resistance and epidemiology and thus requires constant monitoring in healthcare facilities.
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http://dx.doi.org/10.3892/mmr.2017.7746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779955PMC
December 2017

Tissue specific effects of feeds supplemented with grape pomace or olive oil mill wastewater on detoxification enzymes in sheep.

Toxicol Rep 2017 23;4:364-372. Epub 2017 Jun 23.

Department of Biochemistry-Biotechnology, University of Thessaly, Larissa 41500, Greece.

The aim of the present study was to investigate the effects of livestock feed supplemented with grape pomace (GP) or olive oil mill wastewater (OMW) byproducts on the enzymatic activity and protein expression of antioxidants enzymes, in liver and spleen tissue of sheep. Thus, 36 male sheep of Chios breed were divided into 3 homogeneous groups, control group (n = 12), GP group (n = 12) and OMW group (n = 12), receiving standard or experimental feed. Liver and spleen tissues were collected at 42 and 70 days post-birth. The enzymatic activity of superoxide dismutase (SOD) and glutathione-s-transferase (GST) and also the protein expression of γ-synthase glutamyl custeine (γ-GCS) were determined in these tissues. The results showed GP group exhibited increased enzymatic activity of GST and protein expression of γ-GCS in liver compared to control group. In GP group's spleen, GST activity was increased compared to control but γ-GCS expression was not affected. In OMW group's liver, GST activity was increased and γ-GCS expression was reduced compared to control. In OMW group's spleen, GST activity was increased but GCS expression was not affected. SOD activity was not affected in both tissues either in GP or OMW group.
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http://dx.doi.org/10.1016/j.toxrep.2017.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615154PMC
June 2017

Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker.

Mol Med Rep 2017 Nov 28;16(5):6059-6067. Epub 2017 Aug 28.

Department of General and Pharmaceutical Microbiology, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, 020956 Bucharest, Romania.

Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25‑hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.
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http://dx.doi.org/10.3892/mmr.2017.7376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865809PMC
November 2017

Classification of cancer cell lines using matrix-assisted laser desorption/ionization time‑of‑flight mass spectrometry and statistical analysis.

Int J Mol Med 2017 Oct 27;40(4):1096-1104. Epub 2017 Jul 27.

Department of Toxicology, Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, 300041 Timisoara, Romania.

Over the past decade, matrix-assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF MS) has been established as a valuable platform for microbial identification, and it is also frequently applied in biology and clinical studies to identify new markers expressed in pathological conditions. The aim of the present study was to assess the potential of using this approach for the classification of cancer cell lines as a quantifiable method for the proteomic profiling of cellular organelles. Intact protein extracts isolated from different tumor cell lines (human and murine) were analyzed using MALDI‑TOF MS and the obtained mass lists were processed using principle component analysis (PCA) within Bruker Biotyper® software. Furthermore, reference spectra were created for each cell line and were used for classification. Based on the intact protein profiles, we were able to differentiate and classify six cancer cell lines: two murine melanoma (B16‑F0 and B164A5), one human melanoma (A375), two human breast carcinoma (MCF7 and MDA‑MB‑231) and one human liver carcinoma (HepG2). The cell lines were classified according to cancer type and the species they originated from, as well as by their metastatic potential, offering the possibility to differentiate non‑invasive from invasive cells. The obtained results pave the way for developing a broad‑based strategy for the identification and classification of cancer cells.
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http://dx.doi.org/10.3892/ijmm.2017.3083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593469PMC
October 2017

Assessment of the antioxidant activity of an olive oil total polyphenolic fraction and hydroxytyrosol from a Greek Olea europea variety in endothelial cells and myoblasts.

Int J Mol Med 2017 Sep 20;40(3):703-712. Epub 2017 Jul 20.

Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece.

Olive oil (OO) constitutes the basis of the Mediterranean diet, and it seems that its biophenols, such as hydroxytyrosol (HT) may scavenge free radicals, attracting distinct attention due to their beneficial effects in many pathological conditions, such as cancer. To the best of our knowedge, this is the first study in which the functional properties of an OO total polyphenolic fraction (TPF) and pure HT were examined in order to determine their antioxidant effects at a cellular level in endothelial cells and myoblasts. The test compounds were isolated using a green gradient‑elution centrifugal partition chromatography‑based method that allows the isolation of large volumes of OO in a continuous extraction procedure and with extremely low solvent consumption. For the isolation of HT, a combination of two chromatographic techniques was used, which is effective for the recovery of pure compounds from complex natural extracts. Moreover, TPF and HT exhibited potent free radical scavenging activity in vitro. The cells were treated with non‑cytotoxic concentrations and their redox status [in terms of glutathione (GSH) and reactive oxygen species (ROS) levels] was assessed. TPF extract was less cytotoxic than HT, and the observed differences between the two cell lines used suggest a tissue‑specific activity. Finally, flow cytometric analysis revealed that both TPF and HT improved the redox status by increasing the levels of GSH, one of the most important antioxidant molecules, in both endothelial cells and myoblasts, while the ROS levels were not significantly affected.
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http://dx.doi.org/10.3892/ijmm.2017.3078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547916PMC
September 2017

Neuroendocrine factors: The missing link in non‑melanoma skin cancer (Review).

Oncol Rep 2017 Sep 13;38(3):1327-1340. Epub 2017 Jul 13.

Laboratory of Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece.

Non‑melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun‑protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun‑exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well‑known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene‑related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α‑melanocyte‑stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.
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http://dx.doi.org/10.3892/or.2017.5817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549028PMC
September 2017