Papers by Michael Koutsilieris
Anticancer Research, Dec 3, 2017
Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading ... more Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. Despite the development of novel therapeutic modalities, triple-negative breast cancer (TNBC) remains an incurable disease. Androgen receptor (AR) is widely expressed in BrCa and its role in the disease may differ depending on the molecular subtype and the stage. Interestingly, AR has been suggested as a potential target candidate in TNBC, while sex hormone levels may regulate the role of AR in BrCa subtypes. In the presence of estrogen receptor α (ERa), AR may antagonize the ERα-induced effects, whereas in the absence of estrogens, AR may act as an ERαmimic, promoting tumor. Thus, depending on the BrCa microenvironment, both agonists and antagonists of the AR have been suggested as therapeutic approaches. Herein, we review the role of AR signaling in BrCa and the molecular cross-talk mechanisms with other molecules/pathways, as well as its therapeutic implications in the different subtypes of the disease.
Genes and environment, 2017
Breast cancer research : BCR, 2005
Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial... more Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.
Experimental Biology and Medicine, May 7, 2015
Advanced glycation end-products (AGEs) may interfere with insulin intracellular signaling and glu... more Advanced glycation end-products (AGEs) may interfere with insulin intracellular signaling and glucose transport in human granulosa cells, potentially affecting ovarian function, follicular growth, linked with diminished fertility. The potential interaction of AGEs with insulin signaling pathways and glucose transport was investigated in human granulosa KGN cells. KGN cells were cultured with variable concentrations of human glycated albumin (HGA, 50-200 mg/mL) or insulin (100 ng/mL). Combined treatments of KGN cells with insulin (100 ng/mL) and HGA (200 mg/mL) were also performed. p-AKT levels and glucose transporter type 4 (Glut-4) translocation analysis were performed by Western blot. Phosphatidylinositol-3-kinase (PI3K)-specific signaling was checked by using the PI3K-inhibitor, LY294002. p-AKT levels were significantly increased following insulin treatment compared to basal levels or HGA exposure. This insulin-mediated AKT-phosphorylation was PI3K-specific and it was inhibited after combined treatment of insulin and HGA. Furthermore, Glut-4 translocation from the cytoplasm to the membrane compartments of KGN cells was remarkably reduced after the combined treatment of insulin and HGA. The present findings support that AGEs interfere with insulin signaling in granulosa cells and prevent Glut-4 membrane translocation suggesting that intra ovarian AGEs accumulation, from endogenous or exogenous sources, may contribute to the pathophysiology of states characterized with anovulation and insulin resistance such as polycystic ovary syndrome.
Endocrine Abstracts, May 1, 2015
The anticancer action of vitamin D is currently considered one of its main properties. The main a... more The anticancer action of vitamin D is currently considered one of its main properties. The main actions of vitamin D are related to the regulation of calcium levels and the normal function of the musculoskeletal system. However, its anticancer action is currently in the focus of research interests.
Critical Reviews in Oncology Hematology, Oct 1, 2019
Kisspeptins are a family of neuropeptides that are known to be critical in puberty initiation and... more Kisspeptins are a family of neuropeptides that are known to be critical in puberty initiation and ovulation. Apart from that kisspeptin derived peptides (KPs) are also known for their antimetastatic activities in several malignancies. Herein we report recent evidence of the role of kisspeptins in cancer biology and we examine the prospective of targeting the kisspeptin pathways leading to a better prognosis in patients with malignant diseases.
Journal of Hepatology, Aug 1, 2020
The Journal of Clinical Endocrinology and Metabolism, Mar 1, 2011
Context: Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbo... more Context: Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbonate plastics. In experimental animals, neonatal exposure to BPA results in a polycystic ovary-like syndrome (PCOS) in adulthood. A bidirectional interaction between androgens and BPA levels has been disclosed. To determine BPA levels in PCOS women as well as the association between BPA and hormonal/metabolic parameters compared to a control group. Design, Setting, and Participants: Cross-sectional study of 71 PCOS (National Institutes of Health criteria) and 100 normal women, age-and body mass index-matched, in a University hospital setting. Main Outcome Measures: Anthropometric, hormonal, metabolic parameters and BPA blood levels were determined. Patients (PCOS) and controls (C) were further subdivided according to body mass index into lean and overweight subgroups, respectively. Results: BPA levels were significantly higher in the total PCOS group compared with the controls (1.05Ϯ0.56 vs. 0.72Ϯ0.37ng/ml, P Ͻ 0.001). PCOS women, lean (PCOS-L) and overweight (PCOS-OW), had higher BPA levels compared to the corresponding control group lean (C-L) and overweight (C-OW): (PCOS-L ϭ 1.13Ϯ0.63 vs. C-L ϭ 0.70Ϯ0.36, P Ͻ 0.001) (PCOS-OW ϭ 0.96 Ϯ 0.46 vs. C-OW ϭ 0.72 Ϯ 0.39, P Ͻ 0.05). A significant association of testosterone (r ϭ 0.192, P Ͻ 0.05) and androstenedione (r ϭ 0.257, P Ͻ 0.05) with BPA was observed. Multiple regression analysis for BPA showed significant correlation with the existence of PCOS (r ϭ 0.497, P Ͻ 0.05). BPA was also positively correlated with insulin resistance (Matsuda index) in the PCOS group (r ϭ 0.273, P Ͻ 0.05). Higher BPA levels in PCOS women compared to controls and a statistically significant positive association between androgens and BPA point to a potential role of this endocrine disruptor in PCOS pathophysiology. (J Clin Endocrinol Metab 96: E480 -E484, 2011) B isphenol A (BPA), an estrogen-mimic industrial com- pound, is one of the world's most widely produced synthetic chemicals and is used in food and drink packaging, plastic consumer products, and dental materials (1, 2). Hu-man exposure to BPA, one of the most abundant endocrine disruptors, is considered widespread and continuous (3-5).
Medicine and Science in Sports and Exercise, Jun 1, 2019
Long interspersed nuclear element-1 (LINE-1 or L1) is termed a genomic parasite due to its abilit... more Long interspersed nuclear element-1 (LINE-1 or L1) is termed a genomic parasite due to its ability to randomly copy and paste itself back into the genome. Studies have shown that L1 accounts for roughly 17-18% of the total human genome. However, due to various mutations in most of the L1 elements, only approximately 100 copies are functionally active. L1 has been shown to increase with age in mice skeletal muscle tissue. However, there is no data regarding the effects of aging on L1 activity in rat skeletal muscle tissue. PURPOSE: To identify the effects of aging on L1 expression in rat skeletal muscle tissue. METHODS: Sedentary male fischer 344 rats were fed ad libitum and were aged to 3, 12, and 24 months (mo) (n=9 per age group) and then sacrificed. Primer sets for qPCR were designed for the youngest most active form of L1 (L1.3), and older L1 elements (L1.Tot). Gastrocnemius skeletal muscle was harvested and then processed for RNA and DNA isolation. Thereafter, the following analysis ensued: L1 mRNA expression, L1 DNA copy number, L1 promotor methylation and ORF1 protein. Additionally, a subset of the tissues from 3 mo (n=8) and 24 mo (n=8) were shipped to LC Sciences for RNA sequencing to analyze L1 related genes. RESULTS: Primer sets designed for both L1.3 and L1.tot significantly increased with age (L1.3, p=0.003; L1.Tot, p=0.003), and was higher at 24 mo compared to 3 mo (p<0.01). L1.3 integration into the genome was significantly higher at 24 mo compared to 3 mo (p=0.021). ORF1 protein expression significantly increased with age (p<0.001), and was higher in both the 12 and 24 mo compared to 3 mo (p<0.05). There was no statistical difference for L1 promotor methylation. From RNA sequencing CTCF was significantly higher in 24 mo compared to 3 mo (p=0.011). CONCLUSION: L1 gene expression appears to increase with age, which leads to more random insertions back into the genome. This may be a result of an increase in CTCF binding, acting as a co-activator at the L1 promotor, but this hypothesis needs validation. Additionally, L1 promotor methylation, while not statistically significant, was numerically lower with age and this decrease could be contributing to the increase in L1 gene expression. Thus, we provide novel insight as to how L1 gene regulation is altered with age, but more research is need to test how L1 is affecting skeletal muscle health.
Journal of Viral Hepatitis, Dec 16, 2020
Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under... more Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long‐term oral antiviral therapy, but its pathogenesis in the setting of long‐standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell‐free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg‐negative CHB patients with (HCC cases, n = 37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n = 74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNase P coding DNA, copies of mitochondrial DNA and levels of 5‐methyl‐2′‐deoxycytidine as an indicator of DNA methylation was performed. HCC cases compared with controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, p = .042) and RNase P coding DNA (68 vs 15 genomic equivalent, p &lt; .001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNase P coding DNA offered good prediction of subsequent HCC development (c‐statistic: 0.80, p &lt; .001). In conclusion, serum levels of RNase P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg‐negative CHB patients.
The FASEB Journal, Jan 9, 2020
In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resul... more In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity-and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during
Endocrine Abstracts, May 1, 2015
Context: Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbo... more Context: Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbonate plastics. In experimental animals, neonatal exposure to BPA results in a polycystic ovary-like syndrome (PCOS) in adulthood. A bidirectional interaction between androgens and BPA levels has been disclosed. To determine BPA levels in PCOS women as well as the association between BPA and hormonal/metabolic parameters compared to a control group. Design, Setting, and Participants: Cross-sectional study of 71 PCOS (National Institutes of Health criteria) and 100 normal women, age-and body mass index-matched, in a University hospital setting. Main Outcome Measures: Anthropometric, hormonal, metabolic parameters and BPA blood levels were determined. Patients (PCOS) and controls (C) were further subdivided according to body mass index into lean and overweight subgroups, respectively. Results: BPA levels were significantly higher in the total PCOS group compared with the controls (1.05Ϯ0.56 vs. 0.72Ϯ0.37ng/ml, P Ͻ 0.001). PCOS women, lean (PCOS-L) and overweight (PCOS-OW), had higher BPA levels compared to the corresponding control group lean (C-L) and overweight (C-OW): (PCOS-L ϭ 1.13Ϯ0.63 vs. C-L ϭ 0.70Ϯ0.36, P Ͻ 0.001) (PCOS-OW ϭ 0.96 Ϯ 0.46 vs. C-OW ϭ 0.72 Ϯ 0.39, P Ͻ 0.05). A significant association of testosterone (r ϭ 0.192, P Ͻ 0.05) and androstenedione (r ϭ 0.257, P Ͻ 0.05) with BPA was observed. Multiple regression analysis for BPA showed significant correlation with the existence of PCOS (r ϭ 0.497, P Ͻ 0.05). BPA was also positively correlated with insulin resistance (Matsuda index) in the PCOS group (r ϭ 0.273, P Ͻ 0.05). Higher BPA levels in PCOS women compared to controls and a statistically significant positive association between androgens and BPA point to a potential role of this endocrine disruptor in PCOS pathophysiology. (J Clin Endocrinol Metab 96: E480 -E484, 2011) B isphenol A (BPA), an estrogen-mimic industrial com- pound, is one of the world's most widely produced synthetic chemicals and is used in food and drink packaging, plastic consumer products, and dental materials (1, 2). Hu-man exposure to BPA, one of the most abundant endocrine disruptors, is considered widespread and continuous (3-5).
Surgery in Practice and Science
Cureus
Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is... more Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis approaches 6%-10% in the general female population, and in women with pain, infertility, or both, the frequency is 35%-50%. The gold standard recommended process for diagnosing endometriosis is laparoscopy, an invasive surgical procedure, with or without histologic verification. The currently available nonsurgical treatments include oral contraceptives (estrogen-progestogen preparations), progestogen preparations (containing progesterone derivatives), androgenic hormones (danazol), and gonadotropin-releasing hormone (GnRH) agonists and antagonists. Two GnRH types have been discovered in mammals, GnRH I and GnRH II. In particular, GnRH I is released by the hypothalamus; however, it can be present in various tissues and organs of the body, including neural tissue, where it exerts neuroendocrine, autocrine, and paracrine actions in the peripheral and central nervous system (CNS). Interestingly, another GnRH isoform, GnRH III, has been identified, which has 60% similarity with GnRH I from which it varies by four amino acids. This peptide has been shown to have a significant role in reproduction, specifically in gametogenesis and steroidogenesis. Further research is needed to identify innovative treatment options for endometriosis, such as the therapeutic exogenous administration of GnRH II or antagonists of the GnRH I receptor. In this review, we examined the role of GnRH in endometriosis, outlining the specific actions of GnRH and GnRH receptors (GnRHRs). The innovative use of GnRH analogs and antagonists in the treatment of endometriosis is also discussed.
Reviews in Cardiovascular Medicine
Background: Peripheral myopathy consists a hallmark of heart failure (HF) and has been associated... more Background: Peripheral myopathy consists a hallmark of heart failure (HF) and has been associated with poor prognosis. Inflammation has been suggested to dominate this pathology, while exercise training is typically associated with the induction of anti-inflammatory mechanisms. However, the current knowledge regarding the involvement of inflammation-related genes in the exercise training-induced muscle adaptations in HF patients is very limited. Given that high-intensity interval training (HIIT) alone or combined with strength training (COM) has gained ground in HF cardiac rehabilitation, this study aimed to investigate the local muscle expression of inflammatory and tissue remodeling factors in HF patients, who underwent 3 months of these training schemes. In addition, we examined whether these exercise training-induced gene expression responses are associated with changes in exercise capacity in those patients. Methods: Thirteen male patients with chronic HF (age: 51 ± 13 y; body mass index (BMI): 27 ± 4 kg/m 2 ) were randomly assigned to a 3-month exercise program consisted of either HIIT (N = 6) or COM training (N = 7). Muscle tissue biopsies were obtained from vastus lateralis pre-and post-training and transcriptional changes in interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-1 alpha (TNF-1α), urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and transforming growth factor-beta 1 (TGF-β1) were quantified by RT-PCR. Results: An overall increase in the expression levels of selected inflammatory (IL-8, TNF-1α) and remodeling factors (uPAR) was found post-training (p < 0.05), while IL-6, uPA and TGF-β1 gene expression remained unchanged (p > 0.05). The observed alterations did not differ between training groups. Additionally, IL-8 changes were found to be correlated with the improvement in exercise capacity post-training (p < 0.05). Conclusions: This is the first study demonstrating an increase in intramuscular inflammatory and remodeling key factors induced by HIIT or COM training in HF patients. Combining these observations with our previous findings of improved muscle hypertrophy and capillarization post-training in these patients, the findings of the present study may suggest that inflammatory responses are part of an ongoing remodeling process in the exercising skeletal muscle. Clinical Trial Registration: NCT02387411.
Medicine and Science in Sports and Exercise, Sep 1, 2022
Medicine & Science in Sports & Exercise
Hospital chronicles, 2016
BACKGROUND: The implementation of global guidelines for asthma management aims at asthma control.... more BACKGROUND: The implementation of global guidelines for asthma management aims at asthma control. The aim of this study was to investigate the implementation of asthma management guidelines by both patients and physicians in two general pulmonary outpatient clinics in Greece. METHODS: Two questionnaires were administered to pulmonologists (n=43) and patients (n=181) separately. Asthma control was assessed by Asthma Control Test. RESULTS: All physicians informed their patients about asthma and suggested regular visits. The vast majority educated their patients to recognize symptom deterioration (n=42, 97.7%) and asthma triggers (n=41, 95.3%), to readjust treatment (n=41, 95.3%) and use correctly the inhaler devices (n=40, 93%). Greek pulmonologists suggested physical activity (n=40, 93%), peak flow meter use (n=13, 30.2%) and asthma physiotherapy (n=10, 23.3%), while 13 (30.2%) provided a written action plan. Among 181 participants with asthma, 41 (22.7%) had hyperventilation, while ...
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Papers by Michael Koutsilieris