Serum levels of sirtuins, leptin and adiponectin in women with pregnancy-induced hypertension.

INTRODUCTION: Pregnancy-induced hypertension (PIH) and preeclampsia (PE) are associated with disturbed maternal inflammatory response, oxidative stress and vascular endothelial cell dysfunction. Obesity is one of risk factors of PE. Leptin is elevated in obesity and its level correlates positively with the amount of adipose tissue. In contrast, adiponectin levels are decreased in obesity. Sirtuins are expressed in the placenta, however their role in pregnancy-related pathology in humans is not known. AIM OF THE STUDY: The aim of our study was to measure serum concentrations of selected sirtuins, adiponectin and leptin in healthy pregnancy and in women with PIH. MATERIALS AND METHODS: The study included 70 women: 38 healthy pregnant women and 32 women with PIH. Blood samples were obtained between the 20th and 40th week of gestation. Serum levels of sirtuins 1, 3, 6, leptin and adiponectin were measured with ELISA. RESULTS: Leptin levels were significantly higher in PIH group as compared to the controls and correlated positively with BMI. Highest leptin levels were observed in women who needed a cesarean section. Levels of sirtuins 1, 3 and 6 were similar in both groups and did not correlate with BMI. CONCLUSIONS: High leptin levels in PIH women during 3rd trimester might be helpful to predict the necessity for a caesarian section. Blood levels of sirtuins 1, 3 and 6 measured after the 20th week of gestation cannot be regarded as a single diagnostic test for PIH or preeclampsia. More studies to clarify significance of sirtuins in PIH and PE development and diagnosis are needed.

Growth hormone-releasing hormone antagonists counteract hydrogen peroxide - induced paracellular hyperpermeability in endothelial cells.

Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic peptide which regulates the release of Growth Hormone from the anterior pituitary gland, and has been involved in inflammatory processes. On the other hand, GHRH antagonists (GHRHAnt) were developed to counteract those effects. Herein we demonstrate for the first time that GHRHAnt can suppress hydrogen peroxide (H2O2) - induced paracellular hyperpermeability in bovine pulmonary artery endothelial cells. Increased production of reactive oxygen species (ROS) and barrier dysfunction have been associated with the development of potentially lethal disorders, including sepsis and acute respiratory distress syndrome (ARDS). Our study supports the protective actions of GHRHAnt in the impaired endothelium, and suggests that those compounds represent an exciting therapeutic possibility towards lung inflammatory disease.

New View on the Impact of the Low-Frequency Electromagnetic Field (50 Hz) on Stress Responses: Hormesis Effect.

INTRODUCTION: Low-frequency electromagnetic field (50 Hz) (EMF) can modify crucial neuronal processes. Existing data indicate that exposure to EMF may represent a mild stressor and contribute to disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. The important regulatory pathways controlling HPA axis activity include two types of corticosteroid receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors. They are particularly abundant in the hippocampus, a key locus of HPA axis feedback control. The research aimed at determining whether (1) EMF exhibits hormesis, it means bidirectional action depending on EMF intensity (1 or 7 mT) and (2) repeated EMF exposure changes stress response to subsequent stress factors. METHODS: The exposure (7 days, 1 h/day) of adult rats to EMF (1 mT and 7 mT) was repeated 3 times. HPA axis hormones and their receptors were analysed after each following exposure. Moreover, the impact of EMF exposure on hormonal and behavioural responses to subsequent stress factor - open-field test was evaluated. RESULTS: Our data suggest that exposure to EMF can establish a new "set-point" for HPA axis activity. The direction and dynamics of this process depend on the intensity of EMF and the number of exposures. EMF of 1 mT induced an adaptive stress response, but 7 mT EMF caused sensitization. Consequently, EMF changed the vulnerability of the organism to a subsequent stress factor. We have also shown the increase in MR mRNA abundance in the hippocampus of 1 mT EMF-exposed rats, which can represent the possible neuroprotective response and suggest therapeutic properties of EMFs.

Correlations between serum sirtuin levels and cardiovascular risk factors in women with polycystic ovary syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular disease (CVD) and metabolic complications often related to obesity, such as insulin resistance and type 2 diabetes mellitus (T2DM). Sirtuins (SIRTs) are nicotinamide adenine dinucleotide NAD+-dependent histone deacetylases, which modulate protein post-translational modifications (PTMs), gene transcription, increase repairing activities of DNA, and regulate metabolic processes. The aim of our study was to measure the serum levels of SIRTs 1, 2, 3, 6 and 7, and evaluate correlations between SIRTs levels and cardiovascular risk factors in women with PCOS. PATIENTS AND METHODS: The study included 54 women with PCOS and 33 healthy volunteers. Concentrations of SIRTs were measured by ELISA technique. RESULTS: Mean serum levels of SIRTs did not differ significantly between PCOS and controls. SIRTs 1, 2, and 6 positively correlated with HDL, while SIRTs 2 and 6 negatively correlated with LDL cholesterol. Negative correlation between SIRT 3 and HOMA-IR and negative correlations of SIRT 1 and 2 with insulin 120' in oral glucose tolerance test (OGTT) were demonstrated. A positive correlation between BMI and SIRT 7 concentration, and a positive correlation between body weight and SIRT 7 concentration were verified in the study group. The observed correlations between concentrations of SIRTs and metabolic parameters may indicate the involvement of these factors in the development of cardiometabolic complications. CONCLUSIONS: The results may indicate the involvement of SIRTs in the development of cardiometabolic complications. However, additional studies are required to validate this observation.

P53 mediates the protective effects of metformin in inflamed lung endothelial cells.

The endothelial barrier regulates interstitial fluid homeostasis by transcellular and paracellular means. Dysregulation of this semipermeable barrier may lead to vascular leakage, edema, and accumulation of pro-inflammatory cytokines, inducing microvascular hyperpermeability. Investigating the molecular pathways involved in those events will most probably provide novel therapeutic possibilities in pathologies related to endothelial barrier dysfunction. Metformin (MET) is an anti-diabetic drug, opposes malignancies, inhibits cellular transformation, and promotes cardiovascular protection. In the current study, we assess the protective effects of MET in LPS-induced lung endothelial barrier dysfunction and evaluate the role of P53 in mediating the beneficial effects of MET in the vasculature. We revealed that this biguanide (MET) opposes the LPS-induced dysregulation of the lung microvasculature, since it suppressed the formation of filamentous actin stress fibers, and deactivated cofilin. To investigate whether P53 is involved in those phenomena, we employed the fluorescein isothiocyanate (FITC) - dextran permeability assay, to measure paracellular permeability. Our observations suggest that P53 inhibition increases paracellular permeability, and MET prevents those effects. Our results contribute towards the understanding of the lung endothelium and reveal the significant role of P53 in the MET-induced barrier enhancement.

Metformin in acute respiratory distress syndrome: An opinion.

Senior individuals are more susceptible to the irreversible outcomes of endothelial barrier dysfunction, the hallmark of Acute Respiratory Distress Syndrome (ARDS). The Severe Acute Respiratory Syndrome Coronovirus 2 (SARS-CoV-2) - inflicted ARDS delivers the devastating outcomes of the COVID-19 worldwide. Endothelial hyperpermeability has been associated with both the progression and establishment of the COVID-19 - related respiratory failure. In the present study we investigated the in vitro effects of Metformin in the permeability of bovine pulmonary artery endothelial cells. Our preliminary results suggest that moderate doses (0.1, 0.5, 1.0 mM) of this anti-diabetic agent enhance the vascular barrier integrity, since it produces an increase in the transendothelial resistance of endothelial monolayers. Thus, we speculate that Metformin may deliver a new therapeutic possibility in ARDS, alone or in combination with other barrier enhancers.

Serum ß-Klotho concentrations are increased in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a significant cause of menstrual disorders and infertility in women. The aim of this study was to evaluate the levels of Klotho expression in women with polycystic ovary syndrome. The study involved 67 patients with PCOS, as well as 18 controls. Serum levels of FGF19, FGF21 and ß-Klotho were measured by ELISA technique. The blood samples were obtained between days 2 and 7 of menstrual cycle. The concentrations of ß-Klotho, FGF19 and FGF21 were significantly increased in patients with PCOS; and appear to be statistically significant predictors of PCOS incidence. FGF19 (p = 0.031, OR = 1.01), exact ß-Klotho levels (p = 0.022, OR = 1.01) and ß-Klotho beyond the reference range (p = 0.008, OR = 4.66) were the most strongly correlated with the diagnosis of PCOS. In conclusion, FGF19, FGF21 and ß-Klotho are increased in PCOS, and elevated ß-Klotho concentration may become an useful diagnostic test for this disease. However, additional studies are required to further substantiate this observation.

The highly interrelated GHRH, p53, and Hsp90 universe.

p53 universe is composed of a complex regulatory network, destined to counteract multifarious challenges threatening cell survival. Imbalance in those responses may result in human disease associated with inevitable consequences. The present work delivers our view of the corresponding phenomena, by involving the endothelium defender in meticulously orchestrated events against inflammatory stimuli. Immersing into the great depths of p53 cosmos may lead to promising therapies against devastating disorders, including acute respiratory distress syndrome.

Elevated serum concentrations of IGF-1 and IGF-1R in patients with thyroid cancers.

BACKGROUND: The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS: The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS: 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS: Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS: Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.

Dysregulation in IGF-1R, FGFR4 and ßKlotho signaling in patients with medullary thyroid cancer.

BACKGROUND: Medullary thyroid cancer (MTC) is a relatively rare thyroid neoplasm derived from neuroendocrine C cells which secrete calcitonin. αKlotho (αKL) and ßKlotho (ßKL) are transmembrane proteins which modulate different signaling systems, such as endocrine FGFs and IGF1 pathways. Dysregulation of the FGF19/FGFR4/ßKL and IGF-1/IGF-1R/αKL signaling axes has been implicated in the pathogenesis of several cancers. However, their role in the pathogenesis of MTC has not been determined. METHODS: The aim of this study was to assess αKL, ßKL, FGF19, IGF-1, FGFR4, and IGF-1R concentrations in a group of 11 patients with medullary thyroid cancer (MTC). The control group consisted of 20 healthy volunteers. Serum concentrations of these factors were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGFR4 and IGF-1R were found in patients with MTC as compared to controls. CONCLUSIONS: Our results indicate that a disrupted signaling pathway for ßKL, FGFR4 and IGF-1R may play a role in the development of medullary thyroid cancers. However, further studies are required to confirm these findings and to use this knowledge in clinical practice.

P53 supports endothelial barrier function via APE1/Ref1 suppression.

The tumor suppressor protein P53 is strongly involved in orchestrating cellular defenses in the diverse variety of human tissues. Anomalies to lung endothelium permeability are streaming severe consequences towards human health, often associated with fatal outcomes. Ongoing investigations suggest that P53 exerts a prominent strategic role in crucial signaling cascades, in charge of both the maintenance and defense of pulmonary endothelium against toxic intruders. The current study employs human and bovine lung microvascular cells, as well as pharmacologic and genetic P53 modulators to demonstrate the negative regulation of APE1/Ref1 by P53. Moreover, it includes real time measurements of endothelial permeability, to reveal the disruptive role of APE1/Ref1 towards endothelial integrity. Those findings supports our efforts to elucidate the highly sophisticated regulatory network that enact endothelial adaptations under the plethora of challenging environmental factors.

P53, GHRH, inflammation and cancer.

P53 is a transcription factor very often mutated in malignancies. It functions towards the regulation of important cellular activities, such as cell cycle, senescence and apoptosis. Since inflammation and cancer are strongly associated through common pathways, P53 can suppress inflammation in a plethora of human tissues. Growth Hormone - Releasing Hormone is a hypothalamic peptide with a great capacity to affect the complex networks of cellular regulation via GHRH - specific receptors. GHRH antagonistic and agonistic analogs have been developed for clinical applications, including treatment of benign prostatic hyperplasia, breast, prostate and lung cancers, diabetes and neurodegenerative diseases. The epicenter of the current manuscript is the protective role of P53 against inflammation and cancer and emphasizes the p53 - mediated beneficial effects of GHRH antagonists in various human diseases.

[Quality of life in patients with orbitopathy - single center experience]. / Jakosc zycia chorych z orbitopatia tarczycowa.

Thyroid-associated orbitopathy is a syndrome of eye symptoms produced by immunological inflammation of soft tissues of orbit,mostly due to Graves-Basedow disease. This disease is accompanied by proptosis, oedema of lids, double vision, tearing and photophobia. These symptoms lead to significant deterioration of quality of life due to reduction of sharpness of sight and therefore worsen emotional condition of patients. AIM: The aim of study was to assess the impact of Graves orbitopathy on quality of life. Additional aim was assessement of deppression among the subjects. MATERIALS AND METHODS: Study in form of anonymous modified questionnaire EUGOGO grading quality of life of patients with thyroidassociated orbitopathy and the scale of depression by Beck - carried out directly among 30 patients of Clinic od Endocrinology of the Medical Univeristy of Lódz (22 female and 8 male) from November 2011 to April 2012. RESULTS: Patients with thyroid-associated orbitopathy have considerably reduced quality of life - carried out qestionnaires showed they have problems with everyday activity like: riding bicycle (17 patients - 57%), driving car (14 patients - 45%), moving in apartment and outside (9 patients - 30%), watching TV (21 patients - 17%) and reading books (25 patients - 83%). Furthermore, many patients with thyroidassociated orbitopathy have serious emotional disorders - 20 persons have symptoms of depression. CONCLUSIONS: Graves orbitopathy have negative influence on quality of life. Orbitopathy worsens self-evaluation of patients, their interpersonal contacts, making new acquaintances, working and finding new job. Furthermore, many patients with thyroid-associated orbitopathy have serious emotional disorders. It seems reasonable to include psychotherapist in the therapeutic process.

Alteration in the serum concentrations of FGF19, FGFR4 and ßKlotho in patients with thyroid cancer.

INTRODUCTION: ßKlotho (ßKL) is known to act as co-receptor for fibroblast growth factor receptor 4 (FGFR4) which is the main cognate receptor for fibroblast growth factor 19 (FGF19). Dysregulation of this FGF19/FGFR4/ßKL signaling axis has been implicated in the pathogenesis of several cancers. However, its role in the pathogenesis of thyroid cancer has not been determined. MATERIALS AND METHODS: The aim of this study was to assess FGF19, FGFR4 and ßKL concentrations in a group of 36 patients with papillary thyroid cancer (PTC), 11 patients with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and a group of 19 subjects with multinodular nontoxic goiter (MNG). The control group consisted of 20 healthy volunteers. Serum FGF19, FGFR4 and ßKL concentrations were measured using specific ELISA methods. RESULTS: Significantly lower concentrations of ßKL and higher concentrations of FGF19 were found in patients with PTC, FTC and ATC as compared with MNG group and controls. An elevation of FGFR4 serum concentration was observed in all thyroid cancer groups in comparison to MNG group and controls; however, in FTC group it was statistically insignificant. A positive correlation was found between ßKL and FGFR4 concentrations in PTC patients. The levels of ßKL, FGF19 and FGFR4 did not differ significantly between MNG group and healthy controls. CONCLUSIONS: Our results indicate that a disrupted FGF19/FGFR4/ßKL signaling pathway may play a role in the development of thyroid cancers. However, further studies are needed to elucidate the molecular mechanism of the neoplastic transition of thyroid epithelial cells.

The pathogenesis and treatment of polycystic ovary syndrome: What's new?

Polycystic ovary syndrome (PCOS) is currently the leading cause of menstrual complications in women. It is characterized by clinical and/or biochemical hyperandrogenism, ovulation abnormalities and the presence of enlarged and/or polycystic ovaries in ultrasound images (12 or more small bubbles located circumferentially and/or ovarian volume > 10 mL). It is often comorbid with hyperinsulinemia, dyslipidemia, overweight or obesity, and is a risk factor for the development of diabetes and cardiovascular diseases (CVDs). The treatment of patients with PCOS depends on the prevailing symptoms. The aim of this paper is to present the etiopathogenesis, clinical and biochemical implications, and non-pharmacological and pharmacological treatment options - those approved by worldwide scientific organizations as well as new therapies whose initial results are encouraging enough to prompt researchers to explore them further.

Deferoxamine improves antioxidative protection in the brain of neonatal rats: The role of anoxia and body temperature.

After hypoxic-ischemic insult iron deposited in the brain catalyzes formation of reactive oxygen species. Newborn rats, showing reduced physiological body temperature and their hyperthermic counterparts injected with deferoxamine (DF), a chelator of iron, are protected both against iron-mediated neurotoxicity and against depletion of low-molecular antioxidants after perinatal asphyxia. Therefore, we decided to study the effects of DF on activity of antioxidant enzymes (superoxide dismutase-SOD, glutathione peroxidase-GPx and catalase-CAT) in the brain of rats exposed neonatally to a critical anoxia at body temperatures elevated to 39°C. Perinatal anoxia under hyperthermic conditions intensified oxidative stress and depleted the pool of antioxidant enzymes. Both the depletion of antioxidants and lipid peroxidation were prevented by post-anoxic DF injection. The present paper evidenced that deferoxamine may act by recovering of SOD, GPx and CAT activity to reduce anoxia-induced oxidative stress.

Deferoxamine prevents cerebral glutathione and vitamin E depletions in asphyxiated neonatal rats: role of body temperature.

Hypoxic-ischaemic brain injury involves increased oxidative stress. In asphyxiated newborns iron deposited in the brain catalyses formation of reactive oxygen species. Glutathione (GSH) and vitamin E are key factors protecting cells against such agents. Our previous investigation has demonstrated that newborn rats, showing physiological low body temperature as well as their hyperthermic counterparts injected with deferoxamine (DF) are protected against iron-mediated, delayed neurotoxicity of perinatal asphyxia. Therefore, we decided to study the effects of body temperature and DF on the antioxidant status of the brain in rats exposed neonatally to critical anoxia. Two-day-old newborn rats were exposed to anoxia in 100% nitrogen atmosphere for 10 min. Rectal temperature was kept at 33 °C (physiological to rat neonates), or elevated to the level typical of healthy adult rats (37 °C), or of febrile adult rats (39 °C). Half of the rats exposed to anoxia under extremely hyperthermic conditions (39 °C) were injected with DF. Cerebral concentrations of malondialdehyde (MDA, lipid peroxidation marker) and the levels of GSH and vitamin E were determined post-mortem, (1) immediately after anoxia, (2) 3 days, (3) 7 days, and (4) 2 weeks after anoxia. There were no post-anoxic changes in MDA, GSH and vitamin E concentrations in newborn rats kept at body temperature of 33 °C. In contrast, perinatal anoxia at elevated body temperatures intensified oxidative stress and depleted the antioxidant pool in a temperature-dependent manner. Both the depletion of antioxidants and lipid peroxidation were prevented by post-anoxic DF injection. The data support the idea that hyperthermia may extend perinatal anoxia-induced brain lesions.

Decreased serum level of IL-7 in patients with active Graves' disease.

BACKGROUND: Graves' disease (GD) is a common autoimmune disease which is one of the major causes of hyperthyroidism. Interleukin 7 (IL-7) has been recently reported to play an important role in various autoimmune diseases, but its role in the pathogenesis of GD has not been assessed. The aim of this study was to evaluate the levels of IL-7 and the soluble form of its receptor (sIL-7R) in the serum of GD patients, and to identify their association with disease activity. METHODS: A total of 37 GD patients were enrolled into the experimental group and 16 individuals into the control group. All patients were further classified into three subgroups: a GD-active group (hyperthyroidism and TRAb (thyroid stimulating hormone receptor antibody) >7.5 U/L) (N=15), a GD-inactive group (euthyreosis and TRAb<1 U/L) (N=8), and other GD patients (euthyreosis and TRAb>1 U/L) (N=14). Concentrations of IL-7 and sIL-7R were assayed with ELISA. Additionally, the relationship between IL-7 and sIL-7R serum concentrations with disease activity (free triiodothyronine [FT3], free thyroxine [FT4], thyroid stimulating hormone [TSH] and TRAb) was also analyzed. RESULTS: The serum concentrations of IL-7 in GD-active patients were significantly lower than those of the control group as well as the GD-inactive and GD-other groups. The serum level of IL-7 in GD patients negatively correlated with FT4 and TRAb concentrations. Moreover, no significant difference was observed in the serum level of sIL-7R in GD patients compared to the control group. CONCLUSIONS: These observations suggest that IL-7 may play a role in the pathogenesis of GD and may be associated with its clinical activity. To this end, the serum level of IL-7 could be an additional diagnostic biomarker predictive of the disease and could be particularly valuable for TRAb-negative GD patients.