Commenced in January 2007
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Edition: International
Paper Count: 18

Search results for: hypothalamus

18 Light and Electron Study of Acrylamide–Induced Hypothalamic Changes

Authors: Keivan Jamshidi


Distal swelling and eventual degeneration of axon in the CNS and PNS have been considered to be the characteristic neuropathological effects of acrylamide (ACR) neuropathy. This study was conducted to determine the neurotoxic effects of different doses of ACR (0.5, 5, 50, 100, and 500 mg/kg per day × 11days i. p.) on hypothalamus of rat using the de Olmos amino cupric-silver stain and electron microscopy. For this purpose 60 adult male rats (Wistar, approximately 250 g) were randomly assigned in 5 treatment groups as A, B, C, D, E) exposed to 0.5, 5, 50, 100, and 500 mg/kg per dayx11days i. p. and one control group as F received daily i. p. injections of 0.9% saline (3ml/kg). As indices of developing neurotoxicity, weight gain, gait scores and landing hindlimb foot splay were determined. After 11 days, two rats for silver stain, and two rats for EM were randomly selected; dissected and proper samples were collected from hypothalamus. Results did show no neurological behavior in groups A, B and F were observed in group C. Rats in groups D and E died within 1-2 hours due to sever toxemia. In histopathological studies based on de Olmos technique no argyrophilic neurons or processes were observed in stained sections obtained from hypothalamus of rats belong to groups A, B, and F while moderate to severe argyrophilic changes were observed in different nuclei and regions of stained sections obtained from hypothalamus of rats belong to group C. In ultra-structural studies some variations in the myelin sheet of injured axons including decompactation, interlaminar space formation, disruption of the laminar sheet, accumulation of neurofilaments, vacculation, and clumping inside the axolem, and finally complete disappearance of laminar sheet were observed.

Keywords: acrylamide, hypothalamus, rat, de Olmos amino cupric, silver stain, electron microscopy

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17 Light and Electron Microscopy Study of Acrylamide-Induced Hypothalamic Neuropathy

Authors: Keivan Jmahidi, Afshin Zahedi


To evaluate neurotoxic effects of ACR on hypothalamus of rat, amino-cupric silver staining technique of de Olmos and electron microscopic examination were conducted. For this purpose 60 adult male Wistar rats (± 250 g) were selected. Randomly assigned groups of rats (10 rats per exposure group, as A, B, C, D, E) were exposed to 0.5, 5, 50, 100 and 500 mg/kg per day×11days i.p. respectively. The remaining 10 rats were housed in group F as control group. Control rats received daily i.p. injections of 0.9% saline (3ml/kg). As indices of developing neurotoxicity, daily weight gain, gait scores and landing hindlimb foot splay (LHF) were determined. After 11 days, two rats for silver stain, and two rats for EM, were randomly selected, dissected and proper samples were collected from hypothalamus. Rats in groups D and E died within 1-2 hours due to sever toxemia. In histopathological studies no argyrophilic neurons or processes were observed in stained sections obtained from hypothalamus of rats belong to groups A, B and F, while moderate to severe argyrophilic changes were observed in different nuclei and regions of stained sections obtained from hypothalamus of rats belong to group C. In ultrastructural studies some variations in the myelin sheet of injured axons including decompactation, interlaminar space formation, disruption of the laminar sheet, accumulation of neurofilaments, vacculation and clumping inside the axolem, and finaly complete disappearance of laminar sheet were observed.

Keywords: acrylamide (ACR), amino-cupric silver staining technique of de Olmos, argyrophilia, hypothalamic neuropathy

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16 Stability Analysis for an Extended Model of the Hypothalamus-Pituitary-Thyroid Axis

Authors: Beata Jackowska-Zduniak


We formulate and analyze a mathematical model describing dynamics of the hypothalamus-pituitary-thyroid homoeostatic mechanism in endocrine system. We introduce to this system two types of couplings and delay. In our model, feedback controls the secretion of thyroid hormones and delay reflects time lags required for transportation of the hormones. The influence of delayed feedback on the stability behaviour of the system is discussed. Analytical results are illustrated by numerical examples of the model dynamics. This system of equations describes normal activity of the thyroid and also a couple of types of malfunctions (e.g. hyperthyroidism).

Keywords: mathematical modeling, ordinary differential equations, endocrine system, delay differential equation

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15 Macronutrients and the FTO Gene Expression in Hypothalamus: A Systematic Review of Experimental Studies

Authors: Saeid Doaei


The various studies have examined the relationship between FTO gene expression and macronutrients levels. In order to obtain better viewpoint from this interactions, all of the existing studies were reviewed systematically. All published papers have been obtained and reviewed using standard and sensitive keywords from databases such as CINAHL, Embase, PubMed, PsycInfo, and the Cochrane, from 1990 to 2016. The results indicated that all of 6 studies that met the inclusion criteria (from a total of 428 published article) found FTO gene expression changes at short-term follow-ups. Four of six studies found an increased FTO gene expression after calorie restriction, while two of them indicated decreased FTO gene expression. The effect of protein, carbohydrate and fat were separately assessed and suggested by all of six studies. In conclusion, the level of FTO gene expression in hypothalamus is related to macronutrients levels. Future research should evaluate the long-term impact of dietary interventions.

Keywords: obesity, gene expression, FTO, macronutrients

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14 Distribution of Putative Dopaminergic Neurons and Identification of D2 Receptors in the Brain of Fish

Authors: Shweta Dhindhwal


Dopamine is an essential neurotransmitter in the central nervous system of all vertebrates and plays an important role in many processes such as motor function, learning and behavior, and sensory activity. One of the important functions of dopamine is release of pituitary hormones. It is synthesized from the amino acid tyrosine. Two types of dopamine receptors, D1-like and D2-like, have been reported in fish. The dopamine containing neurons are located in the olfactory bulbs, the ventral regions of the pre-optic area and tuberal hypothalamus. Distribution of the dopaminergic system has not been studied in the murrel, Channa punctatus. The present study deals with identification of D2 receptors in the brain of murrel. A phylogenetic tree has been constructed using partial sequence of D2 receptor. Distribution of putative dopaminergic neurons in the brain has been investigated. Also, formalin induced hypertrophy of neurosecretory cells in murrel has been studied.

Keywords: dopamine, fish, pre-optic area, murrel

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13 Physiology of Temporal Lobe and Limbic System

Authors: Khaled A. Abdel-Sater


There are four areas of the temporal lobe. Primary auditory area (areas 41 and 42); it is for the perception of auditory impulse, auditory association area (area 22, 21, and 20): Areas 21 and 20 are for understanding and interpretation of auditory sensation, recognition of language, and long-term memories. Area 22, also called Wernicke’s area, and a sensory speech centre. It is for interpretation of auditory and visual information, formation of thoughts in the mind, and choice of words to be used. Ideas and thoughts originate in it. The limbic system is a part of cortical and subcortical structure forming a ring around the brainstem. Cortical structures are the orbitofrontal area, subcallosal gyrus, cingulate gyrus, parahippocampal gyrus, and uncus. Subcortical structures are the hypothalamus, hippocampus, amygdala, septum, paraolfactory area, anterior nucleus of the thalamus portions of the basal ganglia. There are several physiological functions of the limbic system, including regulation of behavior, motivation, and emotion.

Keywords: limbic system, motivation, emotions, temporal lobe

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12 Development Of Diabetes Mellitus In Overweight People

Authors: Ashiraliyev SHavkat


Relevance of the topic: Diabetes mellitus in overweight people development and absence of treatment measures. Objective: to give patients the correct instructions on proper nutrition, to organize a network of preventive and therapeutic measures. Materials and methods: Multidisciplinary Tashkent Medical Academy. As a result of objective observations in patients who applied to the clinic, 28 11 overweight patients had to type 2 diabetes. Diabetesmellituswasdiagnosed. Results: 11.5 mmol / L on an empty stomach in the morning. EDT yes. Pathogenesis: fat content in the diet of patients with diabetes mellitus. Carbohydrate foods make up 60%. Eating disorders and physical inactivity As a result, the accumulation of glucose in the form of fat increases, and this is constantly in the blood, which led to an increase in the number of fatty acids. Clinic: Frequent fasting in 11 patients (hypothalamus). Associated with glucose deficiency), drinking 8-9 liters of water per day of blood in 7 people Systolic pressure 150 diastolic pressures 100. Sensation of ants in 3 people and poor eyesight in 5 people. Conclusion: Explain to patients that nutritional guidelines should be followed. Assign active movement in accordance with the energy entering the body.

Keywords: mellitus, diabetes, pathogenesis, clinic

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11 Dopamine and Female Sexual Function: A Clinical and Biochemical Study

Authors: Azza Gaber Antar Farag, Eman Abd El Fatah Badr, Wesam Ahmed Tawfik Hasssan Abdel Aal, Mustafa Elsayed Elshaib


Background: Female Sexual Dysfunction (FSD) represents recurrent and persistent problems that distress women and/or strain their relationships with their partners. Dopamine can affect sexual function and interacts with ovarian hormones in the ventromedial area in the hypothalamus. Objective: To investigate the possible role of dopamine in FSD. Method: This prospective case-control study was carried on 100 women having FSD and 100 healthy volunteer females. They were recruited from the Al-Menoufia governorate. All included women were subjected to the questionnaire to assess their demographic and gynecological data as well as sexual function. They were investigated for serum levels of dopamine, estradiol, progesterone and DHEA hormones. Results: Dopamine serum levels were significantly lower in females having sexual dysfunction (6.68±4.14) than controls (57.97±26.26) (P>0.001). This decreased dopamine level was of a significant positive correlation with the arousal domain and significant negative correlation regarding the pain domain (r=-0.19, p=0.01). Also, estradiol serum levels were significantly lower (P>0.001), but progesterone and DHEA serum levels were significantly higher in the FSD group than controls (P>0.001). There was a significant negative correlation between dopamine and DHEA serum levels (r= -0.45, p <0.001). Conclusions: Decreased dopamine serum levels may have an active role in the pathophysiology of FSD, impacting mainly arousal and pain domains, and its targeting should be considered during FSD management.

Keywords: dopamine, estradiol, progesterone, DHEA, females sexual dysfunction

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10 The Fabrication of Stress Sensing Based on Artificial Antibodies to Cortisol by Molecular Imprinted Polymer

Authors: Supannika Klangphukhiew, Roongnapa Srichana, Rina Patramanon


Cortisol has been used as a well-known commercial stress biomarker. A homeostasis response to psychological stress is indicated by an increased level of cortisol produced in hypothalamus-pituitary-adrenal (HPA) axis. Chronic psychological stress contributing to the high level of cortisol relates to several health problems. In this study, the cortisol biosensor was fabricated that mimicked the natural receptors. The artificial antibodies were prepared using molecular imprinted polymer technique that can imitate the performance of natural anti-cortisol antibody with high stability. Cortisol-molecular imprinted polymer (cortisol-MIP) was obtained using the multi-step swelling and polymerization protocol with cortisol as a target molecule combining methacrylic acid:acrylamide (2:1) with bisacryloyl-1,2-dihydroxy-1,2-ethylenediamine and ethylenedioxy-N-methylamphetamine as cross-linkers. Cortisol-MIP was integrated to the sensor. It was coated on the disposable screen-printed carbon electrode (SPCE) for portable electrochemical analysis. The physical properties of Cortisol-MIP were characterized by means of electron microscope techniques. The binding characteristics were evaluated via covalent patterns changing in FTIR spectra which were related to voltammetry response. The performance of cortisol-MIP modified SPCE was investigated in terms of detection range, high selectivity with a detection limit of 1.28 ng/ml. The disposable cortisol biosensor represented an application of MIP technique to recognize steroids according to their structures with feasibility and cost-effectiveness that can be developed to use in point-of-care.

Keywords: stress biomarker, cortisol, molecular imprinted polymer, screen-printed carbon electrode

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9 Effect of Oxytocin on Cytosolic Calcium Concentration of Alpha and Beta Cells in Pancreas

Authors: Rauza Sukma Rita, Katsuya Dezaki, Yuko Maejima, Toshihiko Yada


Oxytocin is a nine-amino acid peptide synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Oxytocin promotes contraction of the uterus during birth and milk ejection during breast feeding. Although oxytocin receptors are found predominantly in the breasts and uterus of females, many tissues and organs express oxytocin receptors, including the pituitary, heart, kidney, thymus, vascular endothelium, adipocytes, osteoblasts, adrenal gland, pancreatic islets, and many cell lines. On the other hand, in pancreatic islets, oxytocin receptors are expressed in both α-cells and β-cells with stronger expression in α- cells. However, to our knowledge there are no reports yet about the effect of oxytocin on cytosolic calcium reaction on α and β-cell. This study aims to investigate the effect of oxytocin on α-cells and β-cells and its oscillation pattern. Islet of Langerhans from wild type mice were isolated by collagenase digestion. Isolated and dissociated single cells either α-cells or β-cells on coverslips were mounted in an open chamber and superfused in HKRB. Cytosolic concentration ([Ca2+]i) in single cells were measured by fura-2 microfluorimetry. After measurement of [Ca2+]i, α-cells were identified by subsequent immunocytochemical staining using an anti-glucagon antiserum. In β-cells, the [Ca2+]i increase in response to oxytocin was observed only under 8.3 mM glucose condition, whereas in α-cells, [Ca2+]i an increase induced by oxytocin was observed in both 2.8 mM and 8.3 mM glucose. The oscillation incidence was induced more frequently in β-cells compared to α-cells. In conclusion, the present study demonstrated that oxytocin directly interacts with both α-cells and β-cells and induces increase of [Ca2+]i and its specific patterns.

Keywords: α-cells, β-cells, cytosolic calcium concentration, oscillation, oxytocin

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8 The Effects of Acupoint Catgut Embedding for Weight Control in Mice Model

Authors: Chanya Inprasit, Ching-Liang Hsieh, Yi-Wen Lin


Obesity (OB) is a hazardous global health problem that has been increasing in prevalence, more severely in last decade. It is the mainly resultant from the imbalance between food consumption and energy expenditure, which is concordant with a modern lifestyle, implying an increase in calories with poorer quality of food intake accompanied by a decrease in physical activities. Obesity does not concern the appearance only but is also a major factor contributing to poor physiology, psychology, society and economic issues. Moreover, OB induces low-grade inflammation in the body through the regulatory effect it enacts on the adipocyte function. Various alternative treatments were investigated for body weight control, including Acupoint Catgut Embedding (ACE). ACE is the implantation of absorbable catgut sutures at specific acupoints, displaying durable and potent stimulation and thereby reducing the treatment frequency. Our study utilized a mouse model to exclude any psychological factors of OB and ACE treatment. High-fat diet and body weight were measured once a week before subjects in ACE and Sham group received the ACE treatment or placebo treatment. We hypothesized that ACE can control body weight through the interaction of the TRPV1 pathways, as TRPV1 accordingly responds to inflammatory factors. The results of body weight variation show a significant decrease in body weight in ACE group compared with the baseline of control and Sham group. Meanwhile, converse results were explored in TRPV1 knockout mice, where a significant maintenance of normal body weight throughout the experiment period was observed. There was no significant difference in food consumption of each group. These finding indicated that TRPV1 pathways and its associated pathways may be involved in the maintenance of body weight, which can be controlled by ACE treatment of genetic manipulation.

Keywords: acupoint catgut embedding, obesity, hypothalamus, TRPV1

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7 Perinatal Ethanol Exposure Modifies CART System in Rat Brain Anticipated for Development of Anxiety, Depression and Memory Deficits

Authors: M. P. Dandekar, A. P. Bharne, P. T. Borkar, D. M. Kokare, N. K. Subhedar


Ethanol ingestion by the mother ensue adverse consequences for her offspring. Herein, we examine the behavioral phenotype and neural substrate of the offspring of the mother on ethanol. Female rats were fed with ethanol-containing liquid diet from 8 days prior of conception and continued till 25 days post-parturition to coincide with weaning. Behavioral changes associated with anxiety, depression and learning and memory were assessed in the offspring, after they attained adulthood (day 85), using elevated plus maze (EPM), forced swim (FST) and novel object recognition tests (NORT), respectively. The offspring of the alcoholic mother, compared to those of the pair-fed mother, spent significantly more time in closed arms of EPM and showed more immobility time in FST. Offspring at the age of 25 and 85 days failed to discriminate between novel versus familiar object in NORT, thus reflecting anxiogenic, depressive and amnesic phenotypes. Neuropeptide cocaine- and amphetamine-regulated transcript peptide (CART) is known to be involved in central effects of ethanol and hence selected for the current study. Twenty-five days old pups of the alcoholic mother showed significant augmentation in CART-immunoreactivity in the cells of Edinger-Westphal (EW) nucleus and lateral hypothalamus. However, a significant decrease in CART-immunoreactivity was seen in nucleus accumbens shell (AcbSh), lateral part of bed nucleus of the stria terminalis (BNSTl), locus coeruleus (LC), hippocampus (CA1, CA2 and CA3), and arcuate nucleus (ARC) of the pups and/or adults offspring. While no change in the CART-immunoreactive fibers of AcbSh and BNSTl, CA2 and CA3 was noticed in the 25 days old pups, the CART-immunoreactive cells in EW and paraventricular nucleus (PVN), and fibers in the central nucleus of amygdala of 85 days old offspring remained unaffected. We suggest that the endogenous CART system in these discrete areas, among other factors, may be a causal to the abnormalities in the next generation of an alcoholic mother.

Keywords: anxiety, depression, CART, ethanol, immunocytochemistry

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6 Phytochemical Screening and Anti-Hypothyroidism Activity of Lepidium sativum Ethanolic Extract

Authors: Reham Hajomer, Ikram Elsiddig, Amna Hamad


Lepidium sativum (Garden Cress) belonging to Brassicaceae family is an annual herb locally known as El-rshad. In Ayurveda it is an important medicinal plant, traditionally used for the treatment of jaundice, liver problems, spleen diseases, gastrointestinal disorders, menstrual problems, fracture, arthritis, inflammatory conditions and for treatment of hypothyroidism. Hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormones (Triiodithyronine T3 and Thyroxine T4) which are commonly caused by iodine deficiency. It’s divided into primary and secondary hypothyroidism, the primary caused by failure of thyroid function and secondary due to the failure of adequate thyroid-stimulating hormone (TSH) secretion from the pituitary gland or thyroid -releasing hormone (TRH) from the hypothalamus. The disease is most common in women over age 60. The objective regarding this study is to know whether Lepidium sativum would affect the level of thyroid hormones. The extract was prepared with 96% ethanol using Soxhlet apparatus. The anti-hypothyroidism activity was tested by using thirty male Wistar rats weighing (100-140 g) were used in the experiment. They were grouping into five groups, Group 1: Normal group= Administered only distilled water. Then 10 mg/kg Propylthiouracil was added to the drinking water of all other groups to induce hypothyroidism. Group 2: Negative control without any treatment; Group 3: Test group= treated with oral administration of 500mg/kg extract; Group 4: treated with oral administration of 250mg/kg of the extract; Group 5: Standard group (positive control) = treated with intraperitoneal Levothyroxine. All rats were incubated for 20 days at animal house with room temperature of proper ventilation provided with standard diet. The result show that the Lepidium sativum extract was found to increases the T3 and T4 in the propylthiouracil induced rats with values (0.29 ng/dl T3 and 0.57 U T4) for the 500mg/kg and (0.27 ng/dl T3 and 0.517 U T4) for the 250mg/kg in comparison with standard with values (0.241 ng/dl T3 and 0.516 U T4) so that Lepidium sativum can be stimulatory to thyroid function and possess significant anti-hypothyroidism effect with p-values ranges from (0.000006*-0.893472). In conclusion, from results obtained, Lepidium sativum plant extract was found to posses anti-hypothyroidism effects so its act as an agent that stimulates thyroid hormone secretion.

Keywords: anti-hypothyroidism, extract, lepidium, sativum

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5 Effects of Endurance Training and Thyme Consumption on Neuropeptide Y in Untrained Men

Authors: M. Ghasemi, S.Fazelifar


Abstract Aim: Over-weight is not desirable and has implications for health and in the case of athletes affects performance. Exercise is a strategy used to counteract overweight owing to create a negative energy balance by increasing energy expenditure and influencing appetite regulating hormones. Interestingly, recent studies have revealed inhibitory effects of exercise on the hunger associated with these hormones in healthy subjects Neuropeptide Y(NPY) is a 36 amino acid protein that is a powerful stimulant appetite. NPY is an important central orexigenic hormone predominantly produced by the hypothalamus, and recently found to be secreted in adipose tissue. This neurotransmitter is secreted in the brain and autonomic nervous system. On the other hand, research has shown that thyme in addition to various properties, also affects the appetite. The purpose of this study was to determine Effects of eight weeks endurance training and thyme consumption on neuropeptide Y in untrained men. Methodology: 36 Healthy untrained men (mean body weight 78.25±3.2 kg, height 176±6.8 cm, age 34.32±4.54 years and BMI 29.1±4.3 kg/m2) voluntarily participated in this study . Subjects were randomly divided into four groups: 1. control, 2. Endurance training, 3. Thyme 4. Endurance training + Thyme. Amount of 10cc Blood sampling were obtained pre-test and post-test (after 8 weeks). The taken blood samples were centrifuged at 1500 × g for 15 min then plasma was stored at -20 °C until analysis. Endurance training consisted three session per week with 60% -75% of reserve heart rate for eight weeks. Exclusion criteria were history of gastrointestinal, endocrine, cardiovascular or psychological disease, and consuming any supplementation, alcohol and tobacco products. Descriptive statistics including means, standard deviations, and ranges were calculated for all measures. K-S test to determine the normality of the data and analysis of variance for repeated measures was used to analyze the data. A significant difference in the p<0/05 accepted. Results: Results showed that aerobic training significantly reduced body weight, body mass index, percent body fat, but significant increase observed in maximal oxygen consumption level (p ≤ 0/05). The neuropeptide Y levels were significantly increased after exercise. Analysis of data determined that there was no significant difference between the four groups. Conclusion: Appetite control plays a critical role in the competition between energy consumption and energy expenditure. The results of this study showed that endurance training and thyme consumption can be cause improvement in physiological parameters such as increasing aerobic capacity, reduction of fat mass and improve body composition in untrained men.

Keywords: Endurance training, neuropeptide Y, thyme, untrained men

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4 The Effects of Circadian Rhythms Change in High Latitudes

Authors: Ekaterina Zvorykina


Nowadays, Arctic and Antarctic regions are distinguished to be one of the most important strategic resources for global development. Nonetheless, living conditions in Arctic regions still demand certain improvements. As soon as the region is rarely populated, one of the main points of interest is health accommodation of the people, who migrate to Arctic region for permanent and shift work. At Arctic and Antarctic latitudes, personnel face polar day and polar night conditions during the time of the year. It means that they are deprived of natural sunlight in winter season and have continuous daylight in summer. Firstly, the change in light intensity during 24-hours period due to migration affects circadian rhythms. Moreover, the controlled artificial light in winter is also an issue. The results of the recent studies on night shift medical professionals, who were exposed to permanent artificial light, have already demonstrated higher risks in cancer, depression, Alzheimer disease. Moreover, people exposed to frequent time zones change are also subjected to higher risks of heart attack and cancer. Thus, our main goals are to understand how high latitude work and living conditions can affect human health and how it can be prevented. In our study, we analyze molecular and cellular factors, which play important role in circadian rhythm change and distinguish main risk groups in people, migrating to high latitudes. The main well-studied index of circadian timing is melatonin or its metabolite 6-sulfatoxymelatonin. In low light intensity melatonin synthesis is disturbed and as a result human organism requires more time for sleep, which is still disregarded when it comes to working time organization. Lack of melatonin also causes shortage in serotonin production, which leads to higher depression risk. Melatonin is also known to inhibit oncogenes and increase apoptosis level in cells, the main factors for tumor growth, as well as circadian clock genes (for example Per2). Thus, people who work in high latitudes can be distinguished as a risk group for cancer diseases and demand more attention. Clock/Clock genes, known to be one of the main circadian clock regulators, decrease sensitivity of hypothalamus to estrogen and decrease glucose sensibility, which leads to premature aging and oestrous cycle disruption. Permanent light exposure also leads to accumulation superoxide dismutase and oxidative stress, which is one of the main factors for early dementia and Alzheimer disease. We propose a new screening system adjusted for people, migrating from middle to high latitudes and accommodation therapy. Screening is focused on melatonin and estrogen levels, sleep deprivation and neural disorders, depression level, cancer risks and heart and vascular disorders. Accommodation therapy includes different types artificial light exposure, additional melatonin and neuroprotectors. Preventive procedures can lead to increase of migration intensity to high latitudes and, as a result, the prosperity of Arctic region.

Keywords: circadian rhythm, high latitudes, melatonin, neuroprotectors

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3 Developing a Methodology to Examine Psychophysiological Responses during Stress Exposure and Relaxation: An Experimental Paradigm

Authors: M. Velana, G. Rinkenauer


Nowadays, nurses are facing unprecedented amounts of pressure due to the ongoing global health demands. Work-related stress can cause a high physical and psychological workload, which can lead, in turn, to burnout. On the physiological level, stress triggers an initial activation of the sympathetic nervous and adrenomedullary systems resulting in increases in cardiac activity. Furthermore, activation of the hypothalamus-pituitary-adrenal axis provokes endocrine and immune changes leading to the release of cortisol and cytokines in an effort to re-establish body balance. Based on the current state of the literature, it has been identified that resilience and mindfulness exercises among nurses can effectively decrease stress and improve mood. However, it is still unknown what relaxation techniques would be suitable for and to what extent would be effective to decrease psychophysiological arousal deriving from either a physiological or a psychological stressor. Moreover, although cardiac activity and cortisol are promising candidates to examine the effectiveness of relaxation to reduce stress, it still remains to shed light on the role of cytokines in this process so as to thoroughly understand the body’s response to stress and to relaxation. Therefore, the main aim of the present study is to develop a comprehensive experimental paradigm and assess different relaxation techniques, namely progressive muscle relaxation and a mindfulness exercise originating from cognitive therapy by means of biofeedback, under highly controlled laboratory conditions. An experimental between-subject design will be employed, where 120 participants will be randomized either to a physiological or a psychological stress-related experiment. Particularly, the cold pressor test refers to a procedure in which the participants have to immerse their non-dominant hands into ice water (2-3 °C) for 3 min. The participants are requested to keep their hands in the water throughout the whole duration. However, they can immediately terminate the test in case it would be barely tolerable. A pre-test anticipation phase and a post-stress period of 3 min, respectively, are planned. The Trier Social Stress Test will be employed to induce psychological stress. During this laboratory stressor, the participants are instructed to give a 5-min speech in front of a committee of communication specialists. Before the main task, there is a 10-min anticipation period. Subsequently, participants are requested to perform an unexpected arithmetic task. After stress exposure, the participants will perform one of the relaxation exercises (treatment condition) or watch a neutral video (control condition). Electrocardiography, salivary samples, and self-report will be collected at different time points. The preliminary results deriving from the pilot study showed that the aforementioned paradigm could effectively induce stress reactions and that relaxation might decrease the impact of stress exposure. It is of utmost importance to assess how the human body responds under different stressors and relaxation exercises so that an evidence-based intervention could be transferred in a clinical setting to improve nurses’ general health. Based on suggestive future laboratory findings, the research group plans to conduct a pilot-level randomized study to decrease stress and promote well-being among nurses who work in the stress-riddled environment of a hospital located in Northern Germany.

Keywords: nurses, psychophysiology, relaxation, stress

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2 Relevance of Dosing Time for Everolimus Toxicity on Thyroid Gland and Hormones in Mice

Authors: Dilek Ozturk, Narin Ozturk, Zeliha Pala Kara, Engin Kaptan, Serap Sancar Bas, Nurten Ozsoy, Alper Okyar


Most physiological processes oscillate in a rhythmic manner in mammals including metabolism and energy homeostasis, locomotor activity, hormone secretion, immune and endocrine system functions. Endocrine body rhythms are tightly regulated by the circadian timing system. The hypothalamic-pituitary-thyroid (HPT) axis is under circadian control at multiple levels from hypothalamus to thyroid gland. Since circadian timing system controls a variety of biological functions in mammals, circadian rhythms of biological functions may modify the drug tolerability/toxicity depending on the dosing time. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer agent that is active against many cancers. It was also found to be active in medullary thyroid cancer. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus on the thyroid gland and hormones in mice. Healthy C57BL/6J mice were synchronized with 12h:12h Light-Dark cycle (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding to Light onset). Everolimus was administered to male (5 mg/kg/day) and female mice (15 mg/kg/day) orally at ZT1-rest period- and ZT13-activity period- for 4 weeks; body weight loss, clinical signs and possible changes in serum thyroid hormone levels (TSH and free T4) were examined. Histological alterations in the thyroid gland were evaluated according to the following criteria: follicular size, colloid density and viscidity, height of the follicular epithelium and the presence of necrotic cells. The statistical significance between differences was analyzed with ANOVA. Study findings included everolimus-related diarrhea, decreased activity, decreased body weight gains, alterations in serum TSH levels, and histopathological changes in thyroid gland. Decreases in mean body weight gains were more evident in mice treated at ZT1 as compared to ZT13 (p < 0.001, for both sexes). Control tissue sections of thyroid glands exhibited well-organized histoarchitecture when compared to everolimus-treated groups. Everolimus caused histopathological alterations in thyroid glands in male (5 mg/kg, slightly) and female mice (15 mg/kg; p < 0.01 for both ZT as compared to their controls) irrespective of dosing-time. TSH levels were slightly decreased upon everolimus treatment at ZT13 in both males and females. Conversely, increases in TSH levels were observed when everolimus treated at ZT1 in both males (5 mg/kg; p < 0.05) and females (15 mg/kg; slightly). No statistically significant alterations in serum free T4 levels were observed. TSH and free T4 is clinically important thyroid hormones since a number of disease states have been linked to alterations in these hormones. Serum free T4 levels within the normal ranges in the presence of abnormal serum TSH levels in everolimus treated mice may suggest subclinical thyroid disease which may have repercussions on the cardiovascular system, as well as on other organs and systems. Our study has revealed the histological damage on thyroid gland induced by subacute everolimus administration, this effect was irrespective of dosing time. However, based on the body weight changes and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13 in both male and females. Yet, effects of everolimus on thyroid functions may deserve further studies regarding their clinical importance and chronotoxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, thyroid gland, thyroid hormones

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1 Pharmacophore-Based Modeling of a Series of Human Glutaminyl Cyclase Inhibitors to Identify Lead Molecules by Virtual Screening, Molecular Docking and Molecular Dynamics Simulation Study

Authors: Ankur Chaudhuri, Sibani Sen Chakraborty


In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

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