Med Hypotheses. 2014 Mar;82(3):271-4. doi: 10.1016/j.mehy.2013.12.008. Epub 2013 Dec 19. "Stress entropic load" as a transgenerational epigenetic response trigger. Bienertová-Vašků J1, Nečesánek I2, Novák J2, Vinklárek J2, Zlámal F2. Relationship between lifetime events, stress entropic load (SEL) and epigenome changes. Lifetime events represent those events that influence the flow of energy, substrates and information within the body. Generally, the organism has to cope with these changes, whereas we consider SEL to be the universal parameter reflecting the “severity” of the influencing events. SEL therefore leads to epigenome changes that are according to SEL “severity” either conserved or reset during meosis and thus passed transgenerationally or not. Med Hypotheses. 2014 Mar;82(3):271-4. "Stress entropic load" as a transgenerational epigenetic response trigger. Bienertová-Vašků J1, Nečesánek I2, Novák J2, Vinklárek J2, Zlámal F2. Relationship between lifetime events, stress entropic load /SEL/ and epigenome changes during time. Grey arrow represents the time flow and it should suggest that as time passes, different events are evaluated differently and their associated SEL level may consecutively increase or decrease and thus affect whether the epigenomic changes are passed to other generation or not. Med Hypotheses. 2014 Mar;82(3):271-4. "Stress entropic load" as a transgenerational epigenetic response trigger. Bienertová-Vašků J1, Nečesánek I2, Novák J2, Vinklárek J2, Zlámal F2. Physical response Grizzly Trauma Exercising Public speach Going in time Psychological response Negative Positive stressor=any factor deflecting body homeostasis stress response= body adaptation to homeostasis restoring stress= the complexity of factors provoking stress response physical activity Hans Selye  A syndrome produced by diverse nocous agents, Nature 138, 32, 1936  General adaptation syndrome-stress reaction of organism:  Experiments with animals showed that different toxic substances applied into the organisms led to stereotyped response explicable by suprarenal gland activation. alarm reaction (fight and flightCannon´s emergent reaction): shock, contra-shock stage of resistence stage of exhaustion Eustress- increases possibilities of the organism, healthy and life motivation Distress- decreases possibilities, facilitates diseases development Stressors= stress causes (frustrations, conflicts) Factors influencing stress severity stressor characteristics subjective stress responsibility Reactions to acute and chronic stress: physical and psychological Nervous system Hormones HPA activation Perception of stress-like event SNS activation other CNS pathways activation glucocorticoids catecholamines in plasma motoric responses Brain CRF release activates behaviour associated with fear (anxiety) vigilance (attention) “freezing”  behavioural reactivity inhibits behaviour which is not associated with stress reproduction food Parasympathetic nervous system Sympathetic nervous system  digestion  salivation  heart rate  intestine perfusion rest state “F& F” response digestion  salivation  heart rate  respiration blood redistribution from intestine to muscles, brain and heart  increased activity and vigilance Catecholamines synthesis and metabolism Glycolysis (a) The major steroid biosynthetic pathways. Enzymes catalysing reactions are in red: p450 enzymes are in mitochondria and each catalyses several reaction steps; 3βHSD (hydroxysteroid dehydrogenase) is in cytoplasm, bound to endoplasmic reticulum; 17βHSD and p450aro are found mainly in gonads. (b) The steroid molecule. Classic stress components of the CNS systems. To the previous picture: The HPA doctrine  (A) Classic components of the HPA–CNS–immune systems.  (B) Neurons of the hypothalamus that synthesize CRF and vasopressin (VP) are found in the paraventricular nucleus (PVN). These cell bodies send axons to the median eminence; here, peptides are released from the nerve terminals and are transported through vessels of the portal system. When they reach the anterior pituitary, these peptides act on their respective receptors, thereby stimulating ACTH secretion.  (C) Following its release into the general circulation, ACTH acts on the cortex of the adrenal glands, which manufacture and secrete glucocorticoids (cortisol in humans). These glucocorticoids exert a classical negative feedback influence on the pituitary, where they inhibit the effect of CRF and VP, and on the PVN, where they inhibit the synthesis of CRF. Thus, after a stimulus stimulates CRF and ACTH release, the production of glucocorticoids will eventually terminate this release, thereby ensuring the maintenance of homeostasis. Stimuli triggering ‘reactive’ vs. ‘anticipatory’ HPA stress responses Control of the hypothalamic-pituitary adrenal axis. CRH, corticotropin-releasing hormone. Neurochemical mechanisms and their site of action, including the HPA axis. ACTH, adrenocorticotropic hormone; CRF, corticotropinreleasing factor; LC, locus ceruleus; NE, norepinephrine. Stresor Minuty15 30 45 60 Plazmatickákoncentrace ACTH Kortizol (Podle Felker B and Hubbard JR: In Handbook of Stress Medicine, CRC Press, Boca Raton, FL, 1998) 0 Pulse and diurnal secretion of glucocorticoids (Podle Felker B and Hubbard JR: In Handbook of Stress Medicine, CRC Press, Boca Raton, FL, 1998) 8 12 16 20 24 4 8 hrs Pulse secretion - stressors Circadian secretion curve Daily activity Sleep Koncentracekortizoluvplazmě The effect of glucocorticoid pulses and an acute stressor on glucocorticoid responsive genes. Note that, at nadir levels of corticosterone, there is only mineralocorticoid receptor (MR) binding to DNA but that, at peak and stress levels, there is both glucocorticoid receptor and MR binding. Scheme for molecular communications circuits existing between the immune and neuroendocrine systems and involving shared ligands and receptors To the previous figure:  Scheme depicting systemic and cellular/molecular interplay between the HPA axis and the immune system in the regulation of glucocorticoid/cytokine secretion and gene expression.  Abbreviations: GR, glucocorticoid receptor; TF, transcription factors. Balance of Th1/Th2 immune resposes Th2 shift as a consequence of stress Th2 shift as a consequence of stress and acute inflammation Treatment by glucocorticoids Respiratory diseases • Asthma • Chronic obstructive pulmonary disease • Sarcoidosis • Prevention/treatment of ARDS Cardiac diseases • Post-myocardial infarction syndrome Renal diseases • Some nephrotic syndromes • Some glomerulonephritides • Gastrointestinal disease • Ulcerative colitis • Crohn's disease • Autoimmune hepatitis Treatment by glucocorticoids Rheumatological diseases • Systemic lupus erythematosus • Polymyalgia rheumatica • Cranial arteritis • Juvenile idiopathic arthritis • Vasculitides • Rheumatoid arthritis Neurological diseases • Cerebral oedema Skin diseases • Pemphigus, eczema Tumours • Hodgkin's lymphoma • Other lymphomas Transplantation • Immunosuppression Major adverse effects of corticosteroid therapy Physiological • Adrenal and/or pituitary suppression Pathophysiological Cardiovascular • Increased blood pressure Gastrointestinal • Peptic ulceration exacerbation (possibly) • Pancreatitis Renal • Polyuria • Nocturia Central nervous • Depression • Euphoria • Psychosis • Insomnia Endocrine • Weight gain • Glycosuria/ hyperglycaemia/diabetes • Impaired growth • Amenorrhoea Major adverse effects of corticosteroid therapy Bone and muscles • Osteoporosis • Proximal myopathy and wasting • Aseptic necrosis of the hip • Pathological fractures Skin • Thinning • Easy bruising Eyes • Cataracts (including inhaled drug) Increased susceptibility to infection • (signs and fever are frequently masked) • Septicaemia • Reactivation of TB • Skin (e.g. fungi) The symptoms and signs of Cushing's syndrome. Bold type indicates signs of most value in discriminating Cushing's syndrome from simple obesity and hirsutism. The hypothalamic-pituitary-adrenal axis response to acute and chronic stressors. ACTH, adrenocortocotrophin; AVP, arginine vasopressin; CRH, corticotrophin-releasing hormone; POMC, pro-opiomelanocortin. adaptive, enabling surveillance akthough different reactions are used, the aim is always the same: = surveillance metabolic: glycemia cardiovaskular/respiratory- glucose traffic to muscles, heart and brain analgesia inhibition of processes decreasing surveillance chance (reproduction, food). Purpose: to increase glycemia using catecholamines and glucocorticoids Glucose uptake is inhibited; proteins, fatty acids and glycogen synthesis is stopped. Lysis og lipids and proteins (immune systém is „sacrificed“) Glykogenolysis by catecholamines (shorttime effects on glycemia), gluconeogenesis (glucocorticoids with long-time effects on glycemia). Purpose: to increase cardiovascular tonus for a quick transport of mobilized glucose to the tissues with the highest oxygen consumption. Vasopressin release from axon neurohypophysal terminals leading to reabsorbtion of water in the kidney Purpose: to increase cardiovascular circulating volume Purpose: to decrease pain perception Two forms of stress-induced analgesia can be distinguished (SIA) -opiates-dependent SIA (enkephalins and -endorphine) -opiates independent SIA (glutamate) Both SIA can combine one to another. maladaptive = imparing effects chronic stress can contribute to development of diseases as peptic ulcer, visceral obesity, lower growth, higher risk of CAD chronic stress influences behaviour: inhibition of reproduction  depression, schizophrenia etc. Physiological and pathological responses to stress. The resilience or vulnerability of any one individual to stressful situations in adulthood will depend upon that person's genetic inherence and early life experiences. Dominant and subdominant primates (males): In stable conditions (no teritorial emergency), dominant males have lower glucocorticoids levels than subdominat ones. But, in unstable conditions, these levels in dominant males increase and they are the same or higher thain in subdominat males. “Personal power” of dominant male correlates with low GCs levels during rest conditions. „Good state of mind” is necessary ! Social supporting groups forming- f.e. non sexually based friendship between men and women in the team Training of ability to anticipate stressful event and undertake the control. Transformation of agresivity (sports) Děkuji vám za pozornost ?