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All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases. © 2014 S. Karger AG, Basel.
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Basic Research concerning Glucocorticoids
Neuroimmunomodulation 2015;22:6–19
DOI: 10.1159/000362736
Stress, the Stress System and the Role of
NicolasC.Nicolaides a,b ElliKyratzi b AgaristiLamprokostopoulou b
GeorgeP.Chrousos a–c EvangeliaCharmandari a,b
a Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens
Medical School, ‘Aghia Sophia’ Children’s Hospital, and
b Division of Endocrinology and Metabolism,
Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens , Greece;
c Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University,
Jeddah, Saudi Arabia
adverse effects on many vital physiologic functions, such as
growth, development, metabolism, circulation, reproduc-
tion, immune response, cognition and behavior. A strong
and/or long-lasting stressor may precipitate and/or cause
many acute and chronic diseases. Moreover, stressors during
pre-natal, post-natal or pubertal life may have a critical im-
pact on our expressed genome. This review describes the
central and peripheral components of the stress system, pro-
vides a comprehensive overview of the stress response, and
discusses the role of glucocorticoids in a broad spectrum of
stress-related diseases. © 2014 S. Karger AG, Basel
All living organisms must respond to many unfore-
seen extrinsic or intrinsic stressful stimuli, the stressors,
which constantly challenge our complex internal balance,
termed homeostasis
[1, 2] . The term stress is used to de-
fine a state of threatened or perceived as threatened ho-
[3] . To respond to this threatened homeostasis,
organisms have developed a highly sophisticated system,
Key Words
Stress system · Stress response · Glucocorticoids ·
Glucocorticoid receptor · Hypothalamic-pituitary-adrenal axis
All living organisms have developed a highly conserved and
regulatory system, the stress system, to cope with a broad
spectrum of stressful stimuli that threaten, or are perceived
as threatening, their dynamic equilibrium or homeostasis.
This neuroendocrine system consists of the hypothalamic-
pituitary-adrenal (HPA) axis and the locus caeruleus/norepi-
nephrine-autonomic nervous system. In parallel with the
evolution of the homeostasis and stress concepts from an-
cient Greek to modern medicine, significant advances in the
field of neuroendocrinology have identified the physiologic
biochemical effector molecules of the stress response. Glu-
cocorticoids, the end-products of the HPA axis, play a funda-
mental role in the maintenance of both resting and stress-
related homeostasis and, undoubtedly, influence the phys-
iologic adaptive reaction of the organism against stressors.
If the stress response is dysregulated in terms of magnitude
and/or duration, homeostasis is turned into cacostasis with
Published online: September 12, 2014
Nicolas C. Nicolaides, MD, PhD
Division of Endocrinology and Metabolism, Clinical Research Center
Biomedical Research Foundation of the Academy of Athens
4 Soranou tou Efessiou Street, GR–11527 Athens (Greece)
E-Mail nnicolaides @
© 2014 S. Karger AG, Basel
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Stress System and Glucocorticoids Neuroimmunomodulation 2015;22:6–19
DOI: 10.1159/000362736
the stress system, which provides the appropriate central
and peripheral neuroendocrine responses
[1–3] . If these
adaptive responses are inadequate, excessive or pro-
longed, they may have severe adverse effects on vital
physiologic functions, such as growth, metabolism, circu-
lation, reproduction and the inflammatory/immune re-
[3] .
The stress system functions through the co-ordinated
activation of the hypothalamic-pituitary-adrenal (HPA)
axis and the locus caeruleus (LC)/norepinephrine (NE)-
autonomic nervous system
[1–3] . Glucocorticoids, the
end-products of the HPA axis, are cholesterol-derived
molecules that exert their pleiotropic genomic and non-
genomic actions through the glucocorticoid receptor
(GR), a ubiquitously expressed transcription factor,
which influences the stress response substantially
[4] . In
this review, we describe the functional components of the
stress system, provide an overview of the physical and be-
havioral alterations observed during the stress response,
and discuss the role of glucocorticoids in the most com-
mon diseases associated with acute and chronic dysregu-
lation of the stress system. Finally, we discuss the emerg-
ing role of the epigenetic modifications of crucial mole-
cules involved in the adaptive response.
Historical Milestones of Stress Concepts
… he who knows things from their beginning
and origins understands them better …
Aristotle , 4th century BC
The term stress derives from the Indo-European root
‘str’. This root has been highly preserved throughout the
centuries. Indeed, the ancient Greek gerund ‘strangalizein’,
its English synonym ‘to strangle’ and the Latin ‘strigere’
have been etymologically associated with the root ‘str’ and
have the meaning of exerted pressure
[1] . Nowadays, we
consider stress as a ‘strangulated’ balance of life.
The concepts of stress were first enunciated clearly by
the ancient Greek philosophers
[1, 2] . The pre-Socratic
philosophers Pythagoras and Alcmaeon were the first to
use the terms ‘harmony’ and ‘isonomia’, respectively, to
express the dynamic balance of the cosmos or life. Py-
thagoras used the term ‘harmony’ to describe the equilib-
rium or balance of the universe (The harmony of the cos-
mos). This ‘harmony’ is threatened by numerous disturb-
ing forces, while other counteracting forces tend to
re-establish it. Alcmaeon of Croton termed ‘isonomia’ the
balance of opposing forces. Empedocles of Agrigentum
proposed that the four basic elements (‘rhizomata’ or ‘ra-
cins’), earth, water, air and fire, being in dynamic opposi-
tion to one another, need to reach a balance for achieving
the harmony of the cosmos ( table1 )
[2, 6] .
Hippocrates of Cos termed health as a harmonious
balance of the four humors: blood, phlegm, black and yel-
low bile, which correspond to the heart, the brain, the
liver and the spleen, respectively. He was the first to use
the term ‘eucrasia’ to describe the balance of the humors
and subsequently proposed that their imbalance, ‘dyscra-
sia’, led to disease
[2] . Hippocrates also suggested that
‘eucrasia’ and ‘dyscrasia’ have their origins in nature, and
introduced the concept that ‘Nature is the healer of dis-
[2] . Many years later, Epicurus spoke of ‘eustatheia’
or ‘eustasis’, which refers to the serene emotional state of
a harmonious balance in a human being. The not uncom-
mon Greek first name ‘Eustathios’ is a remnant of that
era. Epicurus suggested that the mind could be one of
these healing forces and wrote that ‘ataraxia’ or ‘imper-
turbability of mind’ and ‘aponia’ (no pain) represent de-
sirable states in a human being
[2] .
During the years of Renaissance, Thomas Sydenham
proposed that an individual’s adaptive response to the
disturbing forces that lead to systematic disharmony
could result in pathologic changes. Two hundred years
later, Claude Bernard suggested that the ‘milieu intéri-
eur’, the internal medium that surrounds living cells, pro-
vides a steady state and ‘is the pre-condition of a free and
independent life’
[7] . At the beginning of the 20th cen-
tury, Walter Bradford Cannon coined the term ‘fight or
flight response’, and expanded on Claude Bernard’s con-
cept of the stability of the ‘milieu intérieur’ to ‘homeosta-
sis’ (from the Greek ‘homoios’, or similar, and ‘stasis’, or
position) in order to describe the physiologic processes
that maintain the steady state of the organism
[2, 7] . He
popularized his theories in The Wisdom of the Body,
published in 1932.
Finally, Hans Hugo Bruno Selye
[8] , a pioneering
Hungarian endocrinologist, conducted very important
scientific work on the response of an organism to stress-
ors, and described the general adaptation syndrome or
stress syndrome and the diseases of adaptation. He no-
ticed that patients with distinct disorders may present
with common ‘non-specific’ symptoms as a
common re-
sponse to stressors. He borrowed
the term stress from
physics and defined it as ‘the non-specific neuroendo-
crine response of the body’. Selye termed the ‘General Ad-
aptation or Stress Syndrome’ as the condition occurring
in severely ill patients who present with common clinical
manifestations due to severe prolonged adaptation re-
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Neuroimmunomodulation 2015;22:6–19
DOI: 10.1159/000362736
In addition to the first definition of stress, Selye
coined the term ‘heterostasis’ (from the Greek ‘heteros’,
or other, and ‘stasis’, or position) and set it to mean ‘sta-
bility through change’
[2, 7] . Moreover, he clarified that
not all stressful conditions had adverse effects on human
health; thus, ‘eustress’ represented those states of stress
that could cause pleasant feelings and further enhance
human growth and development at the emotional and
intellectual level. On the other hand, he believed that
‘distress’ consisted of all the stressful conditions that
triggered severe pathologic conditions
[2] . More impor-
tantly, Selye suggested that not only the catecholamines,
which are secreted by the adrenal medulla and the sys-
temic sympathetic system, but also the adrenal cortex-
derived ‘corticoids’ participate in the stress response
[9] .
He was also the first to demonstrate that glucocorticoids
(which he named) exert strong anti-inflammatory ef-
[9] . Further to these pioneering findings, the 1950
Nobel Prize in Physiology or Medicine was jointly
awarded to Edward Kendall, Philip Hench and
Reichstein for the isolation, synthesis and use of corti-
sone, a synthetic pre-glucocorticoid, in patients with
rheumatoid arthritis.
The Stress System
The stress system has both central and peripheral com-
ponents ( fig.1 ). The central components include: (i) the
parvocellular neurons, which secrete corticotropin-re-
leasing hormone (CRH); (ii) the neurons of the paraven-
tricular nuclei (PVN) of the hypothalamus that secrete ar-
ginine vasopressin (AVP); (iii) the CRH neurons, which
form the paragigantocellular and parabrachial nuclei of
the medulla and the LC, and (iv) other neural groups in
the medulla and pons (LC/NE system) mostly secreting
NE. The peripheral components include: (i) the neuroen-
docrine HPA axis; (ii) the efferent systemic sympathetic-
adrenomedullary systems, and (iii) components function-
ing under the control of the parasympathetic system
[10] .
The central and peripheral components of the stress sys-
tem have many sites of interaction with other systems at
multiple levels
[1, 2, 10, 11] ( fig.2 ). Indeed, activation of
CRH neurons activates the LC/NE system and vice versa.
In addition to interactions between the two central compo-
nents of the stress system themselves, the stress system ac-
tivates the mesocortical and the mesolimbic dopaminergic
reward system, while it receives inhibitory input from the
Table 1. Historical overview of stress concepts
Historical figure Stress concept
Pythagoras (580 489 BC) The harmony of the cosmos
Alcmaeon (c. 500 BC) The intellect is based in the brain
Health is the equipoise of opposing forces: ‘Isonomia’
Empedocles (500 430 BC) Matter consists of essential elements and qualities in opposition or alliance to one another
Hippocrates (460 375 BC) A harmonious balance of the elements and qualities of life is health – disharmony is disease.
Νούσων φύσεις ιητροί = Vis medicatrix naturae’
Sceptics/Stoics Epicureans Ataraxia (imperturbability of mind, equanimity)
Epicurus (341 270 BC) Ataraxia (imperturbability of mind), aponia (no pain) and ‘hedone’ (tranquil, non-sensual
pleasure) as desirable states. ‘Ευστάθειος’ = good balance, Carpe diem = seize the day
Thomas Sydenham (1624 1689) Symptoms and signs of a disease also arise from the reaction of the patients’ system
Claude Bernard (1813 1878) The milieu intérieur’
Walter Cannon (1871 1945) Homeostasis/stress
Bodily responses to emotions
Fight or flight (and freeze) reaction
Hans Selye (1907 1982) The general adaptation syndrome (the stress syndrome)
Diseases of adaptation, distress versus eustress
Adapted from Chrousos et al. [5].
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latter systems [2, 10, 11] . The stress system also activates the
central nucleus of the amygdala, which participates in the
generation of fear and/or anger; upon activation, the central
nucleus of the amygdala stimulates the stress system, form-
ing a positive regulatory feedback loop with it
[2, 10, 11] .
The PVN of hypothalamus communicates with the arcuate
nucleus through CRH neurons that induce the release of
α-melanocyte-stimulating hormone and β-endorphin from
the pro-opiomelanocortin-containing neurons in the arcu-
ate nucleus. These two molecules both inhibit the activity
of the CRH and LC/NE systems. Moreover, the two com-
ponents of the stress system appear to respond to many
neurochemical modulators, such as serotonin and acetyl-
choline, which are acutely stimulatory, and γ-aminobutyric
acid and benzodiazepines, which are inhibitory to CRH
neurons and the LC/NE system
[2, 10, 11] . Finally, the neu-
ropeptide Y, leptin and substance P have been recently
shown to play an important role in the regulation of stress
system activity
[11] .
Significant progress in the evolving field of neuroendo-
crinology uncovered the key molecules involved in the
complex molecular pathways of the above central and pe-
ripheral anatomical loci responsible for the generation
and regulation of the stress response. CRH, AVP and NE
play the role of bona fide neurotransmitters primarily –
but not exclusively – in the CNS, whereas NE, epinephrine
and the glucocorticoids, which will be discussed in a sepa-
rate section of this review article, are considered to be the
final effector molecules of the peripheral stress system.
The HPA Axis
The HPA axis consists of stimulatory signals and neg-
ative feedback loops that regulate its activity. This neuro-
endocrine axis is composed of three distinct anatomical
loci: the PVN of the hypothalamus, the pituitary gland
and the adrenal cortices ( fig. 1 ). A broad spectrum of
Fig. 1. The stress system. Modified from
[12] .
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stressors trigger the synthesis and secretion of CRH and
AVP by a group of neurons located in the PVN of the hy-
[12, 13] . CRH, through the hypophysial por-
tal system, reaches the anterior lobe of the pituitary gland
and binds to its cognate G-protein-coupled receptor lead-
ing to the production and release of adrenocorticotropic
hormone (ACTH) into the systemic circulation
[14, 15] .
Upon binding to its transmembrane G-protein-coupled
receptor of the adrenocortical cells of the zona fasciculata,
ACTH induces the activity of proteins and the expression
of genes implicated in the biosynthetic pathway of gluco-
corticoids (cortisol in humans, corticosterone in rodents)
[16] . Moreover, ACTH regulates adrenal androgen secre-
tion by the zona reticularis, and participates in the control
of aldosterone secretion by the zona glomerulosa.
Glucocorticoids, the end-products of the HPA axis,
are steroid hormones with pleiotropic effects in almost all
tissues and organs. These molecules regulate the basal ac-
tivity of the HPA axis and terminate the stress response
by acting mainly at the hypothalamus and the pituitary
gland, thereby forming negative feedback loops on the
secretion of CRH and ACTH, respectively. These nega-
tive feedback mechanisms, especially in the case of ACTH,
appear to also be mediated by non-genomic rapid gluco-
corticoid actions
[17] .
Genomic and Non-Genomic Glucocorticoid Actions
Glucocorticoids are cholesterol-derived hormones,
which play a fundamental role in the maintenance of rest-
ing and stress-related homeostasis. These molecules are
involved in the maintenance of proper cardiovascular
tone, regulate the intermediary metabolism primarily
through catabolic actions in the liver, muscle and adipose
tissue, and influence substantially the quantity and qual-
ity of the inflammatory and immune response. Further-
more, vital functions, such as reproduction, growth, be-
Glucocorticoids Catecholamines
mesolimbic systems
hippocampus complex
Serotonin Acetyl-
Arcuate nucleus
Fig. 2. Schematic representation of the cen-
tral and peripheral components of the
stress system, their functional interrela-
tions and their interactions with other
homeostatic systems and molecules in-
volved in the stress response. Activation is
represented by solid lines and inhibition
by dashed lines. POMC = Pro-opiomela-
nocortin; GABA = γ-aminobutyric acid;
BZD = benzodiazepine; NPY = neuropep-
tide Y; SP = substance P. Modified from
Chrousos and Gold
[2] .
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havior, cognition, cell proliferation and survival are under
the control of genomic and non-genomic glucocorticoid
[3, 4, 18] . Glucocorticoids also contribute to water
and electrolyte homeostasis. All these are essential life
functions of glucocorticoids and are mediated by an intra-
cellular, ubiquitously expressed protein, the human GR
(hGR), which belongs to the steroid receptor family of the
nuclear receptor superfamily of transcription factors
[19] .
In humans, the hGR gene is located on the short arm of
chromosome 5 and consists of 10 exons
[19] . Exon 1 forms
the 5 -untranslated region, whereas the rest of the exons
encode the protein. The alternative use of two distinct ex-
ons, 9α and 9β, gives rise to two main protein isoforms, the
hGRα and the hGRβ
[18, 19] . Lu and Cidlowski [20]
showed that the translation of hGRα mRNA could start
from eight alternative sites through ribosomal leaky scan-
ning or ribosomal shunting producing eight functionally
distinct hGRα protein isoforms. Since hGRβ mRNA trans-
lation is initiated by the same 5 termini, it is possible that
the same translation mechanisms could also generate eight
different hGRβ proteins
[18] . The total of sixteen hGRα
and hGRβ isoforms may potentially form 256 homo- or
hetero-dimers to transduce the glucocorticoid signal with-
in the target cells, turning the simplified glucocorticoid sig-
naling pathway into a highly stochastic system.
Within the target cell, the unliganded hGRα is primar-
ily localized in the cytoplasm of cells forming a large
multi-protein complex with the chaperon heat shock
proteins 90 and 70, as well as other proteins, such as the
immunophilins ( fig.3 ). Upon ligand-binding, hGRα dis-
sociates from the multi-protein complex, translocates
into the nucleus and interacts, as a homo- or hetero-di-
mer, with specific DNA sequences, the glucocorticoid re-
sponse elements (GREs) in the promoter regions of tar-
polymerase II
Transcription initiation
Translated RNA
Proteasomal degradation
cPLA2įL-Arginine NO
Fig. 3. Molecular pathways of genomic and non-genomic gluco-
corticoid actions. HSP = Heat shock proteins; FKBP = immuno-
philins; p160 = nuclear receptor co-activators p160; SWI/SNF =
switching/sucrose non-fermenting complex; DRIP/TRAP = vita-
min D receptor-interacting protein/thyroid hormone receptor-as-
sociated protein complex; MAPK = mitogen-activated protein
kinases; cPLA2α = cytosolic phospholipase A2 alpha; PI
3 K =
phosphatidylinositol 3-kinase; eNOS = endothelial nitric oxide
synthetase; NO = nitric oxide.
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get genes, influencing their transcription rate in a posi-
tive or negative way. Following binding to GREs, the
receptor undergoes further conformational changes that
lead to serial and co-ordinated recruitment of nuclear
receptor co-activators [p160, p300/CREB-binding pro-
tein (CBP) and p300/CBP-associated factor] and chro-
matin-remodeling complexes (switching/sucrose non-
fermenting complex and vitamin D receptor-interacting
protein/thyroid hormone receptor-associated protein
complex). This molecular complex influences the activ-
ity of the RNA polymerase II and its ancillary factors,
thereby facilitating initiation of the transcriptional pro-
cess of numerous glucocorticoid-responsive genes
( fig.3 ).
Alternatively, gene expression can be modulated by
the ligand-activated hGRα in a GRE-independent fash-
ion. Several studies have shown that hGRα physically in-
teracted, possibly as a monomer, with other core tran-
scription factors, such as the NF-κB, activator protein-1
(c-Fos/c-Jun, AP-1), p53 and signal transducers and acti-
vators of transcription (STATs), thus increasing or inhib-
iting their transcriptional activity
[18, 19] . Importantly,
the major anti-inflammatory and immunosuppressive ef-
fects of glucocorticoids appear to be mediated mostly by
the interaction of the activated hGRα with the pro-in-
flammatory transcription factors NF-κB and AP-1.
Interestingly, it was recently shown that the transcrip-
tion factor ‘circadian locomotor output cycle kaput’
(CLOCK), which forms a heterodimer with its partner
brain-muscle Arnt-like protein 1 (BMAL1), is a novel
partner of GR and catalyzes the acetylation of lysine resi-
dues within the hinge region of the receptor, thus leading
to decreased sensitivity to glucocorticoids. These in vitro
studies have also demonstrated that the heterodimer
CLOCK/BMAL1 behaves as a negative regulator of hGRα
in peripheral target tissues, and antagonizes the physio-
logic actions of fluctuating cortisol
[21–24] . Further in
vivo and ex vivo studies demonstrated that CLOCK-me-
diated acetylation of hGRα was higher in the morning
(when circulating cortisol concentrations are elevated),
leading to decreased tissue sensitivity to glucocorticoids.
In contrast, hGRα was less acetylated by CLOCK at night
(when cortisol concentrations reach their nadir), which
resulted in increased sensitivity of tissues to glucocorti-
[25] . The CLOCK system and the HPA axis com-
municate with one another at multiple signaling levels;
therefore, any conditions that disrupt their molecular
communication may lead to the development of the met-
abolic syndrome
[22–24] . Indeed, night-shift workers
and people frequently exposed to jet lag are at an in-
creased risk for developing symptoms and signs of chron-
ic hypercortisolemia, such as central obesity, insulin re-
sistance, dyslipidemia and hypertension, which represent
the cardinal clinical manifestations of metabolic syn-
[22–24] .
In addition to the above-described genomic actions,
accumulating evidence suggests that glucocorticoids can
induce some of their pleiotropic actions within seconds
or minutes. Apart from their short time frame, these glu-
cocorticoid actions do not require hGRα-mediated tran-
scription/translation, and thus are referred to as ‘non-ge-
nomic’, and can occur in various systems, including the
neuroendocrine, cardiovascular and immune systems
[26–29] . Representative examples of non-genomic gluco-
corticoid actions are: (i) the immediate suppression of
ACTH secretion from the anterior pituitary by glucocor-
[30] ; (ii) the glucocorticoid-induced rapid in-
crease in the frequency of excitatory post-synaptic poten-
tials in the hippocampus
[31] ; (iii) the rapid and transient
decrease in blood pressure associated with a concomitant
increase in coronary and cerebral blood flow in patients
with myocardial infarction or stroke
[32] , and (iv) the
rapid inhibition of T cell receptor signaling through dis-
ruption of the T cell receptor complex
[33] . These actions
are thought to be mediated by membrane-localized GRs,
which, upon ligand binding, trigger the activation of ki-
nase signaling cascades, such as the mitogen-activated
protein kinase or the phosphatidylinositol 3-kinase path-
[26–29] . Although the downstream events of non-
genomic glucocorticoid signal transduction have been
partially elucidated, the origin and membrane localiza-
tion mechanism(s) of the membrane GR still remain an
The LC/NE, Systemic Sympathetic, Adrenomedullary
and Parasympathetic Nervous Systems
The sympathetic and parasympathetic systems repre-
sent the two functional components of the autonomic
nervous system and influence the activity of many vital
physiologic systems, such as respiratory, cardiovascular,
renal, gastrointestinal, neuroendocrine and others. The
sympathetic system plays an important role through the
adrenal medulla in the ‘fight or flight reaction’ by secret-
ing all circulating epinephrine and some of the NE
[11] .
On the other hand, the parasympathetic system antago-
nizes or assists sympathetic functions by increasing or
withdrawing its activity, respectively
[10, 11] .
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To transmit the neural signal, the sympathetic and
parasympathetic systems employ the well-known neu-
rotransmitters acetylcholine and NE, numerous neuro-
peptides, as well as lipid mediators of inflammation,
adenosine triphosphate or nitric oxide
[11] .
The Adaptive Response to Stress
When homeostasis is threatened or perceived as
threatened by a stressor, the stress system is activated
through two waves of serial hormonal secretion provid-
ing the adaptive response. The first wave begins within
seconds and involves: (i) increased release of epinephrine
and NE from the sympathetic nervous system; (ii) secre-
tion of hypothalamic CRH into the hypophysial portal
system and subsequent enhanced release of ACTH; (iii)
decreased release of hypothalamic gonadotropin-releas-
ing hormone (GnRH) followed by decreased secretion of
follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) from the anterior pituitary, and (iv) enhanced
secretion of pituitary-derived prolactin and growth hor-
mone (GH), and increased release of glycogen from the
[34] .
A second wave of hormonal secretion occurs more
slowly and involves the glucocorticoids. All these stress-
mediated hormonal changes during both waves are trans-
lated in cellular end-effects. The hormones involved in
the first wave signal through GPCRs and rapid second
messenger pathways. By contrast, glucocorticoids acti-
vate the GR, a transcription factor that needs more time
from at least 20 min to hours and even days to complete
the appropriate molecular scenario.
However, mounting evidence suggests that many of
the non-genomic glucocorticoid actions are undoubtedly
involved in the acute phase of the stress response
[35, 36] .
Not only do glucocorticoids bind to membrane GRs, but
they also trigger the mineralocorticoid receptor (MR),
another member of the steroid hormone receptor family
of transcription factors, which is evolutionarily related to
the GR. It seems that glucocorticoids, even at lower con-
centrations than those activating the GR, bind to mem-
brane or cytoplasmic MRs and increase the activity of
multiple kinases involved in distinct signal transduction
cascades. Both the GR and MR play important roles in
glutamatergic neurotransmission ( fig.4 ).
During stress, increased concentrations of glucocorti-
coids activate post-synaptic membrane-localized GRs,
which, through the c-AMP-protein kinase A (PKA) path-
way, induce the production and release of the retrograde
molecules anandamide and 2-arachidonoylglycerol. The
latter activate the cannabinoid receptors type 1, located at
the membrane of pre-synaptic neurons, which finally in-
hibit the secretion of glutamate-containing vesicles
37] . On the other hand, pre- and post-synaptic mem-
brane MRs appear to facilitate glutamatergic transmis-
sion. Presynaptically, glucocorticoids bind to membrane
MRs, which, in turn, induce the activation of the extracel-
lular signal-regulated kinase cascade, leading to gluta-
mate release in the synaptic space. Simultaneously, the
post-synaptic activation of membrane MRs by glucocor-
ticoids results in the inhibition of potassium I
A -currents,
and facilitates the membrane diffusion of AMPA recep-
[35, 36] . The above-discussed examples show con-
vincingly that glucocorticoids, acting through the classic
transcription factor GR, also participate in even the early
non-genomic molecular events underlying the adaptive
Activation of the stress system through the above neu-
roendocrine mechanisms leads to a series of behavioral
and physical adaptation changes that increase acutely the
chances for survival
[1–4, 10, 11] . Therefore, organisms
may present with alertness, increased arousal, vigilance,
improved cognition, focused attention, as well as eupho-
ria, enhanced analgesia, suppression of feeding and inhi-
bition of reproductive function. In addition to behavioral
alterations, physical adaptation changes occur under
stressful conditions. Thus, oxygen and nutrients are redi-
rected to the CNS and the stressed body site(s) through a
high respiratory rate, increased cardiovascular tone and a
shift of intermediary metabolism towards catabolism.
Moreover, organisms activate detoxification processes
for any unnecessary metabolic products from the stress-
related reactions
[10] . Concurrently, organisms ‘switch
on’ restraining mechanisms during stress, which prevent
an over-response from the stress system. If they fail to
control stress-related adaptive changes, the stress re-
sponse may become excessive, prolonged and maladap-
tive and may, thus, contribute to the development of
acute or chronic pathologic conditions.
Stress System Disorders
Everything in moderation
Inscription at the Oracle of Delphi
Homeostasis is effectively achieved through normal
basal activity of the stress system and the appropriate
quantity and quality of the stress response to stressors
2] . These parameters are sine qua non for human health.
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By contrast, if the stress system has low or high basal ac-
tivity and/or excessive or prolonged responsiveness to
stressful stimuli, homeostasis is turned into cacostasis
with many adverse consequences on physiologic biologic
functions, leading to the development of acute or chron-
ic pathologic conditions.
Acute and Chronic Stress System Disorders
Stress may precipitate acute or chronic disorders in
humans with susceptible genetic loci and/or epigenetic
modifications in several genes
[1–4, 10–12, 38] . Under
acute stress, individuals may present with allergic condi-
tions (asthma, eczema or urticaria), or complaint for mi-
graines and/or gastrointestinal symptoms, such as ab-
dominal pain, indigestion, diarrhea and constipation. Of
note, the frequency of panic attacks and psychotic epi-
sodes is higher during acute stress. The molecular basis of
these stress-mediated conditions can be attributed to
acutely increased secretion of CRH, which exerts its ef-
fects through signaling in vulnerable end organs
[39–43] .
On the other hand, a long-lasting stress response may
cause excessive release and prolonged effects of the major
effector molecules of the stress system, including CRH,
cortisol and NE, on vital neuroendocrine and metabolic
axes leading to the development of a broad spectrum of
metabolic and/or neuropsychiatric disorders
[1, 4, 18,
39–43] .
Chronic stress exerts inhibitory effects on the growth
axis. Chronically increased circulating glucocorticoids
suppress the secretion of GH from the pituitary and in-
hibit insulin-like growth factor I actions at its target tis-
sues, possibly through interaction of the c-jun/c-fos het-
erodimer with the ligand-activated hGR
[44–46] . Fur-
thermore, CRH increases the levels of hypothalamic
somatostatin, a known inhibitor of GH secretion. These
mechanisms may explain the delayed or arrested growth
in children with Cushing syndrome
[45, 47] . Another ex-
ample of stress-mediated inhibition of growth is the ‘psy-
Inhibition of
glutamatergic neurotransmission
Facilitation of
glutamatergic neurotransmission
Fig. 4. Inhibition and facilitation of glutamatergic neurotransmis-
sion through membrane GRs and MRs, respectively. cAMP = Cy-
clic-AMP; 2-AG = 2-arachidonoylglycerol; AEA = anandamide;
CB1 = cannabinoid receptor type 1; K
+ = potassium; AMPA =
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-
tor; ERK = extracellular signal-regulated kinase. Modified from
Groeneweg et al.
[35] .
Color version available online
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chosocial short stature’ in children or adolescents who
experienced physical or psychological maltreatment.
These children have typically decreased levels of GH,
which return to within a normal range a few days after
they are separated from the stressful environment
49] .
Prolonged activation of the stress system leads to de-
creased synthesis of thyroid-stimulating hormone due to
increased concentrations of CRH-induced somatostatin,
which in turn suppresses both thyroid-releasing hor-
mone (TRH) and thyroid-stimulating hormone (TSH).
Furthermore, elevated circulating concentrations of glu-
cocorticoids inhibit the activity of the enzyme 5-deiodin-
ase that converts inactive thyroxine to the biologically ac-
tive triiodothyronine in peripheral target tissues (the ‘eu-
thyroid sick’ syndrome)
[50] .
The hypothalamic-pituitary-gonadal axis is strongly
influenced at multiple levels by both CRH and glucocor-
[51] . CRH inhibits the secretion of GnRH from
the hypothalamus
[52, 53] , while glucocorticoids sup-
press the activity of the reproductive axis by decreasing
secretion of GnRH, follicle-stimulating hormone/lutein-
izing hormone and gonadal steroids
[52–55] . Representa-
tive examples of stress-mediated suppression of the go-
nadal axis are highly trained runners and ballet dancers,
who may present with suppression of gonadal function
due to chronic activation of the HPA axis
[56, 57] .
Individuals under chronic stress are more susceptible
to specific infections and autoimmune disorders caused
by the glucocorticoid- and catecholamine-induced switch
from Th1 to Th2
[11, 12, 38, 40, 41] . Indeed, chronically
stressed individuals may have persistent infections with
Helicobacter pylori , Mycobacterium tuberculosis and the
common cold viruses. Moreover, the stress-induced Th1
to Th2 switch increases the risk for certain autoimmune
disorders, such as systemic lupus erythematosus, Graves
disease, and some allergic conditions
[1] .
Stress System and Non-Communicable Diseases
At present, our society is plagued by complex multi-
factorial non-communicable diseases, including obesity/
metabolic syndrome and its detrimental cardiovascular
complications, as well as depression, anxiety and insom-
nia. All these pathologic conditions are associated with an
excessive or long-lasting stress response to a variety of
external or internal stressors.
The pathogenesis of metabolic syndrome is closely as-
sociated with chronic hypersecretion of stress system me-
diators, such as cortisol, NE, epinephrine, immune CRH
and IL-6, which increase the secretion of insulin and de-
crease the release of GH and sex steroids, ultimately lead-
ing to visceral fat accumulation, and loss of muscle mass
(sarcopenia) and bone mass (osteoporosis)
[58, 59] . The
resultant visceral obesity and sarcopenia are closely asso-
ciated with other cardinal clinical manifestations of the
metabolic syndrome, such as dyslipidemia, hypertension
and type 2 diabetes mellitus. Moreover, elevated concen-
trations of IL-6, among other cytokines secreted by in-
flamed adipose tissue, and chronic hypercortisolism con-
tribute to stimulation of acute-phase reaction and blood
hypercoagulation. All these adverse factors may lead to
endothelial dysfunction and atherosclerotic cardiovascu-
lar disease
[1, 58, 59] .
In addition to the metabolic syndrome, stress par-
ticipates in the pathogenesis of major depression
62] . Major depression is a heterogeneous disorder with
two main subtypes: melancholic and atypical depres-
sion. Patients with melancholic depression have a hy-
peractive stress system and may present with anxiety,
guilt, fear, low self-esteem, insomnia and loss of appe-
tite. They also have hypersecretion of hypothalamic
CRH, as evidenced by elevated 24-hour urinary cortisol
excretion, decreased ACTH responses to exogenous
CRH administration, and elevated concentrations of
CRH in their cerebrospinal fluid throughout the 24-
hour period. Furthermore, the concentrations of NE in
cerebrospinal fluid are continuously elevated, even dur-
ing sleep. In contradistinction to melancholic depres-
sion, atypical depression is characterized by lethargy,
fatigue, hypersomnia and hyperphagia, which are asso-
ciated with downregulation of the HPA axis of central
All the above-discussed chronic non-communicable
disorders of modern societies are associated with mal-
adaptive stress responses and their origins lie deep in the
evolutionary process of human beings
[1, 4, 63] . Indeed,
our ancestors faced numerous environmental stressors,
including starvation, dehydration, infectious diseases,
threatening adversaries, dangers and injuries, which ap-
plied selective pressures upon genes implicated in the
adaptive stress response. This genomic selection obvious-
ly favored those individuals who were efficient in coping
with the above stressful stimuli.
Today, the same selected gene networks, subserving
functions important for human survival and species pres-
ervation, must encode effector molecules involved in the
‘contemporary’ adaptive stress response to address the
same types of stressors, but in different quantities and
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contexts. For example, an excess of calories leads to obe-
sity, since the adaptive stress response has been pro-
grammed to cope with food deficiency, not excess. Thus,
the gene networks presented in table2 are now accepted
to be responsible for most of the contemporary diseases
of Western societies.
The Stress System in the Epigenetic Era
Interactions between genetic and environmental fac-
tors have been confirmed by many epidemiological stud-
[64] . However, the molecular mechanisms through
which the environment acts to switch genes ‘on’ and ‘off’
Table 2. Gene networks subserving functions important for human survival and species preservation, which may
produce pathology in contemporary Western societies
Response to survival threat Selective advantage Contemporary diseases
Combat starvation Energy conservation Obesity
Combat dehydration Fluid and electrolyte conservation Hypertension
Combat infectious diseases Potent immune reaction Autoimmunity/allergy
Anticipate adversaries Arousal/fear Anxiety/insomnia
Minimize exposure to danger Withdrawal from danger Depression
Prevent tissue strain and injury Retain tissue integrity and reserve Pain and fatigue syndromes
Adapted from Chrousos and Kino [4].
High maternal licking/grooming Low maternal licking/grooming
5-HT 5-HT
Fig. 5. Molecular mechanisms linking maternal licking/grooming with hippocampal GR expression. cAMP =
Cyclic-AMP; NGFIA = nerve growth factor-inducible A; Nr3c1 = nuclear receptor subfamily 3, group C, member
1 (GR) gene. Modified from Champagne
[68] .
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remain incompletely elucidated and are currently under
intense investigation.
Almost 30 years ago, a brief report published by
Meaney et al. [65] provided the first evidence of an asso-
ciation between post-natal pup handling and GR levels
within the hippocampus. In their pioneering work, they
compared rats exposed to maternal handling with non-
handled ones. They demonstrated that handled rats had
significantly increased protein levels of GR expressed in
the hippocampus compared with the non-handled rats
[65] . At that time, two possible mechanisms were pro-
posed to explain these effects: (i) elevated protein levels of
GR per cell, and (ii) increased post-natal neurogenesis in
the hippocampus in the handled rats. These results set the
stage for further molecular and cellular studies. Thus, it
was later shown that handling could increase the concen-
trations of plasma thyroid hormones (thyroxine and tri-
[66] , and that both handling and thyroid
hormones might boost serotonin (5-HT) turnover in hip-
pocampal neurons
[67] .
Further studies determined the molecules involved in
the serotonin-mediated GR expression
[68] ( fig. 5 ).
Upon binding to the 5-HT receptor, handling-induced
serotonin molecules trigger the production of c-AMP
and the subsequent activation of PKA. The latter facili-
tates – directly or indirectly through CBP – the binding
of the transcription factor nerve growth factor-inducible
factor A (NGFI-A) to a specific region of exon 1
7 of the
Nr3c1 gene inducing the expression of GR within the
hippocampus. The procedure of handling has been
shown to correspond to increased maternal licking/
[69] .
Subsequent studies demonstrated that high maternal
licking/grooming resulted in elevated thyroid hormone
levels, enhanced serotonin signaling and increased bind-
ing of NGFI-A to the Nr3c1 1 7 promoter [70] . By con-
trast, low maternal licking/grooming led to low GR ex-
pression that was attributed to increased hippocampal
cytosine methylation of the Nr3c1 1 7 promoter, an epi-
genetic modification that obviously altered gene expres-
sion without any changes in the underlying DNA se-
[71] . The application of epigenetics research in
humans showed a clear association of childhood abuse
with increased Nr3c1 1 7 methylation at the NGFI-A
binding sites
[72] .
In addition to GR, other studies have investigated
stress-induced epigenetic modifications of genes involved
in the stress response. Among them, the Crh , glial-de-
rived neurotrophic factor (Gdnf) , brain-derived neuro-
trophic factor (Bdnf) and AVP (Avp) genes were studied
exclusively in animal models
[73] . Although all these epi-
genetic modifications are persistent and can be present in
the next generation, recent evidence suggests that drugs
altering DNA methylation/histone modifications can re-
verse the effects of early life experience in adulthood
[74] .
Thus, the emerging field of behavioral epigenetics will be
at the epicenter of stress research and will undoubtedly
provide a significant contribution to our conceptualiza-
tion of the impact of early-life events on the quality of
adult life
[75] .
We now know the central and peripheral compo-
nents of the stress system, the physiologic biochemical
effectors that mediate the behavioral and physical
changes during the stress response, and the molecular
mechanisms through which stress-induced neuroendo-
crine changes are translated to target tissue effects. Dis-
tress is a major factor in the pathogenetic mechanisms
of almost all disorders. Moreover, our lifestyles and en-
vironment in modern societies seem to be particularly
permissive for allostasis. The picture became more com-
plicated when we realized that early stressful life experi-
ences leave deep traces in our expressed genome. It is
imperative to develop effective strategies of stress man-
agement to decrease the incidence and alleviate the
symptoms and consequences of stress system disorders.
Although there remains much to learn about stress-me-
diated pathogenetic mechanisms, it is certain that less
distress improves the quality and increases the length of
our lives.
This work was supported by: (i) the European Union (Euro-
pean Social Fund – ESF) and Greek national funds through the
Operational Program ‘Education and Lifelong Learning’ of the Na-
tional Strategic Reference Framework (NSRF) – Research Funding
Program: THALIS – University of Athens, Athens, Greece; and (ii)
the intramural program of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, National In-
stitutes of Health, Bethesda, Md., USA.
All figures were prepared using image vectors from Servier
Medical Art (, licensed under the Creative Com-
mons Attribution 3.0 Unported License (http://creativecommons.
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... Це стереотипна системна реакція, що активує нейронні, ендокринні та імунні сигнали [52]. Основні складові стресової реакції -активація locus coeruleus/симпатичної нервової системи та вивільнення із мозкової речовини надниркових залоз у кровотік катехоламінів, які визначають «реакцію боротьби або втечі», з боку нервової системи [10] і активацію осі гіпоталамус -гіпофіз -наднирники (ГГН) з наступною секрецією глюкокортикоїдів [45] -з боку гормональної системи. Фізіологічна активація цієї системи підвищує збудження, моторні рефлекси, увагу, когнітивні функції, серцево-судинну діяльність, артеріальний тиск і частоту дихання, а також метаболічні процеси глікогенолізу, глюконеогенезу та ліполізу, які дають змогу швидко мобілізувати енергетичні ресурси організму від місць накопичення до серця, м'язів і мозку [45]. ...
... Основні складові стресової реакції -активація locus coeruleus/симпатичної нервової системи та вивільнення із мозкової речовини надниркових залоз у кровотік катехоламінів, які визначають «реакцію боротьби або втечі», з боку нервової системи [10] і активацію осі гіпоталамус -гіпофіз -наднирники (ГГН) з наступною секрецією глюкокортикоїдів [45] -з боку гормональної системи. Фізіологічна активація цієї системи підвищує збудження, моторні рефлекси, увагу, когнітивні функції, серцево-судинну діяльність, артеріальний тиск і частоту дихання, а також метаболічні процеси глікогенолізу, глюконеогенезу та ліполізу, які дають змогу швидко мобілізувати енергетичні ресурси організму від місць накопичення до серця, м'язів і мозку [45]. Катехоламіни пригнічують противірусні реакції, одночасно посилюючи транскрипцію прозапальних генів. ...
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Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, affecting 25 — 30% of the adult population. Prevalence rates vary by country, with the highest rates reported in regions with the high levels of stress. The frequency of NAFLD correlates with the intensity of the subjective feeling of stress. The war in Ukraine and the migration of a part of the population to European countries had a significant impact on the health of the population, which was caused by a sharp increase in the influence of stressful factors and the formation of signs of mental health disorders. The chronic influence of negative psychosocial factors, in particular the stressful conditions of wartime, is the main reason for the hyperactivation of the stress response and chronic high cortisol levels, which become maladaptive and lead to distant consequences — changes in carbohydrate and lipid metabolism, energy balance, and metabolic changes that cause the formation of and progression of NAFLD, as well as to changes in the immune system. In addition to metabolic factors, chronic stress is a trigger for changes in the functioning of the digestive system and intestinal microbiota, that is, the gut‑liver axis, which is involved in the formation of NAFLD. The presented data justify the need for scientific research to find pathogenetic measures that affect mental processes in humans through the correction of the microbiome, namely psychobiotics — probiotics, the consumption of which in a certain amount has a beneficial effect on the host's mental health through interaction with commensal intestinal bacteria. Despite some progress in the study of the effectiveness of psychobiotics in stress management, the number of studies on this problem is limited, so it is necessary to conduct additional studies on their use in the complex treatment of NAFLD with account of lifestyle factors.
... 5 GC has a prominent role in stress-related homeostasis, behavior, and cognition. 6,7 Further, elevated GC levels increase the production of free radicals and reactive oxygen species. 8,9 Clinical and experimental research has demonstrated that stress is associated with increased psychiatric disorders such as depression and anxiety. ...
Background: Stress and its complications such as anxiety and depression continue to be regarded as health issues in human societies. Therefore, an effective treatment strategy is highly valued for dealing with stress and related disorders. In spite of studies suggesting the neuroprotective effects of silymarin and buspirone alone, the combined effects of these treatments on chronic stress have not been elucidated yet. Thus, this study aimed to investigate the effect of silymarin and buspirone (alone or in combination) on anxiety and depressive-like behaviors and to evaluate corticosterone levels in a mice model of chronic restraint stress (RS). Methods: This study was conducted on seventy-two male BALB/c mice which were allocated in six equal groups. The animals were exposed to chronic RS (2 hours/day for 14 days) to induce a depressive-like model. An elevated plus maze (EPM) was performed to assess anxiety, while a tail suspension test (TST) was implemented to evaluate depressive-like behavior. Furthermore, the serum levels of corticosterone were measured by the enzyme-linked immunosorbent assay method. Results: Our data demonstrated that exposure to RS resulted in prolonged immobility in the TST and reduced time spent in the open arms of the EPM test. Buspirone perorally (5 mg/kg, PO) alone and combined with silymarin (200 mg/kg, PO) increased time spent in the open arms of the EPM apparatus while attenuating immobility time in TST. There was a significant decrease in the blood corticosterone level of buspirone and silymarin co-treated animals. Conclusion: These findings indicated that silymarin potentiates the beneficial effect of buspirone against chronic RS-induced anxiety and depressive-like behaviors in mice by lowering corticosterone serum levels. In this regard, further investigations should be undertaken to clarify the exact mechanism of the observed effects.
... In humans, cortisol is the primary GC [24], which can be measured in serum, saliva, urine, and hair [25]. Hair sample analysis is considered a non-invasive long-term assessment for retrospective cortisol evaluation: as hair grows approximately 1 cm each month, a 1 cm segment, which is more proximal to the scalp, depicts cortisol levels of the past month [26,27]. ...
Purpose: Dysregulation of the stress system via incidental long exposure to glucocorticoids (GCs) can lead to weight gain. In addition, family and maternal stress can also have an impact on children's weight. Hair is used in several studies to evaluate cortisol (GC) levels in children and adolescents with excess weight as a retrospective stress biomarker, depending on the hair length the cortisol measurement depicting different time periods. We aimed to investigate whether there is a difference among segmental hair cortisol concentration (HCC) analysis between children and adolescents with overweight and obesity, their mothers, and normal weight peers. Methods: This study recruited 25 children aged 6-14 years with a body mass index (BMI) ≥ 85th centile and their mothers, as well as 20 children of the same age with a BMI < 85th centile. Hair cortisol concentration was measured using electrochemiluminescence immunoassay. Results: Segmental HCC analysis exhibited gradually decreasing values in all participants as segments of hair were more distantly located from the scalp. A positive correlation was found between BMI z-score and HCC of the first segment of hair in children and adolescents with elevated BMI (b = 1.84, p = 0.033), as well as with maternal HCC / of an only child (b = 15.77, p = 0.01). There were no associations between mother-child dyads and children and adolescents of different BMI groups, even though minors with excess weight exhibited higher HCC levels in all segments of hair in comparison to their normal weight counterparts. Conclusions: Hair cortisol of all participants exhibited a gradually declining concentration. More studies with larger samples and more sensitive methods of analysis are warranted in order to draw firmer conclusions.
... When homeostasis in this network is challenged, the whole system reacts to restore homeostasis. This is a stress response where the stressor can be every challenge strong enough to endanger whole body homeostasis, e.g., psychological stress, injury, or infection [8][9][10][11][12]. ...
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In this review article the current model of the interaction between the sympathetic nervous system (SNS) and the immune system in the context of chronic inflammation is presented. Mechanisms in the interaction between the SNS and the immune system are shown, which are similar for all disease entities: 1) the biphasic effect of the sympathetic system on the inflammatory response with a proinflammatory, stimulating effect before and during the activation of the immune system (early) and a more inhibitory effect in late phases of immune activation (chronic). 2) The interruption of communication between immune cells and the brain by withdrawal of sympathetic nerve fibers from areas of inflammation, such as the spleen, lymph nodes or peripheral foci of inflammation. 3) The local replacement of catecholamines by neurotransmitter-producing cells to fine-tune the local immune response independently of the brain. 4) Increased activity of the SNS due to an imbalance of the autonomic nervous system at the systemic level, which provides an explanation for known disease sequelae and comorbidities due to the long duration of chronic inflammatory reactions, such as increased cardiovascular risk with hypertension, diabetes mellitus and catabolic metabolism. The understanding of neuroimmune interactions can lead to new therapeutic approaches, e.g., a stimulation of beta-adrenergic and even more an inhibition of alpha-adrenergic receptors or a restoration of the autonomic balance in the context of arthritis ) can make an anti-inflammatory contribution (more influence of the vagus nerve); however, in order to translate the theoretical findings into clinical action that is beneficial for the patient, controlled interventional studies are required.
There is an empirical association between stress and symptoms of food addiction (FA), but it is still not clear which domains of stress are the most relevant when it comes to FA, limiting the ability of researchers and practitioners to address problematic eating‐related health outcomes. In order to address this gap in the literature, we analysed how different domains of chronic stress are related to FA. We used data from a subsample of the LIFE‐Adult‐Study ( N = 1172), a German cohort study. We conducted a linear regression analysis with stress domains (Trier Inventory for Chronic Stress, TICS) as predictors of FA (Yale Food Addiction Scale, YFAS). In the second regression analysis we included sociodemographic variables, personality, and smoking as control variables. There was a significant and positive association between Social Overload, Work Discontent, Excessive Demands from Work, and Chronic Worrying and FA. After adding control variables, only Social Overload, Excessive Demands from Work, and Chronic Worrying remained significant predictors. Connections between stress domains and FA can serve as starting points for the development of meaningful interventions that support individuals self‐care strategies (Social Overload), complexity management (Excessive Demands from Work), and coping with negative emotions (Chronic Worrying).
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Metabolomics has gained much attraction due to its potential to reveal molecular disease mechanisms and present viable biomarkers. In this work we used a panel of untargeted serum metabolomes in 602 childhood patients of the COPSAC2010 mother-child cohort. The annotated part of the metabolome consists of 493 chemical compounds curated using automated procedures. Using predicted quantitative-structure-bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines, we created a filtering method for the vast number of quantified metabolites. The metabolites measured in children's serums used here have predicted potential against the chosen target modelled targets. The targets from Tox21 have been used with quantitative structure-activity relationships (QSARs) and were trained for ~7000 structures, saved as models, and then applied to 493 metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. The significant metabolites were reported.
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Sommario Lo stress rappresenta la risposta di adattamento dell’organismo a una minaccia all’equilibrio (omeostasi) dell’organismo da parte di eventi o stressor di natura intrinseca o estrinseca, reali o percepiti. Gli stressor attivano un variegato e intricato repertorio di risposte fisiologiche biologiche e comportamentali (allostasi) volte a ristabilire l’equilibrio ottimale dell’organismo (eustasi). La risposta adattiva agli stressor dipende da una complessa rete psico-neuro-endocrino-immuno-metabolica, cellulare e molecolare altamente interconnessa, chiamata proprio sistema o asse dello stress. I componenti chiave sono rappresentati dall’asse ipotalamo-ipofisi-surrene (HPA) e dal sistema nervoso autonomo (SNA), che interagiscono con altri centri vitali del sistema nervoso centrale (SNC) e con organi periferici e sistemi, dalla cui attivazione complessiva si genera una risposta rapida, efficace, multisistemica e autolimitantesi, che permette all’organismo una reazione corporea e neuropsichica ottimale. Le catecolamine e il cortisolo rappresentano gli attori principali che esplicano e attivano le reazioni psichiche e comportamentali dell’individuo nella reazione di stress, la cosiddetta reazione fight or flight. L’azione delle catecolamine è breve, quella del cortisolo più duratura e mediata dall’attivazione dei recettori del cortisolo (GR e MR, recettori dei glucocorticoidi e mineralcorticoidi rispettivamente) espressi ubiquitariamente. Attraverso azioni non genomiche e genomiche i glucocorticoidi modulano una serie di processi metabolici, con caratteristiche sesso specifiche. Una delle conseguenze della reazione dello stress, in condizioni in cui quest’ultimo sia persistente o non adeguatamente regolato, è lo sviluppo di uno stato infiammatorio cronico. Il cortisolo ha un ruolo rilevante nell’equilibrio citochinico pro/antinfiammatorio. In condizioni di stress cronico questo equilibrio viene meno e si crea uno scenario caratterizzato da risposte infiammatorie eccessive. È oggi definito il ruolo dello stato infiammatorio cronico nella fisiopatologia della sindrome metabolica, dell’obesità e del diabete, così come della depressione. In questa rassegna percorreremo, sulla base delle evidenze della letteratura, i meccanismi psico-neuro-endocrino-metabolici sottesi alla regolazione dello stress e alle conseguenze metaboliche e psichiche potenzialmente generabili e correlate allo stress cronico o all’alterata regolazione dello stesso.
All living organisms have been programmed to maintain a complex inner equilibrium called homeostasis, despite numerous adversities during their lifespan. Any threatening or perceived as such stimuli for homeostasis is termed a stressor, and a highly conserved response system called the stress response system has been developed to cope with these stimuli and maintain or reinstate homeostasis. The glucocorticoid receptor, a transcription factor belonging to the nuclear receptors protein superfamily, has a major role in the stress response system, and research on its interactome may provide novel information regarding the mechanisms underlying homeostasis maintenance. A list of 149 autosomal genes that have an essential role in GR function or are prime examples of GRE-containing genes was composed in order to gain a comprehensive view of the GR interactome. A search for SNPs on those particular genes was conducted on a dataset of 3554 Japanese individuals, with mentioned polymorphisms being annotated with relevant information from the ClinVar, LitVar, and dbSNP databases. Forty-two SNPs of interest and their genomic locations were identified. These SNPs have been associated with drug metabolism and neuropsychiatric, metabolic, and immune system disorders, while most of them were located in intronic regions. The frequencies of those SNPs were later compared with a dataset consisting of 1465 Korean individuals in order to find population-specific characteristics based on some of the identified SNPs of interest. The results highlighted.that rs1043618 frequencies were different in the two populations, with mentioned polymorphism having a potential role in chronic obstructive pulmonary disease in response to environmental stressors. This SNP is located in the HSPA1A gene, which codes for an essential GR co-chaperone, and such information showcases that similar gene may be novel genomic targets for managing or combatting stress-related pathologies.
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Stress has a different meaning for different people under different conditions. The first and most generic definition of stress was that proposed by Hans Selye: "Stress is the nonspecific response of the body to any demand." Other definitions have evolved to cater for different situations-for example, cognitive. This article explores the basis for these definitions and their validity, and outlines the neuroendocrine mechanisms that subserve the stress response. The concept of homeostasis, 'stability through constancy' as the main mechanism by which the body copes with stress, has given way to allostasis, 'stability through change' brought about by central neural regulation of the set points that adjust physiological parameters to meet the stressful challenge. Furthermore, this article reviews relatively new stress concepts based on findings that (1) polymorphisms in certain genes involved in neurotransmission, as well as epigenetic factors, may determine individual susceptibility to stressful life events, and (2) fetal malnutrition may predispose individuals to the metabolic syndrome (obesity, hypertension, dislipidemia, and diabetes type 2) that has reached epidemic proportions in many countries. Finally, studies of heat shock proteins show that Selye's generic definition is applicable to the stress response in all three phylogenetic domains of organisms ranging from bacteria to man.
It has been over 50 years since Hans Selye formulated his concept of stress. This came after the isolation of epinephrine and norepinephrine and after the sympathetic system was associated with Walter Cannon's "fight or flight" response. The intervening years have witnessed a number of dis­ coveries that have furthered our understanding of the mechanisms of the stress response. The isolation, identification and manufacture of gluco­ corticoids, the identification and synthesis of ACTH and vasopressin, and the demonstration of hypothalamic regulation of ACTH secretion were pivotal discoveries. The recent identification and synthesis of CRR by Willie Vale and his colleagues gave new impetus to stress research. Several new concepts of stress have developed as a result of advances in bench research. These include the concept of an integrated "stress sys­ tem", the realization that there are bi-directional effects between stress and the immune system, the suggestion that a number of common psychiatric disorders represent dysregulation of systems responding to stress, and the epidemiologic association of stress with the major scourges of humanity.
Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1-10 μm) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.
Growth retardation to complete growth arrest is the hallmark of Cushing’s syndrome in children. The major mechanism for this has been considered the glucocorticoid-induced resistance of target tissues to insulin-like growth factor-I (IGF-I) and other growth factors. The purpose of this study was to examine the GH secretory dynamics of patients with Cushing’s disease before and up to 12 months after their cure by transsphenoidal adenomectomy. In 14 patients, blood sampling every 20 min over 24 h for determination of plasma GH was performed before and 10-11 days and 3, 6, and 12 months after therapy. These patients also underwent arginine infusion and L-dopa stimulation tests and had measurements of morning baseline GH-binding protein (GHBP), IGF-I, and IGF-binding protein-3 (IGFBP-3) plasma concentrations. Fourteen sex- and pubertal stage-matched normal volunteers were used as controls. Before therapy, the patient group had an increased body mass index (31.5 ± 5 kg/m²) and markedly decreased plasma mean 24-h GH concentration, mean peak height, and peak area values, with pulse frequency (mean number of peaks) similar to that in the controls. GH values after arginine and L-dopa stimulation were also subnormal in many of these patients, with 2 of 8 and 8 of 10 failing to show GH responses greater than 7 ng/mL in the respective test. In spite of these findings, plasma concentrations of IGF-I, IGFBP-3, and GHBP were within the normal range in these patients. Surprisingly, a pattern of GH suppression similar to that observed in patients with active disease was also seen in patients who were studied 10-11 days and 3, 6, and 12 months after their cure, when their body mass indexes were progressively normalizing, being relatively stable at 10 days, 26.9 ± 3.8 kg/m² at 3 months, and 24.8 ± 3.3 kg/m² at 12 months. In these patients, plasma IGF-I and GHBP remained normal, whereas IGFBP-3 decreased significantly, albeit within the normal range. The growth rate of 4 patients who were Tanner stage III or below and had not completed their growth at the time of the study increased the year after surgical cure. These findings suggest that patients with Cushing’s disease have marked GH suppression during their illness, which, however, does not appear to be a major contributor to the growth suppression observed in this condition. GH hyposecretion continues for at least a year during convalescence, in spite of significant increases in the growth rate in all growing patients.