Transcript Oxidative stress

ISMAUK
International Stress
Management Association UK
Promoting wellbeing and stress
prevention
Our Purpose and Mission
ISMA UK is a registered charity with a
multidisciplinary professional membership that
includes the UK and the Republic of Ireland. It
exists to promote sound knowledge and best
practice in the prevention and reduction of
human stress. It sets professional standards for
the benefit of individuals and organisations using
the services of its members.
Adaptive responses to
disease: a necessary evil?
Lessons from transgenic
models
Katia P. Karalis
Biomedical Research Foundation of
the Academy of Athens, Greece
Children’s Hospital, Boston, USA
Disturbing
Forces
II
Stressors
(Physical,
Emotional)
Harmony
Equilibrium
Balance
II
Homeostasis
Counteracting
Reestablishing
Forces
II
Adaptive
Response
Specific
“Nonspecific”
General
Stress Syndrome,
Diseases of
Adaptation
Load=Stressor
Load deformation curve
Distress, Dyshomeostasis
=Allostasis=Cacostasis
Fracture point
Yield point
Stress, Homeostasis,
Eustasis
Plastic region
Elastic region
Deformation=Adaptive response
Human Stressors
Natural catastrophies
Life transitions
Unnatural catastrophies
Starvation, Excessive exercise
Socioeconomic status
Job loss, Downsizing, Loss of control
Bereavement/Caretaking
Addictions/ Toxic substances
Inflammations (Traumatic, Infectious, Autoimmune, Allergic)
Anxiety, Depression, Personality disorder
Stress
James Tighe
Stress in itself isn't necessarily harmful.
Everyone needs goals and challenges.
But too much can be damaging.
We explain how to spot when stress is becoming
unmanageable
and suggest ways to deal with it.
bbc.co.uk
Health
Sources of peripheral CRH
Hypothalamus
leukocytes
CRH
Nerve fibers
?
Pituitary
ACTH
Inflammatory
sites
Adrenals
glucocorticoid
The HPA axis
STRESS
Locus
coeruleus
Hypothalamus
CRH VP
+
+
Anterior pituitary
ACTH
Adrenal cortex
Glucocorticoid
Crh-/- mice are products of full gestation.
Litter size does not indicate implantation or
gestational problems.
Crh-/- mice need in utero treatment with
glucocorticoid for normal lung development
and survival.
CRH is necessary for the normal
development of the adrenal cortex.
Sites of CRH synthesis
BRAIN
SPINAL
CORD
IMMUNE
SYSTEM
GI TRACT
PLACENTA
T-lymphocyte
LUNG
GLUCOCORTICOID
INFLAMMATION
EPINEPHRINE
CRH
CRH AND INFLAMMATION
CRH
INFLAMMATION
ACTH
GC
EPI
PERIPHERAL CRH
The HPA axis
STRESS
Locus
coeruleus
Hypothalamus
CRH VP
+
Anterior pituitary
+
ACTH
Adrenal cortex
EPI
-
PERIPHERAL
CRH
Glucocorticoid
INFLAMMATION
Inflamed muscle following turpentine
Saline
Turpentine
A
B
C
D
Crh+/+
Crh-/-
Dual effects of CRH on the immune
/inflammatory response
* suppressive, by central CRH
*stimulatory, by peripheral CRH
Crh+/+
Crh-/-
control
7d DSS
7d DSS+ 4d
Non-resolving inflammation……
part of inadequate “stress” response ??
reflects compromised ability to return to
homeostasis?
Crh-/- DSS-treated mice do not survive the disease
Cummmulative Survival
1
.8
.6
.4
Crh+/+
Crh-/-
.2
0
2
P<0.0001 by Logrank
test
4
6
days
8
10
12
14
%Loss of Body weight
0
100
90
80
70
60
1 2 3 4 5 6 7 8 9 10 11 12 13
<--------------------------->
DSS treatment
Experimental day
% Animal Body Weight
110
105
100
95
90
85
80
7nth
day
DSS
1st day 2nd day 3rd day 4th day 5th day
H2O
H2O
H2O
H2O
H2O
Days
Crh+/+
Crh-/-
Metabolic response of the Crh-/- mice
to inflammatory stimuli
Crh +/+ saline
Crh+/+ turpentine
Crh -/- saline
Crh-/- turpentine
100
90
80
70
60
1 2 3 4 5 6 7 8 9 10 11 12 13
<--------------------------->
DSS treatment
Body weight (% of control)
Crh-/-
108
*
*
104
*
#
100
#
#
96
92
1
2
3
4
5
6
Day following the injection
The “stress response” is
associated with changes in
food behavior
what is the role of CRF in this
process???
METABOLISM
IMMUNE SYSTEM
Stress neuropeptides/ hormones
High fat diet ->
an experimental
manipulation to induce
obesity and reveal altered
eating behavior
Eating behavior of Crh-/- mice on HFD
W
T
CRHKO
*
31
body weight
25
% weight gain
30
29
28
27
26
20
*
15
10
5
25
week
160
30
0
0
1
2
3
4
weekly food intake (g)
32
140
120
*
100
80
60
40
20
0
WT
CRHKO
week
1
2
3
4
Decreased adiposity in HFD-fed Crh-/- mice
40
serum leptin (ng/ml)
fat pad weight (g)
2.5
35
2
30
25
1.5
20
*
1
15
*
10
0.5
5
0
0
WT
CRHKO
CRHKO
50
40
*
30
20
250
200
150
100
*
TLR4 mRNA (AU)
250
MCP-1 mRNA (AU)
TNFα mRNA (AU)
60
WT
200
150
100
*
10
50
50
0
0
0
WT
CRHKO
WT
CRHKO
WT
CRHKO
Is the response to high fat diet a
“stress” response?
CRH +/glucocorticoid
Insulin
inflammation
tissue repair
CRH
neuronal function
developmental aspects
appetite regulation
obesity
adipocyte biology
Anatomy of the intestinal immune system
Crh +/+ saline
Crh+/+ turpentine
Crh -/- saline
Crh-/- turpentine
0.30
*
*#
*
0.25
Food intake (g)
*
5
Crh-/- controls
Crh+/+ controls
4
3
2
Crh+/+ TNBS
1
0
*#
Crh-/- TNBS
24h
48h
basal
0.20
0.15
LPS
*
average daily
food intake
Food intake (gr)/mouse weight (gr)
Crh deficiency is associated with “paradoxically”
normal anorectic response to inflammatory stimuli
7
0.10
5
3
0.05
1
2
3
4
5
1
-1
Days following the injection
Crh+/+
Crh-/-
Crh/Tnf
Tnfa-/-a
-/-
Novel adipose tissue-mediated resistance to
diet-induced visceral obesity in 11 betahydroxysteroid dehydrogenase type 1deficient mice.
Morton NM, Paterson JM, Masuzaki H, Holmes MC,
Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR.
Diabetes. (2004) 53:931-8
Adipocyte-specific glucocorticoid inactivation
protects against diet-induced obesity.
Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS.
Diabetes. (2005) 54(4):1023-31
Disturbing
Forces
II
Stressors
(Physical,
Emotional)
Harmony
Equilibrium
Balance
II
Homeostasis
Counteracting
Reestablishing
Forces
II
Adaptive
Response
Specific
“Nonspecific”
General
Stress Syndrome,
Diseases of
Adaptation
THE ADAPTIVE RESPONSE= STRESS
SYNDROME
Phenomenology
a.
CNS Functions
- Facilitation-arousal, alertness, vigilance, cognition
attention, aggression
- Inhibition – vegetative functions
(reproduction, feeding, growth)
- Counteregulatory feedback
b.
Peripheral Functions
● Oxygenation – nutrition
cardiovascular tone, respiration,
metabolism (catabolism, inhibition
of reproduction and growth)
● Detoxification
● Counteregulatory feedback (immunosuppression)
Human Stressors
Natural catastrophies
Life transitions
Unnatural catastrophies
Starvation, Excessive exercise
Socioeconomic status
Job loss, Downsizing, Loss of control
Bereavement/Caretaking
Addictions/ Toxic substances
Inflammations (Traumatic, Infectious, Autoimmune, Allergic)
Anxiety, Depression, Personality disorder
METABOLISM
IMMUNE SYSTEM
Stress neuropeptides/ hormones
INNATE IMMUNITY
* First line of defence against infections
* Exists before infection-“in-built”, present from birth
* Evolutionary “ancient” part of host defence, similar
mechanisms in plants and animals-arose before the split of
the two kingdoms.
* Serves 3 important functions:
1. Early response to microbes, prevents infection and its
spread, may eliminate pathogens.
2. Effector mechanisms are often used by adaptive immunity
to destroy microbes.
3. Stimulates adaptive immunity and influences the nature of
host T and B cell responses against different types of
pathogens.
Pattern Recognition Receptors: Toll-like receptors (TLRs)
Tolls were originally identified in
Drosophila as rapidly induced genes
which confer protection against fungal
infections.
 First human homologue identified was
TLR4, with a major role in the
recognition of Gram (–) bacteria by
leukocytes
(TLR4-/- mice are unresponsive to LPS).
 Induces NF-kB activation and proinflammatory cytokine secretion 
signals DANGER!!!
Stress, Inflammation and the
Metabolic Syndrome
•
Stress Concepts
•
Stress Mechanisms
•
Effects of the Stress System on
the Organism
Συμπάσχει η ψυχή τω σώματι νοσούντι και
τεμνομένω, το δε σώμα τη ψυχή
The soul suffers when the body is diseased
or traumatized, while the body suffers when the
soul is ailing
Aristotle
“Both sleep and wakefulness,
when immoderate, are detrimental”
Hippocrates (489-360 BCE)
Οξειδωτικό στρες και μιτοχόνδρια
Αναπνευστική αλυσίδα στα μιτοχόνδρια
Κυτταρόπλασμα
Εξωτερική μεμβράνη
H+
H+
H+
e-
I
H+
Q
e-
H+
H+
e-
Cyt. c
H+
e-
III
IV
H+
H+
H+
H+
H+
H+
Μεσομεμβρανικό
διάστημα
Εσωτερική μεμβράνη
II
H+
NADH+H+
Succinate
Fumarate
NAD+
½ O2 +2H+
ATP
synthase
H2O
ADP+Pi
H+
Στρώμα
ATP
Most dioxygen (O2) use by the cell occurs in the mitochondria. Hence this
organelle (and the eye lense) faces the highest concentrations of toxic oxygen
reduction products. Between 1- 3% of the oxygen in the mitochondria is reduced to O2•–
instead of water (Boveris 1973, Sohal 1996) mainly by leaking electrons from complex III
(Turrens 1997, Genova 2003)
Ποιά είναι η μοίρα του O2•– ;
O2•– + Fe3+ → Fe2+ + O2
Fe2+ + H2O2 → Fe3+ + OH- +OH•
(αντίδραση Fenton)
Mitochondrial DNA
Human mitochondrium: 16.5 kb (nuclear genome is 3 Gb)
Encodes: 13 protein subunits involved in respiration,
22 tRNAs and
two ribosomal RNAs.
Mitochondrial DNA is more susceptible to oxidation than nuclear DNA.
There is an inverse correlation of oxidized mitochondrial DNA [8-oxoG]
with maximal life span of an organism, but this correlation is not seen
with nuclear DNA (that is bound to histone proteins and can be repaired
by DNA repair enzymes).
Ηigh frequency of mitochondrial DNA mutations
Bladder, head, neck and lung primary tumors
Antioxidants
Αντιοξειδωτικά, γενικά χαρακτηριστικά:
Ουσίες με αναγωγικές ιδιότητες, καλοί δότες ηλεκτρονίων.
Εξουδετερώνουν τη δράση ελευθέρων ριζών
(scavengers of free radicals)
Τα μικρού μοριακού βαρους αντιοξειδωτικά
βρίσκονται σε υψηλες συγκεντρώσεις (mM)
Οι αντιοξειδωτικές πρωτεϊνες δρουν σε σχέση
με τα μικρού μοριακού βάρους αντιοξειδωτικά
Σχεδόν όλα τα αντιοξειδωτικά βρίσκονται
σε ανηγμένη κατάσταση παίρνοντας ηλεκτρόνια από το NAD(P)H
If antioxidant systems do not
work..
ROS do not get inactivated,
they can react with macromolecules and
• enhance lipid peroxidation
• cause DNA damage
• induce protein/nucleic acid modifications
Damaged end products include
•
•
•
•
•
•
Oxidized proteins
Oxidized lipids
Oxidized low-density lipoproteins
Oxidized carbohydrates
Oxidized nuclei acid bases
Enzymatic markers of oxidative stress
ex: myeloperoxidase (MPO)
The oxidized or nitrated products
of ROS
Cause compromised biological activity leading to
metabolic dysregulation and changes in cellular functions
implicated in the pathogenesis of diseases including
Inflammation
Atherosclerosis
Cancer
Metabolic syndrome
Congestive heart disease
………….
Oxidative stress:
A ROS-antioxidant imbalance when the
net amount of ROS exceeds the
antioxidant capacity
Oxidative stress due to:
• Increase ROS generation
• Depression of the antioxidant systems
• Combination of both
Overview of generation and antioxidant enzymatic detoxification of ROS. ROS
generating enzymes include NADPH Oxidase, uncoupled nitric oxide synthase,
cyclooxygenase, lipoxygenase and CYP450 monoxygenases.
Levels of ROS are critical
(1)
• Low levels: important for normal cellular
signaling pathways, modulate growth and
apoptosis of endothelium, vascular and
cardiac muscle
Critical during development and during
adaptive changes leading to
hypertrophy and remodeling
Levels of ROS are critical
(2)
• High levels : generated in many disease
states including atherosclerosis and
hypertension, contribute to endothelial
dysfunction and to risk of cardiovascular
consequences
ROS and disease
Oxidative stress and
Cardiovascular diseases
• ROS and superoxide are increased in
arteries in several major cardiovascular
diseases
“Are ROS important for the
pathophysiology of atherosclerosis,
stroke, hypertension, and other..?”
Sources of ROS in CVD
• Leukocytes release ROS 
Kill bacteria 
vascular damage
• Ischemia -> Reperfusion ->
Generation of ROS
Excessive superoxide inactivates NO and
contributes to endothelial dysfunction, a risk
factor for endothelial disease
Superoxide in CVD
• Mainly due to increased generation rather
than inactivation
• Oxidative stress is usually associated with
compensatory increases in SODs
(caution: heart failure and aging show
opposite regulation)
Coronary artery disease and
oxidative stress
• Oxidation of apo-B containing lipoproteins
may play crucial role in atherogenicity
• Oxidative stress markers such as 8-isoPGF2alpha, nitrotyrosine, oxLDL, MPO,
erythrocyte GPX1, predict independently
early risk for CVD and myocardial
infarction
more …………..
• Endothelial dysfunction-mediated oxidative
stress in pts with CVD could predict the risk of
cardiovascular events
• Endothelial dysfunction in obesity appears to be
mediated by oxidative stress
• Hypertension related to endothelial dysfunction
is mediated partly by oxidative stress
(antioxidants ameliorate hypertension and alter
markers of oxidative stress while ACE improves
markers of oxidative stress)
• Hypertensive pts have reduced SOD activity and
inadequate antioxidant capacity in mononuclear
cells
Oxidative stress and the
metabolic syndrome
• May play an important role in
manifestations related to the MS
• It is associated with adiposity and insulin
resistance
??Is it an early event in the pathology of
these chronic diseases, a consequence
or an innocent bystander???
Does oxidative stress contribute
to insulin resistance?
Improved insulin sensitivity in T2D patients
or insulin-resistant pts treated with a-lipoic
acid or other antioxidants
Metformin, the insulin sensitizing agent,
decreases markers of oxidative stress
Evidence…..
Patients with MS have
- elevated oxidative damage
- decreased antioxidant protection
• low serum vitamin C and a-tocopherol,
• decreased SOD activity,
• altered lipid peroxidation byproducts,
• protein carbonyls,
• xanthine oxidase activity
• increased 8-iso-PGF2alpha
……..
- Stepwise increases in oxLDL found in
normal weight, overweight, obese
individuals
- Pts with increased oxLDLs have increased
risk to develop MS
- Increased ocLDL was associated with
elevated CRP and insulin, while lower
adiponectin and HDL
Oxidative stress and diabetes
• Prevalence of insulin resistance among obese
individuals associated with 8-iso-PGF2alpha
levels (Framingham Offspring Study)
• T2D have elevated lipid, protein, DNA oxidation
correlated with levels of glycemic control and
evidence of increased susceptibility to LDL
oxidation, increased 8-oxodG correlated with
the levels of glycated Hb
…………………..
Oxidative stress and aging
Harman
1950s: FREE RADICAL THEORY OF AGING
1970s: MITOCHONDRIAL FREE RADICAL
THEORY OF AGING
Accumulation of oxidatively damaged proteins and
DNA with normal aging -> progressive failure of
cellular machinery-> organ aging-> age-related
disease
Findings from Caenorhabditis elegans
Lack of Peroxisomal Catalase Causes a Progeric
Phenotype in Caenorhabditis elegans
JBC (2004) 279, 19996–20001,
Συνοπτικά
Η γήρανση στον καινοραβδίτη εξαρτάται από:
1. Μεταβολικές παραμέτρους
2. Απόκριση στο οξειδωτικο στρες
3. Συνδυασμό και των δύο
Ο σηματοδοτικός δρόμος του DAF-2 αντιστοιχεί στον αντίστοιχο του
υποδοχέα της ινσουλίνης και καταλήγει στο DAF-16, παράγοντα που
καθορίζει την επαγωγή διαφόρων πρωτεϊνών (αντιοξειδωτικά,
συνοδοί αναδίπλωσης, κα) που επιμηκύνουν το χρόνο ζωής.
Ανεξάρτητα από την ινσουλίνη (DAF-2), τη ρύθμιση του DAF-16
επηρρεάζουν και άλλοι παράγοντες όπως η διαθεσιμότητα τροφής,
η θερμοκρασία, κλπ (SIRT1, JNK1, HSF-1).
Γονίδια που επιμηκύνουν τη ζωή του καινοραβδίτη έχουν
ισχυρή αντικαρκινική δράση
Findings in mice….
Mice expressing a proofreading-deficient version of the mitochondrial
DNA polymerase g accumulate mtDNA mutations and display features
of accelerated aging
Science (2005) 309, 481-4
Science (2005) 308, 1909-11
Kang GS, Gillespie PA, Gunnison A, Moreira AL, Tchou-Wong KM,
Chen LC. Long-Term Inhalation Exposure to Nickel
Nanoparticles Exacerbated Atherosclerosis in a
Susceptible Mouse Model.
Environ Health Perspect. 2010 Sep 23. [Epub ahead of print]
New York University School of Medicine.
Oxidative STRESS
Inflammatory STRESS
Endoplasmic reticulum STRESS
Lung and Cardiovascular system
Soon RK Jr, Yan JS, Grenert JP, Maher JJ Stress Signaling in
the Methionine-Choline-Deficient Model of Murine Fatty
Liver Disease.
Gastroenterology. 2010 Aug 1. [Epub ahead of print]
University of California, San Francisco, California.
• Methionine-choline-deficient (MCD) diets cause severe fatty
liver disease and have the potential to cause many types of
cellular stress.
• MCD feeding causes an integrated stress response in the liver
rather than a classic unfolded protein response.
Risk and resilience:
genetic and environmental influences on development
of the stress response. Depress Anxiety. 2009;26(11):984-92 Dpt of
Gillespie CF, Phifer J, Bradley B, Ressler KJ.
Psychiatry and Behavioral Sciences, Emory University School of Medicine,
Exposure to stressful events during development has consistently been
shown to produce long-lasting alterations in the hypothalamic-pituitaryadrenal (HPA) axis, which may increase vulnerability to disease,
including posttraumatic stress disorder and other mood and anxiety
disorders. Recently reported genetic association studies indicate that these
effects may be mediated, in part, by gene-environment interactions
involving polymorphisms within two key genes, CRHR1 and FKBP5.
…………a large and growing body of preclinical research suggests that
increased activity of the amygdala-HPA axis induced by experimental
manipulation of the amygdala mimics several of the physiological and
behavioral symptoms of stress-related psychiatric illness in humans.
Notably, interactions between the developing amygdala and HPA axis
underlie critical periods for emotional learning, which are modulated by
developmental support and maternal care.
These translational findings lead to an integrated hypothesis: high levels of
early life trauma lead to disease through the developmental interaction
of genetic variants with neural circuits that regulate emotion, together
mediating risk and resilience in adults.
Yau SY, Lau BW, So KF. Adult hippocampal neurogenesis: a
possible way how physical exercise counteracts stress.
Cell Transplant. 2010 Sep 30. [Epub ahead of print]
It was considered that neurogenesis only occurred during the
embryonic and developmental stage. This view has greatly changed
since the discovery of adult neurogenesis in two brain regions: the
hippocampus and the olfactory bulb. Recently, it is suggested that
altered hippocampal neurogenesis is related to pathophysiology
of mood disorders and mechanism of antidepressant
treatments.
Accumulating knowledge about the effects of physical exercise
on brain function suggests a special role of adult hippocampal
neurogenesis in cognitive and mental health, even though the
functional significance of adult neurogenesis is still debated. The
beneficial effects of running correlating with increased adult
neurogenesis may provide a hint that new born neurons may be
involved, at least in part, in the counteractive mechanism of physical
exercise on stress-related disorders, like depression.
Quartana PJ, Burns JW. Emotion suppression affects cardiovascular
responses to initial and subsequent laboratory stressors.Br J Health
Psychol. 2010 Sep;15(Pt 3):511-28. Epub 2009 Oct 16.Dpt of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of Medicine
We examined the effects of experimentally induced anger and
general negative emotion in the context of expressive and
experiential suppression on cardiovascular responses to initial
and subsequent laboratory stressors.
Effortful suppression of negative emotion has immediate and
delayed consequences for stress-induced cardiovascular reactivity.
Theoretical and clinical significance of these findings are discussed.
O'Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation
as a model of brain-gut axis dysfunction.
Psychopharmacology (Berl). 2010 Oct 1. [Epub ahead of print] Alimentary
Pharmabiotic Centre, Biosciences Institute, Univ College Cork, Ireland
RESULTS:
In this review, we describe the components of the brain-gut axis
individually and how they are altered by maternal separation. The
separated phenotype is characterized by alterations of the intestinal
barrier function, altered balance in enteric microflora, exaggerated
stress response and visceral hypersensitivity, which are all evident
in IBS.
Elsenbruch S, Rosenberger C, Bingel U, Forsting M, Schedlowski M, Gizewski
Patients with irritable bowel syndrome have altered emotional
modulation of neural responses to visceral stimuli.
Gastroenterology. 2010. Epub 2010 Jun 22.
Inst of Medical Psychology and Behavioral Immunobiology, University Clinic of Essen
During rectal stimulation, IBS patients demonstrated
more pronounced stress-induced modulation of
neural activation in multiple brain regions, including
the insula, midcingulate cortex, and ventrolateral
prefrontal cortex.
Long MD, Drossman DA. Inflammatory bowel disease, irritable
bowel syndrome, or what?: A challenge to the functional-organic
dichotomy.
Am J Gastroenterol. 2010 Aug;105(8):1796-8.
Many patients with inflammatory bowel disease (IBD) in
clinical remission continue to have symptoms of pain
and diarrhea despite minimal or no ongoing
inflammation. These patients may be considered to have
an overlap of IBD and irritable bowel syndrome (IBDIBS). …………
We propose an alternate biopsychosocial model
whereby mutual effects of peripheral and central
factors influence symptom generation in both IBD
and IBS. Understanding this model has important
implications for treatment of patients with IBD-IBS.
Lackner JM, Brasel AM, Quigley BM, Keefer L, Krasner SS, Powell C,
Katz LA, Sitrin MD. The ties that bind: perceived social support,
stress, and IBS in severely affected patients.
Neurogastroenterol Motil. 2010 Aug;22(8):893-900. Epub 2010 May.
Div of Gastroenterology, University at Buffalo School of Medicine, SUNY, NY
Hepatology. 2010 Aug;52(2):774-88.
Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the
central role of nontriglyceride fatty acid metabolites.
Neuschwander-Tetri BA.
Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO
63110, USA. [email protected]
Abstract
A significant body of evidence now forces us to rethink the causes of NASH. Once
thought to be a disease caused by triglyceride accumulation in hepatocytes with
subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new
data from animal studies and a limited number of human studies now provide
convincing evidence that triglyceride accumulation does not cause insulin resistance or
cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of
NASH suggests that we need to focus our therapeutic efforts on reducing the burden of
fatty acids going to the liver or being synthesized in the liver. This can be accomplished
by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate
peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver.
Excess carbohydrates are the major substrates for de novo lipogenesis, and thus,
reducing carbohydrate consumption through dietary changes and increasing muscle
glucose uptake through exercise remain important cornerstones of treatment and
prevention of lipotoxic liver injury, a disease hitherto called NASH.
Adv Exp Med Biol. 2010;685:34-44.
Clinical features and pathogenesis of Alzheimer's disease: involvement of
mitochondria and mitochondrial DNA.
Mancuso M, Orsucci D, LoGerfo A, Calsolaro V, Siciliano G.
Department of Neuroscience, Neurological Clinic, University of Pisa
Alzheimer's disease (AD) is a neurodegenerative disorder which results in the
irreversible loss of cortical neurons, particularly in the associative neocortex and
hippocampus. AD is the most common form of dementia in the elderly people. Apart
from the neuronal loss, the pathological hallmarks are extracellular senile plaques
containing the peptide beta-amyloid (AP) and neurofibrillary tangles. The Af cascade
hypothesis remains the main pathogenetic model, as suggested by familiar AD,
mainly associated to mutation in amyloid precursor protein and presenilin genes. The
remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex
aetiology due to interactions between environmental conditions and genetic features
of the individual. Mitochondria play a central role in the bioenergetics of the cell and
apoptotic cell death. Morphological, biochemical and genetic abnormalities of the
mitochondria in several AD tissues have been reported. Impaired mitochondrial
respiration, particularly COX deficiency, has been observed in brain, platelets and
fibroblasts of AD patients. Somatic mutations in mitochondrial DNA (mtDNA) could
cause energy failure and increased oxidative stress. No causative mutations in the
mtDNA have been detected and studies on mtDNA polymorphisms are controversial,
but the "mitochondrial cascade hypothesis" here revised, could explain many of the
biochemical, genetic and pathological features of sporadic AD.
PM R. 2010 May;2(5):442-50.
Physiological and psychological fatigue in extreme conditions: overtraining and
elite athletes.
Purvis D, Gonsalves S, Deuster PA.
Dpts of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, USA.
This article will review relevant mechanisms and markers associated with overtraining
syndrome (OTS), and discuss signs and symptoms, differential diagnosis, and current
assessment tools for fatigue within the context of overtraining. The findings are drawn
from original research and review articles referenced by PubMed and ScienceDirect
databases. Sources were selected for their contributions to the current knowledge of
biological, psychological, and molecular mechanisms. Data were reviewed for
relevance to OTS and then evaluated against criteria that included significant OTS
outcomes and findings. Information was systematically analyzed to identify patterns,
dependencies, connections, and causal factors. Comparative analysis was confounded
by inconsistent metrics, terminology, and variable methodology; potential biomarkers,
treatment and prevention approaches, and future research directions are identified.
Diagnosing OTS is difficult because underlying cause(s) are unknown; one must
exclude other factors that degrade performance and mood status. Many studies are
confounded by inadequate experimental designs, poor measures of performance, and
different methods for characterizing OTS. OTS is complex because the demands of
excessive training in combination with other biologic, psychological, and social
stressors are difficult to quantify. However, changes in mood are always noted.
Interrelations among dietary patterns; social, psychological and physiological profiles;
and the neuroendocrine, immune, and central nervous systems are complex and not
adequately elucidated.
Insulin resistance
Inflammation
TLRs
???
CRH
CYTOKINES
ACTH
?
GC
LEPTIN
?
Decreased food intake / Body weight loss-cachexia
CRH +/glucocorticoid
Neurotherapeutics. 2010 Jul;7(3):232-40.
Improving the prediction of response to therapy in autism.
Bent S, Hendren RL.
Department of Psychiatry, University of California, San Francisco, San Francisco,
California 94121, USA. [email protected]
Autism is a heterogeneous disorder involving complex mechanisms and systems
occurring at diverse times. Because an individual child with autism may have only a
subset of all possible abnormalities at a specific time, it may be challenging to identify
beneficial effects of an intervention in double-blind, randomized, controlled trials, which
compare the mean responses to treatments. Beneficial effects in a small subset of
children may be obscured by the lack of effect in the majority. We review the evidence
for several potential model systems of biochemical abnormalities that may contribute
to the etiology of autism, we describe potential biomarkers or treatment targets for
each of these abnormalities, and we provide illustrative treatment trials using this
methodology. Potential model systems include immune over and under reactivity,
inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction,
and excitotoxicity. Including potential biomarkers and targeted treatments in clinical
trials for autism provides a potential method for limiting the heterogeneity of enrolled
subjects, which may improve the power of studies to identify beneficial effects of
treatments while also improving the understanding of the disease.