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Clinical Environmental Medicine
new science and praxis in Complex Multisystem Illnesses (CMI)
Pathomechanisms, immunology (NEIS),
therapy of illnesses associated to the environment
Kurt E. Müller
Brussels 19th of May, 2015
Dr. Kurt E. Müller
Dermatology – Occupational DermatologyEnvironmental Medicine - Preventive Medicine – Stress Medicine
EUROPAEM, dbu, DDG, DBG, D-A-C-HDresden International University (DIU)
Mozartstraße 16D-87435 Kempten – Germany
Fon: +49 (0)831 5126729 – Fax: +49 (0)831 5409294
Incidence of diseases in 6 coutries of EU
caused by 9 environmental stressors
© KEM
* Environmental burden: benzene, formaldehyde, dioxins/furans/PCB, lead,
ozone, transportation noise, second-hand smoke, particulate matter, radon
Hänninen O et al.: European Perspectives
on Environmental Burden of Disease.
National Institute for Health and Welfare
Helsinki, Finland 2011
other causes
93%
9 environmental stressors
cause 7% of all diseases7 %
Belgium
Germany
Finland
France
Italy
Netherlands
Different effect of low dose/long time and
high dose/short time exposure
© KEM
Human
being
Pollutant
dose
Time
High
dose ,
short time:
toxic effect
depending
from
toxicity of
pollutants Low dose – long time: effect
depending from reagibility of
NEIS* and genetic and epigenetic
conditions
*NEIS: neuro-endocrine-immune-system
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Different effect of low dose/long time and
high dose/short time exposure
© KEM
Human
being
Pollutant
Dose
Time
High
dose ,
short time:
toxic effect
depending
from
toxicity of
pollutants Low dose – long time: effect
depending from reagibility of
NEIS* and genetic and epigenetic
conditions
Diseases caused by toxic effects
Diseases depending from genetic
and epigenetic conditions and
reaction of NEIS
Interaction of neuroendocrine-immune system (NEIS)
NEIS: actor – not only reactor
neurogenic
system
endocrine
system
immune
system
NEIS
© KEMDörner 1973; Müller 2008, 2009
natural anthropogenic
social environment
Protection without antigen specific B and T cells – old enemiesRoitt et al. 2006
• C-reactive
protein
• mannose-
binding lectin
polyanions
lipoproteins
lipoteichoic
acid
lipopoly-
saccharide
formylpeptide
muramyl-
peptide
peptidoglycan
BACTERIA
complement C3a,C5a
phagocytes, tissue cells
NK
vascular
permeability
chemotaxis
activation of
phagocytes
adhesion of
Phagocytes
adhesion on
Endothelium
histamine
IFN-y
IL-12, TNF
IL-8
LTB4
CHEMOKINES
CYTOKINES
© KEM
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Protection without antigen specific B and T cells – new enemiesRoitt et al. 2006
• C-reactive
protein
• mannose-
binding lectin
polyanions
lipoproteins
lipoteichoic
acid
lipopoly-
saccharide
formylpeptide
muramyl-
peptide
peptidoglycan
BACTERIA
complement C3a,C5a
phagocytes, tissue cells
NK
vascular
permeability
chemotaxis
activation of
phagocytes
adhesion of
Phagocytes
adhesion on
Endothelium
histamine
IFN-y
IL-12, TNF
IL-8
LTB4
CHEMOKINES
CYTOKINES
metals
solvents
softener
pesticides
herbicides
radiation
electric
and
electro-
magnetic
fields
© KEM
LPS induced cascade of cytokinesDependance of clinical manifestation from quantity of cytokines
(Abbas, Lichtman, Pober (1994): Cellular and Molecular Immunology. Saunders)
LPS TNF-α IL-1ß IL-6 IL-8lipopolysaccharides tumornecrosisfactor-α interleukin-1ß interleukin-6, - 8
low quantities moderate quantities high quantities
locale inflammation
leukocytes
endothelial cells
systemic effects
heart
liver
intestines
central nervous system
damage of organs and
functional systems
heart
liver
kidney
sepsis
septic shock
© KEM
LPS induced cascade of cytokinesDependance of clinical manifestation from quantity of cytokines
(Abbas, Lichtman, Pober (1994): Cellular and Molecular Immunology. Saunders)
LPS TNF-α IL-1ß IL-6 IL-8lipopolysaccharides tumornecrosisfactor-α interleukin-1ß interleukin-6, - 8
low quantities moderate quantities high quantities
systemic inflammation
leukocytes
endothelial cells
systemic effects
heart
liver
Intestines
central nervous system
damage of organs and
functional systems
heart
liver
kidney
sepsis
septic shock
common cinical diseasesalmost unknown
© KEM
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Expression of cytokines by LPS und TNF (Roitt 2006)
„Immunologic engrams“ and induktion of „montonous“ and chronic reactionsLPS = Lipopolysaccharide; TNF = Tumornekrosefaktor
1 2 3 4 5 1 2 3 4 5
Hours after having started the reaction
LPS
TNF-α
IL-1
IL-6
TNF-α
IL-1
IL-6
LPS Challenge TNF-α Challange
© KEM
Expression of cytokines by LPS und TNF (Roitt 2006)
„Immunologic engrams“ and induktion of „montonous“ and chronic reactionsLPS = Lipopolysaccharide; TNF = Tumornekrosefaktor
1 2 3 4 5 1 2 3 4 5
Hours after having started the reaction
LPS
TNF-α
IL-1
IL-6
TNF-α
IL-1
IL-6
LPS Challenge TNF-α Challange
infections
pollutants
© KEM
The new „enemies“ – causing new diseases:
Chronic Multisystem Illnesses (CMI)
Susceptibility
Functional
Modulation
Epigenetic
influence
Genetic
condition
INFECTIONS
© KEM
METALS
GENETIC
ENGENEERING
CHEMICALS
PARTICLES
RADIATION
EMF
Silent
epidemics
caused by
silent(smouldering)
inflammation
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Chron. Multisystem
Illnesses (CMI):
CFS, MCS, FMS, PTSD,
SBS, GWS
Depression ? EHS?
Chronic Pain Disease ?
radiation,
electromagnetic
fields
nutrition,
additivesoccupational
conditions
drugs,
cosmetics
particles, metals,
alloplastic materials
hobbies,
leishure time
activities
living conditions
CMI and environmental influences
© KEM
Pollutants
The new „enemies“ – causing new diseases:
with unspecific symptoms
Susceptibility
Functional
Modulation
Epigenetic
influence
Genetic
condition
INFECTIONS
© KEM
METALS
GENETIC
ENGENEERING
CHEMICALS
PARTICLES
RADIATION
EMF
Symptoms of CMI:
fatigue
myalgia
tendopathia
arthropathia
disturbance
of coordination
cognitive impairment
low stress tolerance
dizziness
vertigo
chemical sensitivity
depression
Therapeutic targets in clinical environmental medicine
© KEM
Control of NEIS (neuroendocrine immune system)
Stop of exposure to pollutants
Optimization of gut function, diet and micronutrients
Regeneration of mitochondrial function
Stress management
Inhibition of NO/ONOOˉ -cycle
Restitution of receptor function
Detoxification
Chronic
Multisystem
Illness
(CMI)
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infections,
pollutants
MHCIITCR
T cell
NF-ĸB APC
proteins or
protein-bound molecules (haptenes)
infections
pollutants
ROS
monoclonal
T cell proliferation:
specificity: IL2
inflammation: IFNy
no proliferation or
specificity → polyclonal
T-cells producing:
IFNy, TNFα, IL1ß; IL6, IL8
MHC II restrictednot MHC restricted
Unspecific immune reaction
© KEM
Cytokine profile in MCS patientens (F. Bartram)
Interferon-y (IFN-y) and susceptibility
Roitt I., Brostoff J., Male D.:Immunology. Sixth Edition, 2001. Mosby; Edinburgh, London, New York, Toronto.
..... IFN y makes cells abnormally
susceptible to intracellular
pathogenes .....
© KEM
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0
100
200
300
400
500
600
IFN-gamma 155 584
IL 2 213 1,13
IL 10 2,85 34,66
Quotient IFN-g/IL2/IL10 0,26 14,91
Influenza Antigen Phthalate
Control: no expression of IFN-y
0
0,2
0,4
0,6
0,8
1
1,2
1,4
IFN-gamma 1 1
IL 2 1,31 1
IL 10 1,04 1
Quotient IFN-g/IL2/IL10 0,73 1
Influenza Antigen Phthalate
TI
TI
Expression of IFN-y caused by phthalates
Silent (smouldering)
inflammation caused
by phthalates
© KEM
Inflammation caused by various pollutants
© KEM
infections
pollutants
MHCIITCR
T cell
NF-ĸBAPC
Proteins or
protein bound molecules (haptens)
infections
pollutants
ROS
Monoclonal
T cell proliferation:
specificity: IL2
inflammation: IFNy
no proliferation or
specificity → polyclonal T
cells producing:
IFNy, TNFα, IL1ß; IL6, IL8
MHC II restrictednot MHC restricted
Specific immune reaction
© KEM
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Path. LTT nach E.
Path. LTT vor E.0
5
10
15
20
25
30
NickelTitan
org. Hganorg. Hg
CadmiumGold
BleiPalladium
Path. LTT nach E. Path. LTT vor E.
Stimulation index (SI) of lymphocyte transformation test (LTT)
before and after removal of metals
n = 124
© KEM © KEM
T cell sensitization caused by various pollutants and moulds
© KEM
© KEM 2014
T cell sensitization to methyl methacrylate
© KEM
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© KEM 2014
T cell proliferation caused by Borrelia burgdorferi
Leaky gut
(GALT = gut associated lymphoid tissue)
Endothelium
tight junctions
leaky gut
physiological and pathological flora
invasive flora
immune reaction
© KEM
T cell mediated food allergy → Colon irritabile?Stimulation index (SI) before and one year after elimination diet
© KEM
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Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Inflammatory
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – NO/ONOOˉ cycle„Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
© KEM
Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Inflammatory
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus - Inflammation„Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
1. Stop of exposure
2. Control of Inflammation:
Curcumin
S-Adenosylmethionine (SAMe)
Omega 3 fatty acids
Bromelaine
Cats Claw
Boswellia serrata (indian incense)
Boswellia carterii (afrikan incense)
Coriolus
Reishi
Diclofenac
Ibuprofen
3. Detoxification
© KEM
Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Inflammatory
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – Control of effects„Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
1. Stop of exposure
2. Control of Inflammation:Curcumin
S-Adenosylmethionine (SAMe)
Omega 3 Fettsäuren
Bromelain
Teufelskralle
Cats Claw
Boswellia serrata (indian incense)
Boswellia carterii (afrikan incense)
Coriolus
Reishi
Diclofenac
Ibuprofen
3. Detoxification
Before use control the effect
by TNF-α inhibition test !
© KEM
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Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Inflammatory
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – Inconstant effects„Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
1. Stop of exposure
2. Control of Inflammation:Curcumin
S-Adenosylmethionine (SAMe)
Omega 3 Fettsäuren
Bromelain
Teufelskralle
Cats Claw
Boswellia serrata (indian incense)
Boswellia carterii (afrikan incense)
Coriolus
Reishi
Diclofenac
Ibuprofen
3. Detoxification
TNF-α Inhibition Test (pg/ml):
LPS stimulated basic level: 885
Boswellia carterii: 301
SAMe: 11
Omega 3: 1450
Bromelain: 1986
Curcuma: 491
© KEM
Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
ProInflammator.
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – Nitric stress „Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
Actions of nitric oxide:
Binding to aromatic
amines:
Dopamine, Norepinephrine,
Epinephrine, L-Thyroxin
Formation of peroxinitrite
with superoxide.
NO-Scavenger:
Vitamin B12
Melatonine
© KEM
Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Inflammatory
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus - Antioxidants
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
Antioxidants:
Melatonin Ubiquinol
Lycopin Vitamin C
Vitamin E Karotinoide
NAC α-Lipoic acid
Flavonoides Selenium© KEM
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Inflammation and …….
Tryptophan
5-HTP
Serotonin
TDO
IDO
Kynurenine
99% 1%
IDO
3-OH-Kynurenine
Quinolate
NMDA-ANTAGONIST
3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor
IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase
KMO
Inflammation
IFN-y
TNF-α
IL-1ß
LEGENDE:
Melatonin
NEURODESTRUCTION
DESTRUCTION OF
ASTROCYTES
© KEM
Inflammation and Depression
Tryptophan
5-HTP
Serotonin
TDO
IDO
Kynurenine
99% 1%
IDO
3-OH-Kynurenine
Quinolate
NMDA-ANTAGONIST
3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor
IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase
KMO
Inflammation
IFN-y
TNF-α
IL-1ß
LEGENDE:
Melatonin
NEURODESTRUCTION
DESTRUCTION OF
ASTROCYTES
DEPRESSION
© KEM
L- Tryptophan
Tryptophanhydroxylase (TPH1, TPH2)Tetrahydrobiopterin
Folate
Dihydrobiopterin
5-Hydroxytryptophan
DOPA-Decarboxylase
Vit. B6
CO2
5-Hydroxytryptamine (Serotonin)
Modulation of function of serotonergic system
Food, Infections
Environment:
chemicals, metals,
EMF, radiation
InflammationINF-y, IL-1ß, TNF-α
Kynurenine
Depression
Serotonintransporter (SERT)
Serrotoninreceptors (15 Typs)
pre- and postsynaptische
NO/ONOO
Genetic - Mikronutrients - Catabolic products
© KEM
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L- Tryptophan
Tryptophanhydroxylase (TPH1, TPH2)Tetrahydrobiopterin
Folate
Dihydrobiopterin
5-Hydroxytryptophan
DOPA-Decarboxylase
Vit. B6
CO2
5-Hydroxytryptamine (Serotonin)
Modulation of function of serotonergic system
Food, Infections
Environment:
Chemicals, Metals,
EMF, Radiation
InflammationINF-y, IL-1ß, TNF-α
Kynurenine
Depression
Serotonintransporter (SERT)
Serotoninreceptors (15 Typs)
pre- and postsynaptic
NO/ONOO
Genetic - Mikronutrients - Catabolic products
SSRI
&
TAD
© KEM
Inflammation and therapy
Tryptophan
5-HTP
Serotonin
TDO
IDO
Kynurenine
99% 1%
IDO
3-OH-Kynurenine
Quinolate
NMDA-ANTAGONIST
3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor
IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase
KMO
Inflammation
IFN-y
TNF-α
IL-1ß
Melatonin
NEURODESTRUCTION
DESTRUCTION OF
ASTROCYTES
1. Identification of causes
2. Inhibition of inflammationCurcumin
SAMe
Omega 3 fatty acid
Cats claw
Boswellia.
Bromelain
Diclofenac u.a.m.
3. Detoxification
© KEM
Depression and substitution
Tryptophan
5-HTP
Serotonin
TDO
IDO
Kynurenine
99% 1%
IDO
3-OH-Kynurenine
Quinolate
NMDA-ANTAGONIST
3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor
IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase
KMO
Inflammation
IFN-y
TNF-α
IL-1ß
Melatonin
NEURODESTRUCTION
DESTRUCTION OF
ASTROCYTES
Substitution:
L-Tryptophan
5-Hydroxytryptophan (5-HTP)
Tetrahydrobiopterin
Vit. B6
Folate
© KEM
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Nitric
oxide(NO˙)
Peroxynitrite(ONOOˉ)
Oxidative
Stress
NF-kB
iNOS
Ca 2+
Superoxide(OO˙ˉ)
Proinflammator.
cytokines:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – Inhibition of COMT „Vicious cycle“ n. M. Pall 2007
iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS
COMT Catechol-O-
methyltransferase
-
© KEM
What has changed?
The Speed
The Speed© KEM
Catecholamines
CORTISOL
PARASYMPATHICUS ??
ATP
© KEM
26/05/2015
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Stress and dysfunction of
dopamine -, norepinephrine - and epinephrin - axis
Dopamin Noradrenalin Adrenalin
praise, satisfaction,
luck, reward,
motoric and intellectual
harmony, peace
restlessness, hurry,
agitation, aggression,
fear, phobia, panic,
© KEM
Catabolism of norepinephrine
NOREPINEPHRINE EPINEPHRINE
COMT
MAO-A
Methionine
S-Adenosylmethionine
(SAMe, AdoMet)
Homocysteine
Methyltetrahydrofolate
ReductaseGlutathion
ATPProtection: SOD2
NO˙/ONOOˉ
DNA-Methylation, Detoxification, Cholin
Vanillinmandelic
acid
© KEM
Catabolism of norepinephrine
NOREPINEPHRINE EPINEPHRINE
COMT
MAO-A
Methionine
S-Adenosylmethionine
(SAMe, AdoMet)
Homocysteine
Folate, Vit. B6,
Vit. B12, BiotinGlutathion
L-Carnitin, NADH,
Q10, Methyl-B12
NO˙/ONOOˉ
DNA-Methylation, Detoxification, Cholin
Vanillinmandelic
acid
© KEM
26/05/2015
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Secretion of catecholamines and receptor expression on immune cells -
interaction with sympathetic nerve system
NK cells,
B-lymphocytes
dentritic cells
macrophages
sympath.
nerve
dopamin
norepinephrine
epinephrine
dopamin-receptor
α-receptor
ß-receptor© KEM
Stress reaction: COMT- polymorphism, ATP synthesis
and immune function
Aggression
Phobia, Panic
COMT V/V, ATP ↑
COMT V/V, ATP ↓
COMT M/M, ATP ↑
COMT M/M, ATP ↓
IL-10
beforeafter
© KEM
Stress reaction: COMT- polymorphism,
ATP and immune function
Aggression
Phobia, Panik
COMT V/V, ATP ↑
COMT V/V, ATP ↓
COMT M/M, ATP ↑
COMT M/M, ATP ↓
IL-10
beforeafter
Expression of catecholamines
• inhibits TH1 cells
• activates TH2 cells
• elevates use of ATP
• needs Tyrosine
• lowers synthesis of ubiquinon
• elevates use of methylcobalamin
© KEM
26/05/2015
17
Function and structure of mitochondria
citric
cycle
NADH
eˉ
O2
H+ H+ H+
2 H2O
NAD+
ADP
ATP
Q10
H+
ATP
acetyl-CoA
pyruvate fatty acids
pyruvate fatty acids
CARNITIN
ATP synthase
CO2
ADP
outer membrane
inner membrane
INSULIN
DNA
© KEM
Damage of function and structure of mitochondria
citric
cycle
NADH
eˉ
O2
H+ H+ H+
2 H2O
NAD+
ADP
ATP
Q10
H+
ATP
acetyl-coA
pyruvate fatty acids
pyruvate fatty acids
L-carnitin
ATP synthase
CO2
ADP
outer membrane
inner membrane
INSULIN
DNA
demage
by
pollutants
demage
by
pollutants
© KEM
pollutant
Adenosine triphosphate (ATP) as energy pool
ADENOSIN -
TRI PHOSPHATE
ADENOSIN –
DI PHOSPHATE
ADENOSIN -
MONO PHOSPHATE
ATPPP
ADPP
AMP
P
P
32.3 kJ/mol
32.3 kJ/mol
ADENOSINE
© KEM
P 32.3 kJ/mol
© KEM
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Adenosine triphosphate (ATP) as energy pool
ADENOSIN -
TRI PHOSPHATE
ADENOSIN –
DI PHOSPHATE
ADENOSIN -
MONO PHOSPHATE
ATPPP
ADPP
AMP
P
P
32.3 kJ/mol
32.3 kJ/mol
ADENOSINE
© KEM
P 32.3 kJ/mol
Sports:
Marathon, Triathlon
excessive work
© KEM
Adenosine triphosphate (ATP) as energy pool
ADENOSIN -
TRI PHOSPHATE
ADENOSIN –
DI PHOSPHATE
ADENOSIN -
MONO PHOSPHATE
ATPPP
ADPP
AMP
P
P
32.3 kJ/mol
32.3 kJ/mol
ADENOSINE
© KEM
P 32.3 kJ/molWhat else?
© KEM
Adenosine triphosphate (ATP) as energy pool
ADENOSIN -
TRI PHOSPHATE
ADENOSIN –
DI PHOSPHATE
ADENOSIN -
MONO PHOSPHATE
ATPPP
ADPP
AMP
P
P
32.3 kJ/mol
32.3 kJ/mol
TOTAL 96.9 kJ/mol
STRESS !! P
ADENOSINE
© KEM
P
P
Rassow 2008
© KEM
26/05/2015
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Adenosine triphosphate (ATP) as energy pool
ADENOSIN -
TRI PHOSPHAT(E)
ADENOSIN –
DI PHOSPHAT(E)
ADENOSIN -
MONO PHOSPHAT(E)
ATPP
ADP
AMP
P
P
32.3 kJ/mol
32.3 kJ/mol
TOTAL ENERGY 96.9 kJ/mol
STRESS !! P
ADENOSINE
© KEM
P
P
Rassow 2008
How much social stress
is caused by the strategies
of health systems?
© KEM
Immune activation
NF-kB,TNF-α,IFN-γ,IL-1ß,IL-6
VasodilationAktivatierung des
Glutamat-Rezeptors
ATP-
deficit
Nitric oxide+
Superoxide
= Peroxinitrite
Lack of energy
Immune activation -
nitric oxide - peroxinitrite - cascade
NO˙/ONOO¯
Loss of energy:
25 – 30 %/day
BH2* → BH4*
* BH2 = Dihydrobiopterin
* BH4 = Tetrahydrobiopterin(Pall 2009)
Straub et al. 2010
Pall 2007
Kuklinski 2007
Hill 2007+2010
Myhill 2010
ROS
L-Carnitine
NADH
Ubiquinol
Vit. B12 (Met-B12)
IHHT
© doc.müller.ke
Published papers about endocrine disruptors
between 1993 and november 2006 (Gies)
Colborn, vom Saal, Soto (1993): EHP
endocrine disruptors
26/05/2015
20
TNF-α activates cortisol axis and
blocks sex hormones
Adrenal Gland
Cholesterol
Progesteron
e
Pregnenolone
11-Desoxycorticosterone
Corticosterone
18-Hydroxy-Corticosterone
Aldosterone
17a-Hydropregnenolone
17a-Hydroprogesterone
11-Desoxycortisol
Cortisol
Cortison
Gonads
DHEADHEA(S)
7ß-Hydroxy-DHEA
Androstendione Estron
Testosteron 17ß-Estradiol
Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1
TNF-α activates cortisol axis and
blocks sex hormones
Adrenal Gland
Cholesterol
Progesterone
Pregnenolone
11-Desoxycorticosterone
Corticosterone
18-Hydroxy-Corticosterone
Aldosterone
17a-Hydropregnenolone
17a-Hydroprogesterone
11-Desoxykortisol
Kortisol
Kortison
TNF-a+
Gonads
DHEADHEA(S)
7ß-Hydroxy-DHEA
Androstendione
TNF-α
TNF-α TNF-α
Estrone
+
Testosterone 17ß-Estradiol
TNF-α
TNF-α
+
Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1
TNF-α aktiviert die Synthese von Kortisol und hemmt
die der Sexualhormone
Adrenal Gland
Cholesterol
Progesterone
Pregnenolone
11-Desoxycorticosterone
Corticosterone
18-Hydroxy-Corticosterone
Aldosterone
17a-Hydropregnenolone
17a-Hydroprogesterone
11-Desoxycortisol
Kortisol
Kortison
TNF-a+
Gonads
DHEADHEA(S)
7ß-Hydroxy-DHEA
Androstendione
TNF-α
TNF-α TNF-α
Estron
+
Testosterone 17ß-Estradiol
TNF-α
TNF-α
+
Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1
26/05/2015
21
NMDA*- ReceptorAgonists, Co-Agonists, Channel Blockers und Antagonists
NMDA*- Receptor (*N-Methyl-D-Aspartat)
Agonists, Co-Agonists, Channel Blockers and Antagonists
Mg
The German Solution
%
psychogenic diseases
225
100
© KEM
26/05/2015
22
END
Stick
oxid
Peroxinitrit
Oxidativer
Stress
NF-kB
iNOS
Ca 2+
Superoxid
Proinflammator.
Zytokine:
IL-1ß, IL-6, IL-8,
TNF-α, IFN-y
nNOS
eNOS
Circulus vitiosus – stress regulaion„Vicious cycle“ n. M. Pall 2007
iNOS=induzierbare; nNOS=neurogene; eNOS=endotheliale Stickoxidsynthase
Blocks
activity of
Catechol-O-
methyltransferase
© KEM
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