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Meccanismi biomolecolari epigenetici , disfunzione mitocondriale
secondaria
modulazione della protein kinase C neuronale,oxidative and
nitrosative stress
endogenous molecules danger signals ( DAMPs )attivit della alpha
- N- acetylgalactosaminidase
nella immuno - neuropatogenesi delle Sindromi immuno - neuro
tossiche correlati a xenobiotici ambientali
( endocrine disruptor , metalli pesanti, particolato ultrafine ,
micotossine )
Dott Rao Giacomo
Specialista in Medicina Legale e delle Assicurazioni
Dirigente Medico INAIL
Tel 3398790509 3296723074 fax 06 23327302
[email protected]
Aggiornamenti in tema di Sensibilit Chimica Multipla.
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ABSTRACT
The aim of this study is to contribute to the knowledge on bio
-molecular mechanisms of environmentalendocrine disruptors and
heavy metals on neuro -immune -endocrine interactions : the
nervousand immune systems use a common chemical language for intra
and inter -system communication .
There is an evidence that cytokines, peptide hormones and
neurotransmitters, are present in the brain,endocrine and immune
systems that act on a common repertoire of receptors in the three
systems.
Recent research led to the concept that through the sharing of
ligands and receptors the immune systemcould serve as a sixth
sense: this theory claims that immune responses are triggered by
or
endogenous molecules released by tissue and cell damage .
The danger model suggests that damaged or dying cells release
endogenous molecules calleddamage/danger -associated molecular
patterns (DAMPs) that activate the immune system in a
fashionanalogous to pathogen -associated molecular patterns
(PAMPs).
Environmental factors, (ozone, atmosphere particulate matter,
long -lived reactive oxygen intermediate,pentachlorophenol,
ionizing radiation, and toluene, mycotoxin ) are trigger Toll-like
receptor 4 Activation ofthe TLR4 pathways may cause chronic
inflammation and increased production of reactive oxygen
andnitrogen species (ROS/RNS)and oxidative and nitrosative
stress.
DAMP molecules, including HMGB-1 heat -shock proteins
(HSPs),uric acid, altered matrix proteins, and S100proteins , these
endogenous or self-molecules function in normal cell homeostasis
but are also recognizedas danger signals when released into the
extracellular space exposing hydrophobic portions of themolecules
that are normally hidden in healthy living cells.
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Endogenous alarmins and exogenous PAMPs convey a similar message
and elicit similar responses : DAMPs are recognized by pattern
recognition receptors (PRRs) such as Toll -like receptor (TLR) and
receptor for advanced glycation end products (RAGE). DAMPs also
induce the phosphorylation of various intracellular proteins and
activate NF -kappaB signaling. This induces an inflammatory
response via cytokine production and activation of macrophages and
dendritic cells.
Endogenous danger signals are raised during damage of self
structures, by oxidative stress.
Danger hypothesis imply an important role of reactive
metabolites in the pathogenesis of Chemical hypersensitivity ;
reactive metabolites have been identified for most drugs associated
with hypersensitivity ,deficit of Xenobiotics metabolism in immune
cells are associated with oxidative stress, adduct formation and
toxicity creating danger signals for antigen presenting cells.
Evidence is accumulating that damage -associated molecular
patterns (DAMPs) are secreted from cells in response to trauma
injury mechanical forces, excessive heat , cold, toxic poisons,
withdrawal of oxygen and nutrients, environmental factors, ozone,
atmosphere particulate matter, reactive oxygen intermediate,
pentachlorophenol, ionizing radiation, toluene mycotoxin , Impact
of chlorophenols on microbiota .
Consideration of the immune system as a sensory system helps in
the establishment of a logical basis for connections between
activation and function of receptor cells. This may help in a new
interpretation of many unexplained, complex condition neuro -immuno
-endocrinologic syndrome as Fibromyalgia syndrome, multiple
chemical sensitivity syndrome, myalgic encephalomyelitis, food
intolerance , Drug hypersensitivity reactions, Endometriosis ,gulf
war, Unspecified respiratory condition due to chemicals, gases,
fumes and vapours , Autism Spectrum Disorders.
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Thissyndrome ,which represents a social emergency, silent share
common etiopathogenetic bases :combines metabolic and genetic,
epigenetic factors, is featured by mitochondrial oxidative stress,
secondarymitochondrial dysfunction, high levels of heavy metals,
altered toxicokinetic ,homeostasis of intra -and
intercellularcommunication between neuro -endocrine - immune
-system ( immune -limbic -hypothalamic -pituitary
-adrenalsystems.)
Epigenetic alteration : xenobiotics interferes at different
levels of gene expression regulation :
Transcriptional/ Post Transcriptional control : interference
with the metabolic pathways of nuclear receptors, such asthose for
steroid hormones, retinoic acid aryl receptor (AHR).
Post-translational control : Inhibition of enzymatic activities
:
inhibition of ALA dehydratase , the consequence of inhibition of
ALA dehydrates, intracellular accumulation ofsubstrates upstream of
this enzyme (delta -aminolevulinic acid -ALA) in cells. ALA binding
to GABA(A) receptors,followed by receptor lesions from oxyradicals
and 4, 5-dioxovalerate (DOVA) generated from metal -catalyzed
ALAoxidation by oxygen .
Partial uncoupling oxidative phosphorylation ;
inhibition of the translocator ADP_ATPactivity .
Effect of the toxic metal ions, aluminium nickel mercury on the
actin and tubulin cytoskeleton , interfere withAxonal transport
mediated by motor proteins : motor proteins kinesin and dynein
control anterograde andretrograde mitochondrial transport .
Mitochondrial dynamics and transport have emerged as key factors
in the regulation of neuronal differentiationand survival and
synaptic function .
Modulation Inhibition of brain protein kinase C by heavy metals
(lead cadmium) , Protein kinase C (PKC) is animportant enzyme in
mediating cellular signal transduction and neuronal plasticity,
homeostatic relationshipbetween neurons and glial cells.
Knowledge of the molecular alterations underlying can lead to
the future prospects in terms of therapeutic strategies
