Boner

(1)

Environment, Oxidative Stress and Micronutrients

Attilio Boner

University of Verona, Italy

[email protected]

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

(2)

Environmental Factors Exposure and Epigenetics

1) by altering nuclear factor kB (NF- kB) activation or

2) by histone modification and 3) chromatin remodeling

•

air pollution

•

cigarette smoke

•

infections

•

allergic reactions

over expression of proinflammatory genes

Oxidative stress epigenetic

effects

Rahman I , Eur Respir J . 2006;28:219-242 .

(3)

Epigenetic modifications in gene

silencing.

Cutfield Ped Res 2007;61:68R Transcriptionally active chromatin

is associated with acetylated histones, (Ac) whereas inactive chromatin has methylated DNA and de-acetylated histones.

DNA methylation, executed by

methyltransferases, allows recruitment of methyl-binding domain proteins

(MBD), which then recruit histone deacetylases (HDAC, transcriptional co-repressors and other chromatin modifying enzymes).

A series of epigenetic modifications transforms transcriptionally active regions of DNA (top) into compact inactive chromatin (bottom).

DNA

open chromatin

closed chromatin

(4)

Environment, Oxidative Stress and Micronutrients

Attilio Boner

[email protected]

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

(5)

The atom

Equal number of electrons (-)

charged and protons (+) charged

(-)

=

(+)

(6)

The atom

Oxidation

(-)

Reduction

(+)

O ₂

(-)

(+)

Free radical

(7)

Free radicals can be defined as molecules or molecular fragments containing one or more unpaired electrons (due to loss of electron:

oxidation) in atomic or molecular orbitals.

•

They attract an electron from another molecule rendering it imbalanced and oxidized.

•

This is a chain reaction that is known as oxidation

•

This is rust in metal and an apple turning brown after being cut and left open.

What are “Free Radicals”?

(-)

Oxidation

O ₂

(8)

Free radicals can be defined as molecules or molecular fragments containing one or more unpaired electrons (due to loss of electron:

oxidation) in atomic or molecular orbitals.

•

They attract an electron from another molecule rendering it imbalanced and oxidized.

•

This is a chain reaction that is known as oxidation

•

This is rust in metal and an apple turning brown after being cut and left open.

What are “Free Radicals”?

(-)

Oxidation

O ₂

Lemon juice, when applied to the fruit slows down oxidizing in two ways.

First,

lemon juice

is abundant in vitamin C which is a natural antioxidant and reduces oxidation.

Secondly, the citric acid in the juice reduces the pH value of the surface of the apple

to a level where oxidation becomes difficult to occur.

(9)

What do “Free Radicals”?



One free radical can initiate tens of thousands of chain reactions that cause tremendous harm:

•

destroy cell membranes,

•

disrupt crucial processes in the body,

•

reprogram DNA,

•

form mutant cells, and more.



Free radicals are a major contributing factor to nearly all situations of non-ideal health as well as in the development of a variety of pathologic states such as

diabetes, cancer and aging.

*

* *

Oxidative stress

(10)

Oxidative stress and:

• Pollution

• Sleep Apnoea

• Bronchopulmonary dysplasia

• Bronchiolitis

• Asthma

• Cystic Fibrosis

• COPD

• RRI

PubMed 03-03-2016

151 38 1163 348

1322 819

Oxidative stress

Antioxidant reserve

598 1762

(11)

Oxidative stress and:

• Pollution

• Sleep Apnoea

• Bronchopulmonary dysplasia

• Bronchiolitis

• Asthma

• Cystic Fibrosis

• COPD

• RRI

PubMed 03-03-2016

151 38 1163 348

1322 819

Oxidative stress

Antioxidant reserve

598 1762

151 38 1163 348

1322 598 1762

• Atopic dermatitis 72

• Food allergy 51

• Urticaria 17

• Anaphylaxis 14

• Allergic rhinitis 62

• Atopy develoment 18

• Aging 12353

(12)

Environment, Oxidative Stress and Micronutrients

Attilio Boner

[email protected]

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

(13)

Maternal active or passive smoking causes oxidative stress in placental tissue

Aycicek A, Eur J Pediatr. 2011;170:645-51

 Cord blood total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI).

 Fetal placental tissue, cord blood, and the maternal peripheral blood.

 19 mothers active smokers, 19 passive smokers, and 22 nonsmokers.

Placental Total Oxidant Status

p‹0.05

(14)

Maternal active or passive smoking causes oxidative stress in placental tissue

Placental Total Antioxidant Capacity

p‹0.05

 Cord blood total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI).

p‹0.05

(15)

Maternal active or passive smoking causes oxidative stress in placental tissue

Oxidative Stress Index (OSI) (% of TOS level to TAC level)

 Cord blood total antioxidant

capacity (TAC), total oxidant status (TOS),

and oxidative stress index (OSI).

p‹0.05 p‹0.05

(16)

Maternal active or passive smoking causes oxidative stress in placental tissue

Correlation graphic of TOS levels in placental tissue and cord blood

r=0.304, P<0.016

 Cord blood total antioxidant

capacity (TAC), total oxidant status (TOS),

and oxidative stress index (OSI).

(17)

Effects of tobacco smoking during pregnancy on oxidative stress in the umbilical cord and mononuclear blood cells

of neonates.

Rua Ede A, J Biomed Sci 2014;21:105

% reduction in blood mononuclear cells viability

in newborn from smokers

-00

-05 –

-10 –

-10%

 10 non-smokers and 12 smokers during gestation.

 Viability of blood mononuclear cells (MNC) from umbilical cords of newborns.

 Degree of oxidative stress in cord blood cells.

(18)

Scanning electron microscope (SEM) photographs of the

vascular endothelium from umbilical arteries of pregnant patients

A typical image from a non-smoking patient shows a regular surface

accompanying the longitudinal direction of the vessel.

A typical image from a smoking patient shows diffuse areas of endothelial thickening with loss of the typical architecture and disposition

of endothelial cells (white arrows).

Effects of tobacco smoking during pregnancy on oxidative stress in the umbilical cord and mononuclear blood cells

of neonates.

Rua Ede A, J Biomed Sci 2014;21:105

(19)

Smoking and mechanisms of endothelial dysfunction and early atherogenesis.

Messner B, Arterioscler Thromb Vasc Biol. 2014; 34:509-15

already in umbilical arteries there are the origins of atherosclerosis !

ROS

(20)

 Exposure to PM₁₀ and PM_2.5 and polycyclic aromatic

hydrocarbons.

 120 schoolchildren.

 In 4 cities--two in China

(Ala Shan and Beijing) and two in Korea

(Jeju and Seoul)-between 4 and 9 June 2007.

 Daily ambient levels of PM and their metal components.

Exposures to particulate matter and polycyclic aromatic hydrocarbons and oxidative stress in schoolchildren.

Bae S, Environ Health Perspect 2010; 118:579-583

Urinary malondialdehyde

p ‹0.0001

PMs ambient concentrations

(21)

 Diesel exhaust particles (DEP) induction of oxidative DNA damage.

 Human lymphoblasts treated with DEP at various

concentrations (25-100 μg/ml).

 Oxidative DNA damage determined by 8-hydroxy- deoxyguanosine (8-OHdG).

 51 healthy subjects residing in traffic-congested areas.

Oxidative DNA damage and inflammatory responses in cultured human cells and in humans exposed to

traffic-related particles.

Vattanasit U, Int J Hyg Environ Health. 2014; 217:23-33

dose-dependent responses to DEP in the lymphoblasts and lung cells for DEP-induced oxidative DNA damage

(22)

Outdoor air pollution, preterm birth, and low birth weight: analysis of the world health organization global

survey on maternal and perinatal health.

Fleischer NL, Environ Health Perspect. 2014;122:425-30

 Outdoor PM_2.5

 22 countries in the World Health Organization Global Survey on Maternal and

Perinatal Health from 2004 through 2008.

1.5 –

1.0 –

0.5 –

00

OR for

low birth weight

1.22

fourth quartile of PM_2.5 (> 20.2 μg/m³) compared with the first quartile (< 6.3 μg/m³)

(23)

Outdoor air pollution, preterm birth, and low birth weight: analysis of the world health organization global

survey on maternal and perinatal health.

Fleischer NL, Environ Health Perspect. 2014;122:425-30

 Outdoor PM_2.5

 22 countries in the World Health Organization Global Survey on Maternal and

Perinatal Health from 2004 through 2008.

1.5 –

1.0 –

0.5 –

00

OR for

low birth weight

1.22

fourth quartile of PM_2.5 (> 20.2 μg/m³) compared with the first quartile (< 6.3 μg/m³)

Increased risk of:

 metabolic syndrome,

 cardiovascular diseases,

 asthma and COPD

(24)

Air pollution and brain damage.

Calderón-Garcidueñas L, Toxicol Pathol. 2002;30(3):373-89.

32 healthy mongrel canine residents

in Southwest Metropolitan Mexico

City (SWMMC), a highly polluted urban

region.

8 dogs from Tlaxcala, a less polluted,

control city.

Increased Brain Inflammation secondary to oxidative stress

(25)

Air pollution and brain damage.

region.

control city.

expression of nuclear neuronal NF-kappaB

in cortical endothelial cells occurred at ages 2 weeks;

subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells.

Neurodegenerative disorders such as

Alzheimer's may begin early in life

with air pollutants playing a crucial role.

(26)

Air pollution and brain damage.

region.

control city.

The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease:

A recent update.

Ghosh S.Food Chem Toxicol. 2015 Sep;83:111-24.

3/03/2016 PubMed:

Alzheimer's disease and curcumin = 400 reports

(27)

Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses:

it is time to face the evidence

Calderón-Garcidueñas L, Biomed Res Int. 2013;2013:161687

 Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death.

 Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and

adaptive immune responses.

 Early dysregulated neuroinflammation, brain microvascular damage,

production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive

neurodegenerative processes.

 The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and

Parkinson's diseases.

(28)

Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses:

it is time to face the evidence

Calderón-Garcidueñas L, Biomed Res Int. 2013;2013:161687

Mexico City Metropolitan Area (MCMA) children with no known risk factors for neurological or cognitive disorders

exhibit significant deficits in a combination of fluid and crystallized cognition tasks

versus control children.

56% of MCMA children showed

prefrontal white matter hyperintense lesions by MRI and similar lesions were observed in MCMA dogs (57%).

(29)

Residential proximity to freeways and autism in the CHARGE study.

Volk HE, Environ Health Perspect. 2011; 119:873-77

 304 autism cases and 259 typically developing controls enrolled in the

Childhood Autism Risks from Genetics and the Environment (CHARGE) study.

2.5 –

2.0 –

1.5 –

1.0 –

0.5 –

00

2.2 OR for Autism

Residential proximity to a freeway during

the third trimester

(30)

Effect of rising atmospheric carbon dioxide concentration on the protein composition of cereal grain

^.

Wroblewitz S, J Agric Food Chem. 2014;62(28):6616-25.

effects of rising atmospheric CO2 concentration on protein composition of maize, wheat, and barley grain, especially on the fractions prolamins and glutelins.

Cereals were grown at different atmospheric CO2 concentrations to simulate future climate

conditions.

elevated CO2 concentration

decrease of protein content

in the grains of staple food crops

and

an overall decreasing trend of

trace elements

contents in the crops.

In 2050 it will be difficult to have

“spaghetti al dente”

and Glicemic Index will increase !

(31)

 Plasma malondialdehyde

(MDA) and F2-isoprostanes (IsoPs) concentrations.

(lipid peroxidation of polyunsaturated fatty acids)

 292 healthy adults.

 Dietary glycemic index and glycemic load by food-

frequency questionnaire.

Relations of glycemic index and glycemic load with plasma oxidative stress markers

Hu Y, Am J Clin Nutr. 2006; 84:70-6

MDA concentrations

(micromol/L) IsoP concentrations (ng/mL)

0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0

p=0.03

0.034 0.04 0.55

0.73

1° 4° 1° 4°

Glicemic Index Quartiles

p=0.02

(32)

Relations of glycemic index and glycemic load with plasma oxidative stress markers

Hu Y, Am J Clin Nutr. 2006; 84:70-6

MDA concentrations

0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0

p=0.03

0.034 0.04 0.55

0.73

1° 4° 1° 4°

p=0.02

Chronic consumption of high-GI foods may

lead to chronically high oxidative stress.

A low-GI diet, not a low-carbohydrate diet, appears to be beneficial in reducing

oxidative stress.

(33)

Relations of glycemic index and glycemic load with plasma oxidative stress markers

Hu Y, Am J Clin Nutr. 2006; 84:70-6

MDA concentrations

0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0

p=0.03

0.034 0.04 0.55

0.73

1° 4° 1° 4°

p=0.02

Increasing dietary intakes of low-GI foods, such as most

fruit, vegetables, dairy products, and whole grains, may be

beneficial in terms of reduced

oxidative stress.

(34)

in relation to a governmental air quality intervention implemented during the 2008 Beijing Olympic Games.

substantial reductions in air pollution

(-19% to -72%)

 36 schoolchildren during 5 time periods before and during the Olympic Games in Beijing.

 Oxidative stress biomarkers 8-oxo-7,8-dihydro-2'-

deoxyguanosine (8-oxodG) and malondialdehyde were

measured in urine samples collected daily during each period.

Association between changes in exposure to air pollution and biomarkers of oxidative stress in children before and

during the Beijing Olympics

Lin W, Am J Epidemiol. 2015; 181:575-83

(35)

 36 schoolchildren during 5 time periods before and during the Olympic Games in Beijing.

 Oxidative stress biomarkers 8-oxo-7,8-dihydro-2'-

deoxyguanosine (8-oxodG) and malondialdehyde were

measured in urine samples collected daily during each period.

Association between changes in exposure to air pollution and biomarkers of oxidative stress in children before and

during the Beijing Olympics

Lin W, Am J Epidemiol. 2015; 181:575-83

During the Olimpic Games mean % reduction in urinary

-37.4%

8-oxodG

-00 -10 –

-20 –

-30 –

-40 –

-25.3%

malondialdehyde

(36)

Environment, Oxidative Stress and Micronutrients

Attilio Boner

[email protected]

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

(37)

Resiratory Tract

Infections

(38)

Concentrations of the oxidative stress markers in nasopharyngeal secretions (NPS) of infants with naturally acquired respiratory syncytial virus (RSV) infections.

F2-isoprostane concentration Malondialdehyde concentration

**p < 0.01 and ***p < 0.001 compared with upper respiratory tract infection

Viral-mediated Inhibition of Antioxidant Enzymes

Contributes to the Pathogenesis of Severe Respiratory

Syncytial Virus Bronchiolitis

Hosakote AJRCCM 2012;183:1550

(39)

Superoxide dismutase 1 (SOD 1), SOD 2, SOD 3, catalase,

glutathione peroxidase, and glutathione S-transferase,

as well as NF-E2-related factor 2 (Nrf2 )expression,

were measured in murine bronchoalveolar lavage, cell

extracts of conductive airways, and/or inhumannasopharyngeal secretions.

Antioxidant enzyme activity and markers of oxidative cell injury were measured in either murine bronchoalveolar lavage or

nasopharyngeal secretions.

Markers of oxidative damage correlated with severity of clinical illness

in RSV infected infants.

Nrf2 expression was also significantly reduced in the lungs of viral-infected

mice.

Viral-mediated Inhibition of Antioxidant Enzymes

Contributes to the Pathogenesis of Severe Respiratory Syncytial Virus Bronchiolitis

Hosakote AJRCCM 2012;183:1550

(-)

(40)

Serum heavy metal and antioxidant element levels of children with recurrent wheezing.

Razi CH, Allergol Immunopathol (Madr). 2011;39:85-9.

100 children with recurrent wheezing from 1 to 6 years

116 age- and sex- matched healthy children.

serum mercury, lead, aluminium, zinc, selenium, and copper levels in blood

(41)

Oxidative stress and enzymic-non-enzymic antioxidant responses in children with acute pneumonia.

Cemek M, Cell Biochem Funct. 2006;24(3):269-73.

28 children with acute pneumonia

29 control subjects.

blood malondialdehyde (MDA) and reduced glutathione (GSH), serum beta-carotene, retinol, vitamin C, vitamin E, catalase (CAT),

ceruloplasmin (CLP), total bilirubin, erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels

Serum and whole blood (GSH) non-enzymic antioxidants levels in

the patient and control groups

1

(42)

Oxidative stress and enzymic-non-enzymic antioxidant responses in children with acute pneumonia.

Cemek M, Cell Biochem Funct. 2006;24(3):269-73.

28 children with acute pneumonia

29 control subjects.

blood malondialdehyde (MDA) and reduced glutathione (GSH), serum beta-carotene, retinol, vitamin C, vitamin E, catalase (CAT),

ceruloplasmin (CLP), total bilirubin, erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels

Serum and whole blood (GSH) non-enzymic antioxidants levels in

the patient and control groups

1

antioxidant vitamin deficiency can result in

a decreased immune

response, phagocytosis and killing of bacteria and oxidative stress plays a

role in worsening the inflammation.

Halliwell B. Antioxidants in human health and disease.

Ann Rev Nutr 1996;16:33–50.

(43)

Paraoxonase and arylesterase activity and total oxidative/anti-oxidative status in patients

with chronic adenotonsillitis.

Koc S, Int J Pediatr Otorhinolaryngol. 2011;75:1364-7.

total oxidant status (TOS), total antioxidant status (TAS)

oxidative stress index (OSI) in blood

22 children with

recurrent adenotonsillitis during pre- and post-

adenotonsillectomy period

Total Oxidant Status (µmol H₂O₂ equiv./L)

Preoperative Postoperative

11.0 8.7

p<0.001

15 – 10 – 55 – 0

(44)

Reduction in oxidative stress biomarkers after adenotonsillectomy.

Cho JH, Int J Pediatr Otorhinolaryngol. 2015 Sep;79(9):1408-11.

22 children with sleep disordered breathing (SDB) with tonsil and adenoid hypertrophy enrolled prior to adenotonsillectomy.

20 healthy children as controls.

Levels of three urinary

biomarkers for oxidative status:

- 8-hydroxy-2-deoxyguanosine

(a marker of DNA damage), - F(2)-isoprostane, and

- malondialdehyde (MDA)

8-hyrdroxy-2-deoxyguanosine (µg/g creatinine)

(45)

Oxidative stress and specific lung diseases

• Sleep

Disordered

Breathing

(46)

Correlation of 8-isoprostane, interleukin-6 and cardiac functions with clinical score in childhood obstructive sleep apnoea.

Biltagi MA. Acta Paediatr. 2008;97:1397-405.

40 children with

adenoidal hypertrophy and 20 controls

OSA clinical score

IL-6 and 8-isoprostane in exhaled breath

condensate (EBC).

Echocardiography

8-isoprostane (pg/mL) in EBC

35.0 controls

p<0.0001

60 - 50 – 40 – 30 – 20 – 10 –

0

58.6 OSA > 40

isoprostanes are prostaglandin

like compounds formed in vivo

from peroxidation of

essential fatty acids (primarly arachidonic acid)

(47)

Correlation of 8-isoprostane, interleukin-6 and cardiac functions with clinical score in childhood obstructive sleep apnoea.

IL-6 (pg/mL) in EBC

controls 7.0

p<0.0001

38.0 OSA > 40

40 children with

condensate (EBC).

Echocardiography

60 - 50 – 40 – 30 – 20 – 10 –

0

(48)

60 - 50 – 40 – 30 – 20 – 10 –

0

40 children with

condensate.

Echocardiography

Correlation of 8-isoprostane, interleukin-6 and cardiac functions with clinical score in childhood obstructive sleep apnoea.

IL-6 (pg/mL) in EBC

controls 7.0

p<0.0001

38.0 OSA > 40 a significant positive

correlation between IL-6 production in

the lung and the pulmonary vascular resistance has been

previously demonstrated

Naoko M

Chest 2002;121:1195

.

(49)

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea

Kim AJRCCM 2012;185:330

DNA methylation

levels of 24 inflammatory-related genes.

47 OSA cases

 31 control subjects.

Forkhead box P3 (FOXP3)* and interferon regulatory factor 1

(IRF1) showed higher

methylation (less transcription) in 6 children with OSA and high high-sensitivity C-reactive

protein (hsCRP) levels compared with matched children with OSA and low

hsCRP levels (p<0.05).

* FOXP3 also known as scurfin is a protein involved in immune system responses and appears to function as a master regulator in the development and function of regulatory T cells.

FOX proteins are transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription.

(50)

Pediatric Sleep Disorders and Special Educational Need at 8 Years: A Population-Based Cohort Study

Bonuck K., Pediatrics 2012;130:634 2 –

1 –

0

1.38

6mo

1.31 1.43

18mo 30-57mo

Age of peak of symptoms OR for Special Educational

Need at age 8 yrs

 Sleep disordered

breathing (SDB) through 5 years of age

(11 049 children).

 Special educational need (SEN) at 8 years.

 Parents reported on children’s snoring, witnessed apnea, and

mouth-breathing at 6, 18, 30, 42, and 57 months.

(51)

Oxidative stress in allergies and asthma prevalence

Some researchers have proposed that the increased prevalence of allergic diseases is a consequence of decreasing intake of antioxidants as people adopt Western diets characterized by a reduced amount of fresh fruits and vegetables.

Allan K, Clin Exp Allergy 2009;40:370-80.

Others have suggested that it is linked to the increased consumption of processed and oxidants enriched foods.

Feary J, Thorax 2007;62:466-8.

(-)

(+)

(52)

Mediterranean diet in pregnancy is protective for wheeze and atopy in childhood

Chatzi Thorax 2008;63:507



Women presenting for antenatal care at all general

practices in Menorca.



460 children were included in the

analysis after 6.5 years of

follow-up.



Food frequency

questionnaires. PERSISTENT

WHEEZE ATOPIC ATOPY

WHEEZE

0.22

1.0 –

0.5 –

0.0

With High Mediterranean Diet Score during pregnancy

OR

^for

0.30

0.55

(53)

OR for WHEEZING EVER 1.0 –

0.5 –

0

0.26

GRAPES

p=0.001 for trend

Protective effect of fruits, vegetables and the Mediterranean diet on asthma and allergies among

children in Crete

Chatzi L, Thorax 2007;62:677



Cross-sectional survey.



690 children aged 7-18 years in rural Crete.



Questionaire on

respiratory and allergic symptoms and a 58-item food frequency

qestionaire.



SPTs.

< 1/DAY ≥1/DAY

0.19

(54)

Dietary antioxidants and asthma in adults.

Population based case-control study.

Shaheen SO, AJRCCM 2001;164:1823-8.

a population-based case-control study in South London,

food frequency questionnaire from

607 asthmatics and 864 controls

1.0 –

0.5 –

0

OR ^{for Asthma}

per quintile increase of SELENIUM intake

0.84

p=0.002

(55)

Antioxidant intake and allergic disease in children.

Rosenlund H, Clin Exp Allergy. 2012;42(10):1491-500.

Associations between

antioxidant intake during the past year and current allergic

disease in 2442 (8-year-old children) from the

Swedish birth cohort study BAMSE

parental questionnaires on exposures and health, including a food-frequency questionnaire and blood sample

magnesium intake

highest vs. lowest quartile in the past year OR for

asthma

0.65

1.0 –

0.5 –

0.0

0.78

atopic sensitisation

P for trend 0.039

P for trend 0.041

at 8 years of age

(56)

Allergic sensitization is associated with inadequate antioxidant responses in mice and men

Utsch L , Allergy 2015;70:1246–1258

Also in human subjects, oxidative stress before allergen exposure and poor

antioxidant responses

predisposition to occupational allergy.

37 laboratory animal workers were followed for 2 years.

Occupational allergic sensitization to rodent urinary proteins was monitored.

knockout oxidative defense

easy to sensitize

(57)

Allergic sensitization is associated with inadequate antioxidant responses in mice and men

Utsch L , Allergy 2015;70:1246–1258

Also in human subjects, oxidative stress before allergen exposure and poor

antioxidant responses

predisposition to occupational allergy.

37 laboratory animal workers were followed for 2 years.

Occupational allergic sensitization to rodent urinary proteins was monitored.

knockout oxidative defense

easy to sensitize

Allergic sensitization to rodent proteins in humans is associated with reduced

capacity to express

Nuclear factor erythroid- derived (2Nrf2)

(+) (-)

(58)

A comprehensive evaluation of the enzymatic and nonenzymatic antioxidant systems in childhood asthma

Sackesen, JACI 2008;122:78

164 children with mild asthma and 173 healthy children

Levels of glutathione

peroxidase and superoxide

dismutase, reduced glutathione, ascobic acid, a-tocopherol,

lycopene, b-carotene, amino

acids participating in glutathione synthesis, and amino acids

susceptible to oxidation.

childhood asthma is associated with significant

decreases in

various components of both enzymatic

and nonenzymatic antioxidant

defenses.

(59)

Increased exhaled 8-isoprostane in childhood asthma.

Baraldi E, Chest. 2003;124(1):25-31^.

12 healthy children,

12 steroid-naïve asthmatic children,

30 children in stable condition with mild-to- moderate persistent

asthma treated with inhaled corticosteroids (ICSs)

[average dose, 300 micro g per day]

exhaled breath condensate (EBC),

8-isoprostane levels in EBC (marker of lipid peroxidation)

ns

(60)

Urinary Bromotyrosine Measures Asthma Control and Predicts Asthma Exacerbations in Children

Wedes, J Ped 2011;159:248



Urinary bromotyrosine, a non invasive marker of eosinophil-catalyzed protein oxidation.



57 children with asthma.



Follow-up 6 weeks.

ORs for the associations between high levels of bromotyrosine and uncontrolled asthma at baseline

(61)

in asthmatic

airways Oxidative

Stress

Asthma and the REDOX System

1)

peroxidation of lipids, proteins, and DNA

2)

production of chemoattractants,

3)

^BHR,

4)

airway secretion,

5)

vascular permeability, increases

Barnes Free Rad Biol Med 1990;9:235.

Rahman I. J Biochem Mol Biol 2003;36:95.

Henderson WR J Immunol 2002;169:5294.

ROS also promote the

activities of

6)

proinflammatory redox-sensitive nuclear factors, (NF-kB).

thus increasing the allergic inflammation

(62)

Histone deacetylase-2 and airway disease.

Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43.

The increased expression of inflammatory genes in inflammatory lung diseases

is regulated by

acetylation of core histones,

increased expression of inflammatory genes

suppresses inflammatory gene expression

(63)

Histone deacetylase-2 and airway disease.

whereas

histone deacetylase-2 (HDAC2) suppresses

inflammatory gene expression.

(64)

Histone deacetylase-2 and airway disease.

whereas

The reduction in HDAC2 appears to be secondary

to increased oxidative stress in the lungs.

(65)

Histone deacetylase-2 and airway disease.

whereas

The reduction in HDAC2 appears to be secondary

to increased oxidative

stress in the lungs.

Antioxidants such as curcumin ^may

therefore restore corticosteroid

sensitivity

(66)

Markers of oxidative stress are increased in exhaled breath condensates of children with atopic dermatitis.

Peroni DG, Br J Dermatol. 2012;166:839-43.

33 ch with AD and 23 healthy controls

EBC for:

-pH,

-LTB4, -8-isoprostane,

-H₂O₂ ,

-malondialdehyde , -4-hydroxynoneal.

Levels of 8-isoprostane and LTB4 in patients with AD vs normal controls.

(67)

 Biopyrrin, one of the oxidative metabolites of bilirubin, is excreted into the urine

 Urinary biopyrrin levels as an indicator of the internal oxidative

stress

 33 patients with Atopic Dermatitis (AD)

Urinary biopyrrin levels in patients with AD by SCORing of AD severity

Urinary biopyrrin: a potential inflammatory marker of atopic dermatitis

Chiba T, Ann Allergy Asthma Immunol 2014;112:182

(68)

Trace element levels in children with atopic dermatitis.

Toyran M, J Investig Allergol Clin Immunol. 2012;22:341-4.

92 AD patients and 70 controls.

levels of iron, copper, and magnesium in serum

levels of zinc in erythrocytes.

Serum Trace Element Levels in Patients with and without Atopic Dermatitis^a

Mg Zn

(69)

Increased oxidative stress and altered antioxidants status in patients with chronic allergic rhinitis

S. Sequeira, Adv. Biosci. Biotechnol. 2012;3:951-56.

39 chronic allergic rhinitis

patients (mean age 36.33 ± 2.03) years and 53 healthy individuals

Erythrocyte lipid peroxidation, erythrocyte antioxidants viz.,

glutathione, glutathione reductase, superoxide dismutase, catalase and plasma antioxidants viz.,

ceruloplasmin, glutathione-S- transferase, vitamin C, total antioxidant activity

Mean plasma antioxidant activity

allergic rhinitis

1.1 – 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0

mmM/L

0.61

controls

mmM/L

1.01

P<0.001

(70)

Total antioxidant status and oxidative stress and their relationship to total IgE levels and eosinophil counts in

children with allergic rhinitis.

Emin O, J Investig Allergol Clin Immunol. 2012;22(3):188-92.

In children with

High Total Oxidative Status OR for

2.1

3.0 –

2.0 –

1.0 –

0.0

p=0.025

106 children newly diagnosed with allergic rhinitis and 70

nonallergic children (7-12 years).

Plasma total oxidant status (TOS)

Plasma total antioxidant status (TAS),

Severe Perennial Allergic Rhinitis

(71)

Urticaria

(72)

Platelet oxidative stress and systemic inflammation in chronic spontaneous urticaria (CSU).

Rajappa M, Clin Chem Lab Med. 2013;51(9):1789-94.

45 patients with CSU and 45 age- and gender-matched healthy controls.

Severity grading completed

according to the urticaria severity score (USS).

Autologous plasma skin test (APST) in all patients with CSU.

Platelet malondialdehyde (MDA), platelet superoxide dismutase

(SOD), platelet glutathione peroxidase (GPx) and

inflammatory markers plasma IL-6 and hs-CRP

Platelet malondialdehyde

p < 0.0001

chronic urticaria

(73)

Oxidative stress status in patients with chronic idiopathic urticaria.

Sagdic A, Allergol Immunopathol (Madr). 2011;39:150-3.

25 patients with CIU and 36 healthy controls

Erythrocyte lipid

peroxidation status,

scavenger enzyme

activities

erythrocyte CuZn-SOD activity (U/gHb)

controls

500 – 400 – 300 – 200 – 100 –

0

404.3

^p<0.001

258.9

patients with urticaria

(74)

Environment, Oxidative Stress and Micronutrients

Attilio Boner

[email protected]

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

(75)

Antioxidants

Valko: Int J Biochem Cell Biol 2007;39:44

•

Defence mechanisms against free radical-induced oxidative stress involve:

(i) preventative mechanisms, (ii) repair mechanisms,

(iii) physical defences, and (iv) antioxidant defences.

Enzymatic antioxidant defences include superoxide dismutase

(SOD), glutathione peroxidase (GPx), catalase (CAT), zinc, magnesium, selenium.

Non-enzymatic antioxidants are represented by ascorbic acid

(Vitamin C), α-tocopherol (Vitamin E), glutathione (GSH), carotenoids, flavonoids such as resveratrol, quercetin, natural phenols such as

curcumin, and isothiocyanates such as sulforaphane.

(76)

Immunobiology of mild micronutrient deficiencies.

Bhaskaram P, Br J Nutr. 2001 May;85 Suppl 2:S75-80.

to subtle functional impairment in subclinical deficiencies which could nevertheless, significantly influence

the health and survival of the population.

Micronutrient deficiencies a wide spectrum of effects ranging from

clinical disorders due to severe deficiency

Zinc deficiency

is widespread among populations

Deficiencies of vitamin A and iron are widely prevalent among preschool children and are important public health problems in most developing countries.

increasing incidence and severity of childhood infections

(77)

Immunobiology of mild micronutrient deficiencies.

Bhaskaram P, Br J Nutr. 2001 May;85 Suppl 2:S75-80.

to subtle functional impairment in subclinical deficiencies which could nevertheless, significantly influence

the health and survival of the population.

Micronutrient deficiencies a wide spectrum of effects ranging from

clinical disorders due to severe deficiency

Zinc deficiency

is widespread among populations

Deficiencies of vitamin A and iron are widely prevalent among preschool children and are important public health problems in most developing countries.

increasing incidence and severity of childhood infections

In healthy infants in developed countries, the most likely scenario for pure dietary zinc deficiency is in the older breastfed infant, especially one who has

been exclusively or predominantly breastfed and has transitioned according to traditional

complementary feeding practices.

(78)

(79)

Serum heavy metal and antioxidant element levels of children with recurrent wheezing.

Correlation between serum zinc levels and n° of Acute Respiratory Tract Infections.

r:−0.332, p = 0.001

serum mercury, lead, aluminium, zinc, selenium, and copper levels in

blood

(80)

% children with acute

lower respiratory infections during 180 days follow-up

The efficacy of zinc supplementation in young children with acute lower respiratory infections: a randomized double-blind controlled trial.

Shah UH, Clin Nutr. 2013;32:193

60 – 50 – 40 – 30 – 20 – 10 –

0

20.8%

P=0.009

45.8%

Zinc Placebo

96 children living in India

10 mg zinc

gluconate or placebo for 60 days.

Follow-up:

180 days.

supplementation

(81)

Serum zinc and pneumonia in nursing home elderly.

Meydani SN, Am J Clin Nutr 2007; 86:1167–1173.

% reduction in all-cause mortality in

those normal (≥70 microg/dL) serum zinc concentrations

-00

-10 – -20 – -30 – -40 –

-39%

p=0.049

pneumonia in 420 USA elderly patients

1-y supplementation trial with 7 mg/day of zinc.

zinc concentrations

categorized as

low (<70 microg/dL) or normal (≥70 microg/dL) serum zinc concentrations.

(82)

Bronchial reactivity and dieatry anti-oxidants.

Soutar A, Seaton A. Thorax 1997;52:166–170.

validated dietary

questionnaire in 2000 subjects to measure food intake

people with seasonal allergic-type symptoms those with bronchial hyperreactivity

confirmed by

methacholine challenge, and of controls

5 - 4 - 3 – 2 – 1 – 0

4.70 in people with low zinc intake

OR

for allergic symptoms

p=0.016

in zinc deficiency there is a shift from Th1 to Th2

functions

(83)

Serum heavy metal and antioxidant element levels of children with recurrent wheezing.

Correlation between serum zinc levels and n° of wheezy attacks during the previous year

r:−0.776, p < 0.001

serum mercury, lead, aluminium, zinc, selenium, and copper levels in

blood

(84)

Zinc status in infantile wheezing.

Tahan F, Pediatr Pulmonol. 2006;41:630-4.

Wheezy infants (n = 34) living in Turkey

Healthy children (n = 14)

Levels of zinc in hair

34

140 – 120 – 100 - 800 - 600 – 400 – 200 –

0

Wheezing Controls CHILDREN WITH

136.5

Hair zinc level (μg/g hair)

p<0.001

A normal hair zinc range is around 150 - 240µg/gram.

Levels of < 70µg/gram would be indicative of zinc deficiency.

(85)

Effect of zinc supplementation in children with asthma:

a randomized, placebo-controlled trial in northern Islamic Republic of Iran.

Ghaffari J, East Mediterr Health J. 2014;20(6):391-6

284 children on ICS

zinc supplements (50 mg/day) (n = 144 cases)

or placebo (n = 140 controls) for 8 weeks

130 - 120 - 110 – 100 – 090 – 080 – 070 – 060 – 050 – 040 – 030 – 020 – 010 – 000

serum zinc concentrations (μg/dL)

61.8 60.9

baseline after supplementation

129

63

Boner

Environment, Oxidative Stress and Micronutrients

Attilio Boner

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

Environmental Factors Exposure and Epigenetics

•

•

•

•

Oxidative stress epigenetic

effects

Environment, Oxidative Stress and Micronutrients

Attilio Boner

 Introduction

 Oxidative stress definition

 Pollution and Red-Ox

 Diseases and Red-Ox

 Anti-oxidant micronutrients

 Susceptible populations

 Summary & Conclusions

The atom

Equal number of electrons (-)

charged and protons (+) charged

=

The atom

Oxidation

Reduction

O 2

Free radical

•

•

•

What are “Free Radicals”?

O 2

•

•

•

What are “Free Radicals”?

O 2

lemon juice

What do “Free Radicals”?



•

•

•

•



*

* *

Oxidative stress and:

• Pollution

• Sleep Apnoea

• Bronchopulmonary dysplasia

• Bronchiolitis

• Asthma

• Cystic Fibrosis

• COPD

• RRI

Oxidative stress and:

• Pollution

• Sleep Apnoea

• Bronchopulmonary dysplasia

• Bronchiolitis

• Asthma

• Cystic Fibrosis

• COPD

• RRI

• Atopic dermatitis 72

• Food allergy 51

• Urticaria 17

• Anaphylaxis 14

• Allergic rhinitis 62

• Atopy develoment 18

• Aging 12353

O ₂

O ₂

O ₂