for investigations regarding persistent pneumonia. The girl suffered
from several episodes of recurrent infections such as neonatal sepsis
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and gastroenteritis, since the 6th day of her life. At the time of
admission, she had received three recent course of antibiotics from
--- Content provided by FirstRanker.com ---
the previous hospital including cefepime, clindamycin and imipenemdue to persistent pneumonia. On admission, physical examination
revealed mild chest retraction and rales in both lung fields. She was
--- Content provided by FirstRanker.com ---
alert and responsive, with no neurological deficit. Her height and
weight were at the 25th-50th percentile and the 50th-75th percentile for
--- Content provided by FirstRanker.com ---
her age respectively.? A chest X-ray confirmed the presence of bilateral pulmonary
consolidation and atelectasis. Diagnostic bronchoalveolar lavage (BAL)
--- Content provided by FirstRanker.com ---
was performed to obtain specimens for cytology and culture. A
computed tomography (CT) of the thorax showed a left sided
--- Content provided by FirstRanker.com ---
consolidation and evidence of hematogenously disseminatedmultifocal pneumonia.
? She had no family history related to primary immunodeficiency. Her total
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leucocyte count was 10,500/?L, with 34% neutrophils and 52%lymphocytes. The ESR was 12 mm/hr, and CRP 3.54 mg/dL. Aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) levels were
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raised (174 IU/L and 398 IU/L, respectively). Electrolyte levels and the
results of renal function tests were normal. Investigations for her
--- Content provided by FirstRanker.com ---
immunologic work-up showed Ig G, Ig A, Ig M, Ig E, C3, C4, and CH50 levelsto be within her age specific reference range. Lymphocyte subset analysis
revealed normal B cells and T cells for her age.
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? She had negative neutrophil nitroblue tetrazolium (NBT) slide test and
abnormal neutrophil respiratory burst activity test.
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? What could be the possible diagnosis ?What is its pathophysiology?
Learning objectives
--- Content provided by FirstRanker.com ---
? Definition ? free radicals, reactive oxygen
species
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? Generation? Damage
? Clinical significance
? Scavenger system
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4Free radical
? Free radical: is a molecule or an atom with an
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unpaired electron in its outer most orbital. It ishighly reactive and has an extremely short half
life of microseconds. It reacts indiscriminately
with any molecule that comes in its contact to
achieve stability by either accepting an
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electron or donating an electron.
ROS& oxidative damage
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? Normal y the oxygen is completely reduced towater and successive reduction with four
electrons. However incomplete reduction
produces ROS such as superoxide, ?O2
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-, hydroxyl, ?OH, and perhydroxyl, ?O2H.H2O2 is not a radical by definition but is a highly
reactive ROS and produces other species of ROS.
? Tissue damage caused by oxygen radicals is often
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cal ed oxidative damage
ROS encountered in living cells
? Sources of ROS in cell
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1. Leakage from electron transport chain inmitochondria
2. Cytochrome P450 in Endoplasmic Reticulum
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3. Degradation ofPurine nucleotides
to Uric acid
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4. Interaction with metal
5. Peroxisome
? Hydrogen peroxide produced during oxidation
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of long chain FA in a FAD dependent reaction
in peroxisome.
13
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4
6. Respiratory burst
? Neutrophils, eosinophils, monocytes and
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macrophages produces superoxide anion by
respiratory burst during phagocytosis by
NADPH oxidase.
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15NADPH oxidase
Activation of
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macrophages andconsumption of
oxygen by the cell
is increased
drastically called
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as respiratoryburst
16
Other exogenous sources
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? Drugs and chemicals: Acetaminophen : Hgh
dose cause liver damage
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? Peroxidation catalyzed by lipo-oxygenase inplatelets and leukocytes.
? H2O -------(gamma, UV radiation)---- e- + OH?
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? Oxygen photolysis by light produced singlet oxygen? Cigarate smoking
? Environmental pollution
18
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FORMATION OF FREE RADICALS19
Damage caused by free radicals
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1. Proteins
2. Lipid peroxidation
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3. Nucleic acids20
Cellular damage caused by ROS
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? Protein? Aminoacids like proline, histidine, arginine,
methionine are particularly susceptible to
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oxidative damage .? Protein fragmentation
? Protein aggregation
? Protein-protein cross linking
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Lipid Peroxidation
In vitro, peroxidation would lead to rancidity of fats
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and oils.In vivo, the membrane lipids are more liable to attack
by free radicals and produce damage to integrity of
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the membrane.
22
Lipid peroxidation
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Damages to DNA
? Damage to DNA
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? in germ line cells in ovaries and testes ? heritablemutation
? in somatic cells ? cancers.
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? dialdehydes formed as a result of radical-induced
lipid peroxidation in cell membranes can also
modify bases in DNA
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? Chain break
24
Tissue damage by radicals
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Role of free radicals in autoimmune
disease
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? Modification of amino acids in the protein ? bydirect radical action or by reaction with
products of lipid peroxidation.
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? Protein recognized as non-self by the immune
system.
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? Production of antibodies ? cross react withnormal tissue proteins ? initiating autoimmune
disease.
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26
Total body radical burden can be
estimated by measuring products of lipid
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peroxidation:-
? FOX (Ferrous Oxidation in Xylenol) Assay
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? Estimation of dialdehydes? Measurement of Pentane and Methane in
Exhaled air
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F OX assay
? Lipid peroxides can be measured by the ferrous
--- Content provided by FirstRanker.com ---
oxidation in xylenol orange (FOX) assay.? Acidic conditions fe++
fe+++
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? Which form chromophore with xylenol orange.
28
TBARS assay
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? The dialdehydes (malondialdehyde) formed
from lipid peroxides can be measured by
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reaction with thiobarbituric acid, they form redfluorescent product - generally reported as
TBARS (thiobarbuturic acid reactive
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substances).
29
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Pentane and Ethane assay? Peroxidation of n-6 PUFA form ? pentane
? Peroxidation of n-3 PUFA form ? ethane
? Both can be measured in exhaled air.
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30
Clinical significance of free radicals
? Chronic inflammation ? rheumatoid arthritis
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due to free radicals released by neutrophils
? ROS induced tissue damage ? ulcerative colitis,
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chronic glomerulonephritis? Acute inflammation ? macrophages produce
free radicals at inflammatory site
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? Respiratory burst ? increase activity of NADPH
oxidase in macrophages and neutrophils
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31In chronic granulomatous disease (CGD),
NADPH oxidase is absent.
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? So, bacteria are ingested normally but they
cannot be destroyed.
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32Respiratory disease
? Breathing of 100% oxygen for more than 24 hr
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produce destruction of endothelium and lungedema ? due to free radicals release
? Premature newborn ? high oxygen exposure
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for prolonged period causes ?
bronchopulmonary dysplasia
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? Adult ? ARDS due to pulmonary edemacaused by free radicals
33
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Disease of eyes
? ROP (Retrolental fibroplasia) ?
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? Premature newborn treated with pure oxygen forlong time.
? Free radicals causing thromboxane release,
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sustained vascular contracture and cellular injury.
? Cataract - related with aging and photochemical
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generation of free radicals34
Atherosclerosis and MI
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? LDL deposited in the endothelial cells,undergo oxidation by free radicals.
? Attracts macrophages ? form foam cells ?
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formation of plaque ? atherosclerosis.
35
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Skin disease? Plant products like psoralens are administered
in the treatment of psoriasis and leucoderma.
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? Drug applied to affected skin and irradiated by
UV light
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? Singlet oxygen is produced with clinicalbenefit
36
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Carcinogenesis and treatment? Cancer is treated by radiotherapy
? Irradiation produced reactive oxygen species
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in the cells which trigger the cell death37
? Antioxidant
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Antioxidants? Substances which protect against cellular
injury by ROS or other oxidants by scavenging
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them are called antioxidants? In normal healthy state a balance is
maintained between FRs & antioxidants.
--- Content provided by FirstRanker.com ---
? Moreover we can as well supplement these
from outside (in vitro Antioxidants).
Free radical scavenging system
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? Preventive antioxidant: reduce the rate of chain
initiation
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? Glutathione peroxidase? Catalase
? Chain breaking antioxidant: Interfere with chain
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propagation
? SOD
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? Uric acid? Vit E
? Enzymes
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? SOD
? Catalase
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? Glutathione peroxidase? Non enzymes
? Transferrin and ferritin
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? Cerruloplasmin
? Albumin
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? Glutathione? Uric acid
? Bilirubin
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? Ubiquinone
? Vit E
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? Vit C? Beta carotene
? Selenium
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Superoxide dismutase2O . -
2 + 2H+ H O
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2 2+ O 2
? SOD - is present in all oxygen-metabolizing cells,
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different cofactors (metals)? SOD contain Mn, Cu and Zn as co-factor.
? mitochondrial SOD is Mn dependent.=SOD2=Chr 6=
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idiopathic cardiomyopathy, premature aging? Cytoplasmic SOD is Cu and Zn dependent= SOD1= Chr
21.
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? Defect in SOD1 ? amyotrophic lateral sclerosis(Lou
Gehring's
--- Content provided by FirstRanker.com ---
? SOD 3= extracellular SOD [Cu-Zn]=Chr 4= diseaseassociated Asbestosis
43
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SOD
? Increase concentration of SOD during exercise
? Because aerobic metabolism - increases ROS
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generation during exercise
? This is turn stimulates the cell to synthesize
--- Content provided by FirstRanker.com ---
more enzymes.? The net effect is increase protection during
the post-exercise or rest periods.
--- Content provided by FirstRanker.com ---
44
ANTIOXIDANTS
Catalase
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2 H 2O
2
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2 H 2O + O2?
High affinity to H2O2 : peroxisomes,
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mitochondria, cytoplasm of erytrocytes
45
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Glutathione peroxidases? It is selenium dependant enzyme
? It catalyses reduction of hydrogen peroxide
--- Content provided by FirstRanker.com ---
and lipid peroxide by glutathione? Sulfhydryl groups of reduced glutathione
(GSH) serves as a electron donor.
--- Content provided by FirstRanker.com ---
? It is oxidized to the disulphide form (GS-SG)
which is reduced back by reductase enzyme
using NADPH
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46
Glutathione reductase
? Is flavo-protein enzyme using FA D as a co-
--- Content provided by FirstRanker.com ---
factor to reform the reduced glutathione from
oxidized glutathione
? The reducing equivalent donor is NADPH
--- Content provided by FirstRanker.com ---
? NADPH comes from HMP shunt.47
48
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49Non-enzymatic antioxidants
? Metal binding proteins ? Transferrin, Ferritin,
--- Content provided by FirstRanker.com ---
Ceruloplasmin.
? Albumin ? bind with various oxidizing
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substances.? Glutathione
? Bilirubin ? principal antioxidants in plasma.
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One molecule of bilirubin scavenges
two hydroperoxy radicals and gets
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oxidized to biliverdin.50
? Uric acid
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? Capability of scavenging free electron andprevents the propagation of FR damage in plasma.
51
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Vitamin E
?
--- Content provided by FirstRanker.com ---
Fat-soluble antioxidant?
Absorbed in Small Intestines
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?
Primary defender against effects of free
--- Content provided by FirstRanker.com ---
radicals in the body?
Stored in liver and fat cells.
--- Content provided by FirstRanker.com ---
?
Protects components of the cell and their
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membrane from destruction52
Vitamin E Is the Major Lipid-Soluble
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Antioxidant in Cell Membranes & PlasmaLipoproteins
Vitamin E
--- Content provided by FirstRanker.com ---
? Lipid peroxides are neutralized by glutathione
peroxidase
--- Content provided by FirstRanker.com ---
? Thus vitamin E acts synergistical y with glutathioneperoxidase enzyme which contains selenium.
? So sparing effect on dietary requirement of selenium
--- Content provided by FirstRanker.com ---
by supplementing the activity of this enzyme.
? Organel es in the cells exposed to the highest
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amounts of oxygen like mitochondria seemto
have the highest amount of Vitamin E.
--- Content provided by FirstRanker.com ---
? Evidence suggests that it protects LDL against
oxidation, which in turn protects us against heart
disease.
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54
ANTIOXIDANTS
Vitamin C
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? Gives up electrons very easily when they are needed.
? Helps to reactivate Vitamin E, glutathione, urate and beta
--- Content provided by FirstRanker.com ---
carotene.?Having the ability to recycle themselves over and over
again.
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?Protects oxygen and iron from oxidation.
? Helps protect arteries against oxidative damage.
--- Content provided by FirstRanker.com ---
?It works in aqueose environment by breaking chain reactionand can scavenge physiologically important reactive oxygen
and nitrogen species
--- Content provided by FirstRanker.com ---
55
ANTIOXIDANTS
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Vitamin A and Beta carotene? Beta Carotene is a water soluble precursor of Vitamin A,
and is an antioxidant in itself;
--- Content provided by FirstRanker.com ---
? It is chain breaking antioxidant by trapping peroxyradicals in tissues at low partial pressure of oxygen.
Found In:
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Corn, squash and carrots, egg yolk, and otherpigmented fruits and vegetables. This is what
helps give them their yellow color.
--- Content provided by FirstRanker.com ---
56
ANTIOXIDANTS
Selenium
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?
An essential trace mineral,
--- Content provided by FirstRanker.com ---
RDA of 70 ug/day.?
Found in Glutathion peroxidase which is a free
--- Content provided by FirstRanker.com ---
radical scavenging enzyme that contains
selenium.It destroys peroxides and thus protects
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lipid membranes as does Vitamin E.57
ANTIOXIDANTS
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BHA (Butylated Hydroxyanisole)
?
--- Content provided by FirstRanker.com ---
Generally made in the lab as an antioxidant?
Used as a food preservative.
--- Content provided by FirstRanker.com ---
?
Protects the oxidation of fats or oils.
--- Content provided by FirstRanker.com ---
?Naturally found in Rosemary
?
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Encourages the development of tumors
?
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May enlarge liver and bladder58
ANTIOXIDANTS
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Phytochemicals?Compounds found in plant-derived foods that have biological
activity in the body.
--- Content provided by FirstRanker.com ---
?Contribute to food taste, aromas, colors and other characteristics.
?Act as antioxidants, suppressing the development of diseases.
--- Content provided by FirstRanker.com ---
?Work better when combinedwith other phytochemicals.
?May help keep cholesterol in
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check
59
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FoodPhytochemical(s)
Allium vegetables
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Phytochemicals
Allyl sulfides
--- Content provided by FirstRanker.com ---
(garlic, onions, chives, leeks)Most Commonly Studied Phytochemicals
Cruciferous vegetables
--- Content provided by FirstRanker.com ---
(broccoli, cauliflower,
Indoles/glucosinolates
--- Content provided by FirstRanker.com ---
cabbage, Brussels sprouts,Sulfaforaphane
kale, turnips, bok choy,
--- Content provided by FirstRanker.com ---
Isothiocyanates/thiocyanates
kohlrabi)
--- Content provided by FirstRanker.com ---
ThiolsSolanaceous vegetables
(tomatoes, peppers)
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Lycopene
Umbelliferous vegetables
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Carotenoids(carrots, celery, cilantro,
Phthalides
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parsley, parsnips)
Polyacetylenes
--- Content provided by FirstRanker.com ---
Compositae plants (artichoke)Silymarin
Citrus fruits
--- Content provided by FirstRanker.com ---
Monoterpenes (limonene)
(oranges, lemons, grapefruit)
--- Content provided by FirstRanker.com ---
CarotenoidsGlucarates
Other fruits (grapes, berries,
--- Content provided by FirstRanker.com ---
Ellagic acid
cherries, apples, cantaloupe,
--- Content provided by FirstRanker.com ---
Phenolswatermelon, pomegranate)
Flavonoids (quercetin)
--- Content provided by FirstRanker.com ---
Beans, grains, seeds
Flavonoids (isoflavones)
--- Content provided by FirstRanker.com ---
(soybeans, oats, barley, brownPhytic acid
rice, whole wheat, flax seed)
--- Content provided by FirstRanker.com ---
Protease inhibitors
Saponins
--- Content provided by FirstRanker.com ---
Herbs, spices (ginger, mint,rosemary, thyme, oregano,
Gingerols
--- Content provided by FirstRanker.com ---
There are also hundreds more
sage, basil, tumeric, caraway,
--- Content provided by FirstRanker.com ---
Flavonoidsphytochemicals existing and in need
fennel)
--- Content provided by FirstRanker.com ---
Monoterpenes (limonene)
of discovery!
--- Content provided by FirstRanker.com ---
Licorice rootGreen tea
Glycyrrhizin Catechins
--- Content provided by FirstRanker.com ---
60
Polyphenols
ANTIOXIDANTS
--- Content provided by FirstRanker.com ---
Flavanoids
? Sometimes referred to as "Super Antioxidants."
--- Content provided by FirstRanker.com ---
? Shown to have: antiviral, antiallergic, anti-inflammatory,antithrombogenic and anticarcinogenic effects.
? Over 4000 flavanoids have been found, fall in four different
--- Content provided by FirstRanker.com ---
groups: flavones, flavanones, catechins, and anthocyanins.
?Found in: certain fruits, flowers, roots, stems, tea, wine,
--- Content provided by FirstRanker.com ---
grains and vegetables.61
ANTIOXIDANTS
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Flavanoids
?
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20 times stronger antioxidant then Vitamin Cand 50 times stronger then Vitamin E.
?
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Water soluble
?
--- Content provided by FirstRanker.com ---
Ability to attach to cells and their proteins forup to 72 hours protecting them from oxidation
and free radical damage.
--- Content provided by FirstRanker.com ---
?
Able to cross the blood-brain barrier
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62FREE RADICALS AND ANTI-OXIDANTS
? The Antioxidant Paradox -
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ProoxidantThe Antioxidant Paradox--Antioxidants
Can Also Be Pro-Oxidants
--- Content provided by FirstRanker.com ---
Vitamin C? these pro-oxidant actions require relatively
high concentrations of ascorbate, which are
--- Content provided by FirstRanker.com ---
unlikely to be reached in tissues
? once the plasma concentration of ascorbate
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reaches about 30 mmol/L, the renal thresholdis reached,
? at intakes above about 100 to 120 mg/d the
--- Content provided by FirstRanker.com ---
vitamin is excreted in the urine quantitatively
with intake.
-carotene.
--- Content provided by FirstRanker.com ---
? carotene is protective against lung and other cancers.? two major intervention trials in the 1990s showed an
increase in death from lung (and other) cancer
--- Content provided by FirstRanker.com ---
? -carotene is a radical-trapping antioxidant:
under conditions of low partial pressure of oxygen,
--- Content provided by FirstRanker.com ---
? Under high partial pressures of oxygen (as in the lungs)and especial y in high concentrations, -carotene is an
autocatalytic pro-oxidant,
--- Content provided by FirstRanker.com ---
? can initiate radical damage to lipids and proteins.
vitamin E
--- Content provided by FirstRanker.com ---
? vitamin E is protective against atherosclerosis andcardiovascular disease.
? meta-analysis of intervention trials with vitamin E
--- Content provided by FirstRanker.com ---
shows increased mortality among those taking
(high dose) supplements.
--- Content provided by FirstRanker.com ---
? vitamin E acts as an antioxidant by forming astable radical that persists long enough to
undergo metabolism to nonradical products.
--- Content provided by FirstRanker.com ---
? radical also persists long enough to penetrate
deeper in to the lipoprotein, causing further
--- Content provided by FirstRanker.com ---
radical damage,Summary
? Free radicals are highly reactive molecular specie
--- Content provided by FirstRanker.com ---
? They can modify, proteins, nucleic acids and fattyacids in cel membranes and plasma lipoproteins.
? Radical damage to lipids and proteins in plasma
--- Content provided by FirstRanker.com ---
lipoproteins is a factor in the development of
atherosclerosis and coronary artery disease;
--- Content provided by FirstRanker.com ---
? radical damage to nucleic acids may induceheritable mutations and cance
? radical damage to proteins may lead to the
--- Content provided by FirstRanker.com ---
development of autoimmune diseases.
? Oxygen radicals arise as a result of exposure to ionizing
--- Content provided by FirstRanker.com ---
radiation, nonenzymic reactions of transition metalions, the respiratory burst of activated macrophages
? Protection against radical damage is afforded by
--- Content provided by FirstRanker.com ---
enzymes that remove superoxide ions and hydrogen
peroxide, enzymic reduction of lipid peroxides linked to
--- Content provided by FirstRanker.com ---
oxidation of glutathione, nonenzymic reaction of lipidperoxides with vitamin E
? Except in people who were initial y deficient,
--- Content provided by FirstRanker.com ---
intervention trials of vitamin E and -carotene have
general y shown increased mortality among those
--- Content provided by FirstRanker.com ---
taking the supplements? at higher concentrations of oxygen carotin is an
autocatalytic pro-oxidant
--- Content provided by FirstRanker.com ---
? Vitamin E forms a stable radical penetratingfurther into lipoproteins and tissues, so
increasing radical damage.
--- Content provided by FirstRanker.com ---
? Radicals are important in cel signaling for
apoptosis of DNA damaged cel s
--- Content provided by FirstRanker.com ---
? high concentrations of antioxidants, may quenchthe signaling radicals, so increasing, the risk of
cancer development.
--- Content provided by FirstRanker.com ---
MCQ 1
? Which one of the following is NOT a source of
--- Content provided by FirstRanker.com ---
oxygen radicals?A. Action of superoxide dismutase
B. Activation of macrophages
C. Nonenzymic reactions of transition metal ions
--- Content provided by FirstRanker.com ---
D. Reaction of -carotene with oxygenE. Ultraviolet radiation
MCQ 2
? Which one of the following best explains the antioxidant action
--- Content provided by FirstRanker.com ---
of vitamin E?
A. It forms a stable radical that can be reduced back to active
--- Content provided by FirstRanker.com ---
vitamin E by reaction with vitamin C.B. It is a radical, so that when it reacts with another radical a
nonradical product is formed.
--- Content provided by FirstRanker.com ---
C. It is converted to a stable radical by reaction with vitamin C.
D. It is lipid soluble and can react with free radicals in the blood
--- Content provided by FirstRanker.com ---
plasma resulting from nitric oxide (NO) formation by vascularendothelium.
E. Oxidized vitamin E can be reduced back to active vitamin E by
--- Content provided by FirstRanker.com ---
reaction with glutathione and glutathione peroxidase.