Free Radical injury and acute phase reactants Basvatarakam indo american cancer hospital

1. Presentor Dr.Siddartha
Moderator : Dr.Daphne

2. A free radical can be defined as any molecular
species capable of independent existence that
contains an unpaired electron in an atomic
orbital.

3.  Free radicals and oxidants play a dual role as
both toxic and beneficial compounds.
 Many free radicals are unstable and highly
reactive. They can either donate an electron to
or accept an electron from other molecules,
therefore behaving as oxidants or reductants.

4.  Oxidative phosphorylation
 Absorption of radiant energy
 Inflammation
 Enzymatic metabolism of exogenous
chemicals or drugs
CCl4   .CCl3 (trichloromethyl
radical)

5.  Superoxide radical
 Hydrogen peroxide
 Hydroxy radical

6. O2 + e-  O2
-
This reaction is mediated by NADPH oxidase
= single electron reduction product of oxygen
Both anion and free radical

7.  Two electron reduction product is Hydrogen
peroxide
 O2
- + e-   H2O2
 From free radical reactants a non radical
product is formed, hence it is called
dismutation.

8.  Superoxide dismutase also catalyses the
above reaction.
 O2
- + O2
- + 2 H+  H2O2 + O2

9.  Three electron reduction product of oxygen
is hydroxy radical
 Most powerful free radical
 Produced by either Fenton reaction or Haber
weiss reaction

11. Peroxynitrite
 Peroxynitrite (ONOO-) is formed by the
interaction of two free radicals
 NO + O2- → ONOO- + ONOO-

12.  Cardiovascular
 Respiratory
 Kidney related
 Aging
 Neurological
 Carcinogenic
 Fetal

13. Free radicals
Endothelial injury
Atherogenesis
Lipid oxidation
Scavenger receptor
Foam cells

15. Oxidative stress – neurological diseases
including Alzheimer’s disease, Parkinson’s
disease, multiple sclerosis, amyotrophic
lateral sclerosis , memory loss, depression.

16.  The production of ß-amyloid, a toxic peptide
in Alzheimer’s patients’ brain, is due to
oxidative stress and plays an important role
in the neurodegenerative processes
 ALS – mutation in SOD-1 gene

17.  Denham Harman first proposed the free
radical theory of aging in the 1950s
 Oxidative damage initiated by ROS is a major
contributor of aging.

18.  The chain reaction caused by free radicals
can lead to cross-linking of atomic
structures.
 DNA cross linking can in turn lead to various
effects of aging, especially cancer.
 Cross-linking can occur between fat &
protein molecules - wrinkles.

19. Free radicals can cause DNA damage that leads
to mutation and carcinogenesis.
Both exogenous and endogenous ROS have
been shown to enhance proliferation of
cancer cells

20.  Oxidative stress plays a role in a variety of
renal diseases such as
 Glomerulonephritis
 Tubulointerstitial nephritis,
 Chronic renal failure,
 Proteinuria,
 Uremia

21.  Oxidative stress is involved in many
mechanisms in the development of fetal
growth restriction and pre-eclampsia
 In pregnancies complicated by pre-
eclampsia, increased expression of NADPH
oxidase 1 and 5 isoforms are seen.

25. The antioxidants acting in the defense systems
act at different levels such as
 Preventive – first line
 Radical scavenging – second line
 Repair and De-novo – third line

26. Types of anti oxidants
 Enzymatic and
 Non-enzymatic

28.  SOD
 Glutathione system
 Catalase

29.  Glutathione,
 Glutathione Reductase,
 Glutathione Peroxidases, And
 Glutathione S-transferases

31. SOD1 – Cytoplasm
SOD2 – Mitochondria
SOD3 – Extra cellular
SOD1 and SOD3 contain copper and zinc, while
SOD2 has Manganese in its reactive center.
O2
- + O2
- + 2 H+  H2O2 + O2

33.  High conc.are seen in liver

35.  = Ascorbic Acid
 Essential vitamin
 Free radical scavenger and interacts with
free radicals in both intra and intercellular
compartments
 It is essential for collagen, carnitine and
neurotransmitters biosynthesis
 Vitamin C is remarkably safe even in
enormously high doses

36. Citrus friuts

39.  Vit C generates Vit E from Tocopheroxyl
radical after neutralizing free radicals.
 RDA : 90 and 75 mg in male and female resp.
Vit C and cancer
 Suppress formation of carcinogens like
nitrosamines and quinones

40. Vit C and CVD
 Prevents oxidation of LDL
 Increases HDL levels
 Decreases total cholestrol levels
Vit C and cataracts
 Inverse realtionship

41.  Fat sol vitamin
 Total of 8 stereoisomers are seen
 α, β, γ,δ tocopherol & α, β, γ, δ tocotrienol.
 Only α-tocopherol is the most bioactive form
in humans
 Protects PUFA in cell membranes from
peroxidation
 RDA – 15 mg

44. Vit E and Cancer
 May cause regression of pre-malignant
lesions,
 Inhibits conversion of nitrites to nitrosamines
in the stomach
Vit E and CVD
 Prevents oxidation of LDL cholestrol
 Reduces the incidence of Angina
 Inhibits platelet aggregation and PG synthesis

45. Vit E and Eye
 Inactivate harmful free radicals and protein
splitting enzymes thus reducing chances of
cataract
Vit E and CNS
 Attenuate the progression of neurological
disorders like Parkinsons,Alzhiemers

46. Vit E and aging
 Through its anti oxidant action free radicals
are removed which are involved in damage
to DNA and RNA

47.  Grp of red orange and yellow pigments
 Inverse relation b/w cancer and carotenoids
 They include Beta carotene and lycopene
 Betacarotene is converted to retinol, which
is essential for vision.
 Strong antioxidant
 Best quencher of singlet oxygen.

48. Beta carotenoids and cataract
 Like vit C and E it also reduces the risk of
catarctogenesis.

49.  Lycopene, a carotenoid, possesses
antioxidant & antiproliferative properties
 Lycopene has been found to be very
protective,particularly for prostate cancer.

50.  Se is a trace mineral found in soil, water
vegetables (garlic, onion, grains, nuts,
soybean), sea food, meat, liver, yeast.
 It forms the active site of several antioxidant
enzymes including glutathione peroxidase.
 At low dose, health benefits of Se are
antioxidant, anti-carcinogenic &
immunomodulator
 Selenium is also necessary for the thyroid
function

51.  Flavonoids are polyphenolic compounds
present in most plants.
 Potent antioxidant activity

52. Essential long chain PUFA
And also in nut oils, flax seeds etc.,
Omega-3s may also increase activity of
antioxidant enzymes manufactured by the
body.

53.  =Ubiquinone
 Oil-soluble, vitamin-like substance
 Component of ETC.
 CoQ10 inhibits lipid peroxidation by
preventing the production of lipid peroxyl
radicals (LOO).
 In contrast to other, it inhibits both the
initiation and propagation of lipid and
protein oxidation.
 It also regenerates other antioxidants such as
vitamin E

55. The acute phase response is a prominent
systemic reaction of the organism to local
or systemic disturbances in its
homeostasis caused by infection, tissue
injury, trauma or surgery, neoplastic
growth or immunological disorders.

56.  Cytokines,
 Nitric oxide and
 Glucocorticoids
trigger and modulate the systemic
acute phase reaction and the hepatic acute
phase protein response

57.  Two types
Positive APP
Negative APP

58. 3 grps
  50%: Ceruloplasmin and C3 complement
  2-3 fold :- Haptoglobin, Fibrinogen, α-
globulins And LPS Binding Protein,
  5-1000 fold :- CRP and SAA

60.  Adheres to the “capsule” antigen of
pneumococcus
 1st found
 It binds - several microorganisms,
degenerating cells
 Activates complement by the classical
pathway, and acts as opsonin.

61.  Rises within a few hours.
 Peaks within 2-3 days.
 t1/2 -19 hours .
 Levels α inflammatory stimulus
 Normal levels < 0.2 mg/dl

63.  From liver
 Two roles
 Component of the common pathway of
coagulation.
 It takes part in the acute phase response
after tissue inflammation and damage
 Fibrinogen is also used as a disease activity
marker in Familial Mediterranean fever
 200-400 mg/dl

64.  It reflects the iron stores in the body.
 N values - 27-329 ng/ml for men
 - 9-125 ng/ml for women.
 It may increase as an acute phase response in
inflammation
 It increases in cases of liver damage and
malignancies also

65. Member of the apolipoprotein family.
During inflammation, it binds to HDL and alters
the cholesterol metabolism.
SAA effect the adhesion of phagocytic cells and
lymphocytes, and is responsible of their
chemotaxis.

66. Another serum amyloid protein is serum
amyloid P (SAP)
Pentameric structure.
It has a role in the inflammation process

67. Some of the APPs are fetal proteins normally
not found in large quantities in sera of adult
subjects,
α1-acid glycoprotein (AGP) one among them

68.  Some acute phase proteins have anti-
inflammatory properties.
 Haptoglobulin and hemopexin have
antioxidant properties, and have protective
roles against reactive oxygen species.
 Alpha 1-protease inhibitor and alpha 1-
chymotrypsin inhibit proteolytic enzymes

69.  Alpha 1-antichymotrypsin inhibits the
production of superoxide anions.
 Haptoglobulin helps wound healing by
stimulating angiogenesis

71.  Robbins and cotran
 Text book of medical biochem by Dinesh Puri
 Free Radicals, Antioxidants in Disease and Health
by Lien Ai Pham-Huy1, Hua He2, Chuong Pham-
Huy3
 Free radicals and antioxidants in health and
disease by Bagchi and Puri
 Acute Phase Reactants by Alpaslan
KILICARSLAN1*, [MD],Ayşegul UYSAL2, [MD] Emir
Charles ROACH3, [MD]
 Free radicals, antioxidants and functional foods:
Impact on human health by V. Lobo, A. Patil, A.
Phatak, and N. Chandra