Says about most important free radicals and main physiologic roles of free radicals(on transduction and transcriptional gene factors), about stress oxidative , effects of stress oxidative on some common cochlear anthologies and its related processes

1. Stress Oxidative
And its role in cochlea

2. Free Radicals
 Having free electrons
 Contain high energy and they can damage tissues and cells
 At physiological concentrations : essential for cell normalization
(signaling and redox regulation)
 In high concentrations : Very strong tendency to react with other
molecules and thus cause damage to lipids, DNA and proteins
and alteration signal transduction

3. Free Radicals
ROS and RNS Sources (reactive oxygen/nitrogen species) :
 Gamma rays and UV- rays
 Catalytic reactions of metals
 By neutrophils, macrophages during inflammation
 By-product of electron transfer reactions in mitochondria
 Products within the phagosome

4. Free radicals formation
O2˚-, H2O2, NO, OH, ONOO-, HOCL

5. Super Oxide (O2˚-)
Formation:
Fenton:

6. Hydrogen peroxide(H2O2)

7. Hydroxyl radical(OH)

8. Nitric oxide(NO)

9. Physiologic roles of free radicals
 Against infections
 Regulation of transcription factor activity
 Intracellular signaling

10. Against infections
 phagocytes are activated
 Decompositions of bacteria by Produced ROS
 O2 Super Oxide (O2˚-) H2O2
OH HOCL
SOD
NADPH
MPO

12. Physiologic roles of free radicals
 Against infections
 Regulation of transcription factor activity
 Intracellular signaling

13. ROS can affect transduction and carcinogens
proteins like:
 c- Mitogen Activated Protein Kinas (MAPK-c)
 Collagenase
 tyrosine kinase
ROS are physiological mediators of transcriptional
control:
 NF-κB )nuclear factor kappa-light-chain-enhancer of
activated B cells
 AP-1 : activator protein 1

14. Regulation of signaling factor activity
 Changing the transduction and signaling………….. MAPKs
 Changing the expression level of gene
 Affect cell proliferation or apoptosis

17. ERK, JNK and P38
 ERK:
• Cell survival, under special circumstances response can lead to
apoptosis
• Cell survival ,rapid and transient action of ERK
• Apoptosis as a result of slow and sustained activity of ERK
 JNK and P38 :
• Activated by ROS……………cellular apoptosis
• Normal redox……….. Non activated………………inhibition of apoptotic ki
kinases ………. Inhibition of apoptosis

18. ROS can affect transduction and carcinogens proteins like:
 c- Mitogen Activated Protein Kinas (MAPK-c)
 Collagenase
 tyrosine kinase
ROS are physiological mediators of transcriptional
control:
 NF-κB )nuclear factor kappa-light-chain-enhancer of
activated B cells
 AP-1 : activator protein 1

19.  Phosphorylation of JNK activation of JNK
affect transcriptional factor of AP1 transcription of AP1 gene
 AP1: is a transcription factor
regulates gene expression in response to a variety of
stimuli, including cytokines, growth factors, stress,
and bacterial and viral infections
controls a number of cellular processes including
differentiation, proliferation, and apoptosis.
AP1

21.  NF-κB transcription antiapoptotic
 NFkB: contribution in various processes includes
inflammation and growth control and apoptosis
NF-kB

22. Regulation of transcription factor activity

23. oxidative stress is thought to be involved in
the development of:
 ADHD, cancer, Parkinson's disease,Alzheimer's disease,
atherosclerosis heart failure, myocardial infarction
 fragile X syndrome, autism, infection, chronic fatigue
syndrome, and depression,Asperger syndrome
 Short-term oxidative stress may also be important in
prevention of aging by induction of a process named
mitohormesis

24. Free radicals and oxidative damage to
macromolecule

25. Free radicals and oxidative damage to
macromolecule
 free radicals and oxidative damage of DNA
Hydroxyl radical attacks a C-8 –position of Guanin
Chemical alteration in DNA(Cross Protein link, oxidation of
purines…)
mutagenic
 free radicals and oxidative damage of Lipids

26.  Free radicals and oxidative damage of proteins
Lateral chain of all amino acids in proteins especially
cysteine and methionine are prone to oxidation
fragmentation, loss of enzymatic activity, changing cell
function and changing type and amount of cellular proteins

27. Oxidative Stress in the Cochlea

28. Stress oxidative and Aminoglycoside
(1)
 Aminoglycosides interfere with phosphoinositides
metabolism, particularly phosphatidylinositol-
biphosphate (PIP2)
 by binding to their polar head
 This binding induces sequestration of PIP2 and therefore
inhibits PIP2-dependent processes ,including the reduction
of phosphatidylinositol-trisphosphate (PIP3) formation and
the inhibition of the survival activities of the PIP3/Akt
signalling pathway

29. AKT plays an important role in several cellular
processes such as glucose metabolism, apoptosis,
cell growth, genetic transcription, and cell
migration.

30. Stress oxidative and Aminoglycoside
(2)
 activate iNOS producing NO
 Nitric oxide has been suggested to be involved in hair cell
death

31. Stress oxidative and Aminoglycoside
(3)
 ROS subsequently activate apoptotic or necrotic
intracellular pathways
 Activate the JNK pathway leading to hair cell apoptosis

32. Stress oxidative and Aminoglycoside
(4)
 Loss of spiral ganglion neurons as a consequence of loss of
hair cells
 lipid peroxidation products that act as mediators of
apoptosis

33. Stress oxidative and Cisplatin

34. Stress oxidative and Cisplatin
 O2 production
 NOX isoform…………………activating the pro-apoptotic
pathway
 Bcl2 protein ……………….. mitochondrial release of
cytochrome c

36. Stress oxidative and Noise trauma
 increased levels of O2- ,OH- and RNS(NO-,…)
 Markers of lipid peroxidation have been demonstrated in
the hair cells, supporting cells, spiral ganglion neurons
and stria vascularis after noise trauma
 activation of JNK and p38MAPK, the release of cytochrome
c from the mitochondria……………pathway of apoptosis

37. Stress oxidative and presbycusis
 Decrease of antioxidant defenses such as glutathione level
in the auditory nerve or antioxidant enzymes in the organ
of Corti and spiral ganglion neurons
 Markers of oxidative and nitrosative stress are present in
the organ of Corti and spiral ganglion of ageing mice

38. References:
 The role of oxidative stress and free radicals in
diseases,2020
 The Role of Oxidative Stress in Proliferation and Cell
Death,2015
 Oxidative stress: development and progression of breast
cancer: review article ,April 2017
 Oxidative Stress in the Cochlea: An Update, 2010
 The role of mitochondrial oxidative stress in hearing
loss,2017
 Increased Oxidative Stress, Inflammation, and Glutamate:
Potential
 Preventive and Therapeutic Targets for Hearing Disorders