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Toxicology of Nitric Oxide and Oxygen Radicals
 
April 10 - 13
Coordinators: João Laranjinha and Rafael Radi

Lecturers:
 
 
Rafael Radi, MD, PhD
 
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avda. General Flores 2125, 11800 Montevideo, Uruguay.
 
 
Lab. Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias.
 
Universidad de la República, Iguá 4225, 11400 Montevideo, URUGUAY
 
 
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Avda. General Flores 2125, 11800 Montevideo, Uruguay.
 
AIM
The course will focus in the biochemistry of nitric oxide and oxygen free radicals and the chemical and toxicological mechanisms by which these transient species participate in the pathophysiology of various disease states including inflammation, vascular degeneration and neuronal death. Methodologies for measurement of nitric oxide, nitric oxide-derived oxidants and oxygen free radicals in vitro and in vivo will be presented in experimental activities. Post-translational modifications in proteins such as tyrosine nitration and the formation and biological actions of nitrated lipids will be analyzed. Novel pharmacological strategies to cope against toxicological effects of excess nitric oxide and oxygen free radicals will be presented.
 
 
Program description
CONFERENCES (two per morning)
1.
Biological formation and reactions of nitric oxide and oxygen free radicals. (RR)
2.
Antioxidant mechanisms in mammalian tissues (HR)
3.
Nitric Oxide partition and diffusion across biological compartments (AD)
4.
Protein nitrosylation and nitration: biochemical mechanisms and functional consequences (RR)
5.
Lipid oxidation and nitration: biochemical mechanisms and functional consequences (HR)
6.
Kinetics of free radical reactions with target molecules (AD)
7.
Peroxynitrite formation and drug-induced toxicity (AD)
8.
Nitric oxide, lipids and inflammation (HR)
 
 
SEMINARS (discussion/presentation of two related papers per afternoon. The students will be provided with the papers in advance)
1.
Free Radical/Nitric Oxide kinetics and diffusion in biological systems
2.
Nitric oxide-derived oxidants-induced toxicity
3.
On the biological formation and role of nitrated lipids
4.
Pharmacological strategies against nitric oxide-derived oxidants
 
 
EXPERIMENTAL SESSION
 
Superoxide radical reaction with nitric oxide: peroxynitrite formation, oxidation and nitration reactions  (with the collaboration of Joao Laranjinha).
 
Friday seminar
 
FINAL PLENARY CONFERENCE (includes students + Faculty):   Nitric Oxide-derived oxidants, mitochondria and apoptotic signaling (Rafael Radi)
COURSE SCHEDULE:
 
 
April 10, Monday
9:00 - 12:30
CONFERENCES
 
1) Biological formation and reactions of nitric oxide and oxygen free radicals (RR)
 
2) Antioxidant mechanisms in mammalian tissues: Nitric oxide as a major endogenous lipophilic antioxidant (HR)
 
3) Diffusion of  nitric oxide and oxygen radicals across biological compartments (AD)
 
 
14:00-18:00
EXPERIMENTAL SESSION 1a (group A) (AD, HR, RR)
 
EXPERIMENTAL SESSION 2 (group B) (JL)
 
 
April 11, Tuesday
9:00 - 12:30
CONFERENCES
 
4) Protein nitrosylation and nitration: biochemical mechanisms and functional consequences (RR)
 
5) Lipid oxidation and nitration: biochemical mechanisms and  functional consequences (HR)
 
6) Peroxynitrite formation and drug-induced toxicity (AD)
 
 
14:00-18:00
EXPERIMENTAL SESSION 1b (group A) (AD, HR, RR)
 
FREE TIME FOR SEMINAR PREPARATION (group B)
 
April 12, Wednesday
9:00 - 9:45
CONFERENCE
 
7) Nitric oxide, lipids and inflammation (HR)
10:00-12:30
SEMINARS 1-2, 3-4 (group B)
 
 
14:00-18:00
EXPERIMENTAL SESSION 1a (group B) (AD, HR, RR)
 
FREE TIME FOR SEMINAR PREPARATION (group A)
 
April 13, Thursday
9:00 - 9:45
CONFERENCE
 
8) Pharmacological strategies against nitric oxide-and oxygen derived oxidants (AD)
10:00-12:30
SEMINARS 5-6, 7-8 (group A)
 
 
14:00-18:00
EXPERIMENTAL SESSION 1b (group B) (AD, HR, RR)
 
EXPERIMENTAL SESSION 2 (group A) (JL)
18:00-19:00
FINAL PLENARY CONFERENCE
 
9) Nitric Oxide-derived oxidants, mitochondria and apoptotic signaling (RR)
 
 
 
Notes:
Groups A and B mean 6 students each.
 
Experimental session 1a and 1b: Nitric oxide and peroxynitrite detection, oxidation and nitration reactions.
 
Experimental session 2: Direct measurement of nitric oxide in brain tissue
SEMINARS (discussion of four related papers per morning)
 
 
On Peroxynitrite diffusional properties in biological membranes:
 
 
On nitric oxide diffusion and partition into LDL:
 
 
On the biological formation and roles of nitrated lipids:
 
 
On kinetic aspects and biological relevance of nitration:
 
 
 
SUPLEMENTAL REVIEWS:
 
Rubbo H and Radi R.  Antioxidant properties of nitric oxide.  In: Handbook of Antioxidants: Biochemical, Nutritional and Clinical aspects, 2nd Edition. E. Cadenas and L. Packer eds. Marcel Dekker Inc., New York, 32, 689-706, 2001.
 
 
Rubbo H, Botti H, Batthyány C, Trostchansky A, Denicola A and Radi R. Antioxidant and diffusion properties of nitric oxide in LDL. Meth Enzymol 359, 200-209, 2002.
 
 
 
 
Relevant Publications
Rubbo H, Radi R, Anselmi D, Kirk, Barnes S, Buttler J, Eiserich JP and Freeman B (2000) Nitric oxide reaction with lipid peroxyl radicals spares alfa-tocopherol during lipid peroxidation. J. Biol. Chem.275, 10812-10818.
Denicola A, Souza JM and Radi R (1998) Diffusion of peroxynitrite across erythrocyte membranes. Proc. Natl. Acad. Sci. USA. 95, 3566-3571.
 

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