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Title
DECLARATION
CERTIFICATE
ACKNOWLEDGEMENT
CONTENTS
1 Introduction and Review of Literature
1.1 Introduction
1.2 Review of Literature
1.2.1 Causes of cancer
a. Tobacco.
b. Alcohol
c. Occupational hazards
d. Environmental pollution
e. Ultra violet (UV) radiation
f. Medications
g. Viruses
h. Diet and nutrition
i. Genetic susceptibility
j. Ionizing radiation
Mechanism of radiation induced damage
Fig. 1 Development of Radiation Injury
Direct and indirect damage by ionizing radiation
Radiation tolerance of normal tissues
1.2.2. Biological factors influencing radiosensitivity
a. Intrinsic radiosensitivity
b. Repair of cellular damage
c. Repopulation by tumour cells.
d. Reoxygenation during the course of irradiation
e. Redistribution of cells in the cell cycle.
1.2.3. Effects of radiation on normal tissues.
1.2.4. Effect of radiation on haemopoietic tissues
1.2.5. Effects of ionizing radiation on DNA
1.2.6. Radiation and the cell cycle.
1.2.7. Radiation induced mutagenesis
1.2.8. Radiation induced carcinogenesis
1.2.9. Role of oncogenes on radiation induced cancer
1.2.10. Role of tumor suppressor genes in radiation inducedcarcinogenesis.
1.2.11. Effect of chemotherapy on normal tissues
1.2.12. Radioprotectors and chemoprotectors
1.2.13. Protection of tissue oxidative damage
Table 1 Free Radical Mediated Diseases
Fig. 2 Mechanisms of formation of reactive oxygen species
Fig. 3 Sources of Oxidative Damage
1.2.14. Antioxidant Defense System
Fig. 4 Antioxidant Defense System
1.2.14.a. Enzymatic antioxidants (endogenous)
1. Superoxide dismutase (SOD)
2. Glutathione peroxidase (GPX)
3. Catalase (CAT)
4. Glutathione reductase (GR)
5. Glutathione - S - transferase (GST)
1.2.14.b. Non-enxymatic nutrient antioxidant (endogeltous)
1. Glutathione (GSH)
Fig. 5 Antioxidant Roles of the Glutathione System (Meister, 1981)
1.2.14.c. Non-enzymatic nutrient antioxidants (exogenous)
a. Natural antioxidants
1.Vitamin E (a- tocopherol)
2. Selenium
3. Vitamin C (ascolbic acid)
4. Vitamin A and p- carotene
5. Polyphenols
b. Synthetic antioxidants
1. Butylated hydroxy anisole (BHA) and htrtylated hydroxy toluene (BHT)
2.Mercaptoalkylamines
1.2.14.d. Non - nutrient antioxidants
Table 2 Non-Nutrient Antioxidants
1.2.15. Biological response modifiers (BRMs)
Table 3 Major Cytokines and Their Antitumour Properties
1.2.16. lmmunomoduIators from plant sources
Table 4 Plant lmmunomodulators with Anticancer Activity
Table 5 composition of Brahma Rasayana (BR) and mode ofpreparation (Vaidya Jadavaji Trikanji Acharya, 1981)
2 Antioxidant Activity of Brahma Rasayana, In vitro and In vivo
2.1. Introduction
2.2. Materials And Methods
2.2.1.Determination of antioxidant activity of BrahmaRasayana (BR) in oitro
2.2.1.a. Effect of BR on inhibition of lipid peroxide formationinduced by ferrous Fez+ - ascorbate system
2.2.1.b. Effect of BR on inhibition of lipid peroxide formationinduced by femc Fe3+- adenosine diphosphate (ADP) - ascorbate system
2.2.1.c. Hydroxyl radical scavenging activity of BR
2.2.1.d. Effect of BR on inhibition of superoxide radical generation
2.2.1.e. Effect of BR on inhibition of nitric oxide radical generation
2.2.1.f. Effect of BR on inhibition of nitrite production in miceperitoneal macrophages
2.2.2. Determination of antioxidant activity of BrahmaRasayana in viuo
2.2.2.a. Effect of BR on nitrite production in mice peritonealmacrophages
2.2.2.b. Effect of BR on PMA induced superoxide generation inmice peritoneal macrophages
2.2.3. Antiinflammatory Activity of Brahma Rasayana (BR)
2.3. Statistical Analysis
2.4. Results
2.4.1. Antioxidant activity of Brahma Rasayana (BR) In vitro
2.4.l.a. lnhibition of lipid peroxidation induced by Fe 2+. ascorbate system by BR
2.4.l.b. Inhibition of lipid peroxidation induced by Fe 3+ - ADPascorbatesystem by BR
Fig. 6 Effect of Brahma Rasayana (BR) on Lipid Perxidation
Fig. 7 Time Course of Inhibition of Brahma Rasayana (BR) on Lipid PeroxideFormation Induced by ~ e- A~scor bate System
2.4.l.c. lnhlbition of hydroxyl radical by BR
2.4.1.d. lnhibition of superoxide radical by BR
2.4.1.e. lnhibition of nitric oxide radical by BR
2.4.1.f. Inhibition of nitrite production in mice peritoneal macrophagesby BR.
2.4.2. Antioxidant activity of Brahma Rasayana (BR) in uiuo
2.4.2.a. Inhibition of nitrite production in mice peritonealmacrophages by BRTable 6 represent
Fig. 8 Effect of Brahrna Rasayana (BR) on Inhibition of Hydroxyl Radical Generation Inducedby Fenton Reaction
Fig. 9 Effect of Brahma Rasayana (BR) on Inhibition of Superoxide RadicalGeneration
2.4.2.b. Inhibition of PMA induced superoxide generation in miceperitoneal macrophages by BR
2.4.3. Antiinflammatory activity of Brahma Rasayana (BR)
2.5. Discussion
Table 7 Effect of Brahma Rasayana (BR) on PMA inducedsuperoxide generation (in vivo) in mice peritonealmacrophages.
3 Role of Brahma Rasayana on Antioxidant Systems in Normal Mice and Mice Treated Radiation
3.1. Introduction
3.2. Materials And Methods
3.2.1.Estimation of liver superoxide dismutase (SOD) activity (Mc Cord and Fridovich, 1969)
3.2.2. Estimation of liver catalase (CAT) activity (Aebi, 1983)
3.2.3. Estimation of liver and serum glutathione (GSH) activity (Moron 1979)
3.2.4. Estimation of liver glutathione peroxidase (GPX) acitivity (Hafemann 1974)
3.2.5. Estimation of blood glutathione peroxidase (GPX) activity (Paglia and Valentine, 1967)
3.2.6. Estimation of cytosolic glutathtione reductase (GR) activity (Racker, 1955)
3.2.7. Estimation of cytosolic glutathione-S-transferase (GST) activity (Habig 1974)
3.2.8. Estimation of serum lipid peroxidation (Yagi. 1984)
3.2.9.Estimation of liver lipid peroxidation (0hkawa et 01, 1979)
3.3. Statistical Analysis
3.4. Results
3.4.1. Effect of BR on liver superoxide dismutase (SOD) and catalase (CAT) activity in normal and irradiated mice.
3.4.2. Effect of BR on serum and liver glutathione (GSH) level innormal and irradiated mice.
Fig. 14 Effect of Brahma Rasayana (BR) on Liver Superoxide Dismutase (SOD) Activityin Normal and Irradiated Mice
3.4.3. Effect of BR on blood and liver glutathione peroxidase (GPX) activity in normal and irradiated mice
3.4.4. Effect of BR on cytosolic liver glutathione -Stransferase (GST) and glutathione reductase (GR) activity in normal and irradiated mice
3.4.5. Effect of BR on serum and liver lipid peroxidation (LP) innormal and irradiated mice.
3.4.6. Effect of B& on serum and liver alkaline phosphatase (ALP) level in normal and irradiated mice.
3.4.7. Effect of BR on serum and liver glutamate pyruvatetransaminase (GPT) activity in normal and irradiated mice.
3.5. Discussion
4 Effect of Brahma Rasayana in Amelioration of Radiation induced Damage
4.1. Introduction
4.2. Materials and Methods
Fig. 26 Effect of Brahrna Rasayana (BR) on Total Leukocyte Count andDifferential Count in Irradiated Mice
4.2.1.Effect of BR on haematological parameters in normaland irradiated mice.
4.2.2.Effect of BR on body weight, organ weight, bonemarrow cellularity and cr - esterase activity in normal andirradiated mice.
4.2.3. Determination of effect of BR on spleen colony assay
4.2.4. Effect of BR on cytokine production in normal andirradiated mice.
4.3. Statistical Analysis
4.4. Results
4.4.1. Effect of BR on total white blood cells (WBC) andpercent of polymorphonuclear (PMN) cells in normal andirradiated mice.
4.4.2. Effect of BR on body weight, organ weight, bonemarrowcellularity and a- esterase activity in normaland irradiated mice
4.4.3. Effect of BR on spleen colony assay
4.4.4. Effect of BR on cytokine levels in normal andirradiated mice.
4.5. Discussion
5 Effect of Brahma Rasayana on Antioxidant Systems and Cytokine Level in Mice Treated with Cyclophosphamide
5.1. Introduction
5.2. Materials and Methods
5.2.1. Animals
5.2.2 Determination of effect of BR on cytokine production
5.3. Statistical analysis
5.4. Results
5.4.1.Effect of BR on liver superoxide dismutase (SOD) andcatalase (CAT) a~tivity in cyclophosphamide (CTX) treatedmice
5.4.2. Effect of BR on serum and liver glutathione (GSH) level in CTX treated mice
5.4.3. Effect of BR on blood and liver glutathione peroxidase (GPX) activity in CTX treated mice
5.4.4. Effect of BR on liver cytosolic glutathione Stransferase (GST) and glutathione reductase (GR) in CTXtreated mice.
5.4.5. Effect of BR on serum and liver lipid peroxidation inCTX treated mice.
5.4.6.Effect of BP on serum and liver alkaline phosphatase (ALP) activity in CTX treated mice
5.4.7.Effect of BR on serum and liver glutamate pyruvatetransaminase (GPT) activity in CTX treated mice.
5.4.8. Effect of BR on cytokine production in CTX treatedmice
5.5. Discussion
6 Role of Brahma Rasayana in Immune Responses of Normal and Irradiated Mice
6.1. Introduction
6.2. Materials and Methods
6.2.1. Effect of BR on Daltons Lymphoma Ascitses (DLA) cells - in oitro short term cytotoxicity assay
6.2.2. Effect of BR on lung fibroblast (L-929) cells inpresence and absence of serum in vitro (MTT assay)
6.2.3. Effect of BR on [3H]-thymidine uptake of PHAstimulated and non stimulated thymus, spleen and bonemarrow cells of mice, in vitro
6.2.4.Effect of BR on [3H] thymidine uptake of thymus, spleen and bonemarrow cells of normal and irradiated mice (in vivo)
6.2.5.Effect of BR on circulating antibody titre in irradiatedmice
6.2.6.Effect of BR on antibody forming cells in normal andirradiated mice.
6.3. Statistical Analysis
6.4. Resulis
6.4.1. Effect of BR on Daltons lymphoma ascites (DLA) cells- in uitro short term cytotoxicity assay
6.4.2. Effect of BR on lung fibroblast (L-929) cells inpresence and absence of serum, in uitro (MTT assay)
6.4.3 Effect of BR on 13H]- thymidine uptake of PHAstimulated and non-stimulated thymus, spleen andbonemarrow cells of mice, in uitro
6.4.4.Effect of BR on [31j]th ymidine uptake of thymus spleenand bonemarrow cells of normal and irradiated mice, in uiuo
6.4.5.Effect of BR on circulating antibody titre in irradiatedmice.
6.4.6. Effect of BR on antibody forming cells in normal andirradiated mice.
6.5. Discussion
7 Anticlastogenic Activity of Brahma Rasayana
7.1 Introduction
7.2. Material and Methods
7.2.1. Effects of BR on radiation induced micronucleiformation
7.2.2. Effect of BR on radiation induced chromosomalaberrations (Bone marrow metaphase Analysis)
7.3. Statistical Analysis
7.4. Results
7.4.1.Effect of BR on radiation induced micronucleiformation
7.4.2.Effect of BR on radiation induced chromosomalaberrations
7.5. Discussion
Fig. 46 Effect of Brahma Rasayana (BR) on Micronuclei Formationand Chromosomal Aberrations in Irradiated Mice
a) Polychromatic erythrocytes with micronuclei
b) Normal metaphase chromosome
c) Aberrated metaphase chromosome
8 Summary and Conclusion
APPENDIX
8.2.1. Instruments
8.2.2.Preparation of posphate buffered saline (PBS, pH 7.2)
8.2.3. Preparation of Alsevers solution for SRBC collection
8.2.4. Preparation of scintillation fluid
8.2.5. Estimation of glutamate -pyruvate transaminase (GPT) activity (Bergmeyer and Bernt, 1980)
8.2.6. Estimation of alkaline phosphatase (ALP) activity (King and Armstrong, 1980)
8.2.7.Estimation of protein (Lowry 1951)
8.2.8.Determination of total count of lenkocytes (TC) (Cheesebrough and Mac. Arthur, 1976)
8.2.9.Turks fluid preparation
8.2.10. Determination of differential count of leukoytes (Cheesebrough and Mac. Arthur, 1976)
8.2.11. Leishmans stain preparation
8.2.12. Determination of bonemarrow cellularity (BMC)
8.2.13. Determination of alpha - naphthyl acetate esteraseactivity (azodye coupling method of Bancroft and Cook, 1984)
8.2.14.Determination of cytokines (IFN-y, IL-2 and GM-CSF) (Mouse EIisa Kits Endogen, USA)
8.2.15. Giemsa stain preparation
8.2.16. Statistical analysis
BIBILIOGRAPHY
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