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Title Page 1
Contents 6
Abstract 17
Graphic abstract 19
Abbreviations 20
Ⅰ. Introduction 23
A. Literature Review 23
1. Cancer cachexia and its related metabolism 23
2. Beta-carotene 32
3. Gut microbiota 36
4. Organoid 39
B. Hypothesis 42
Ⅱ. Study 1. Beta-carotene suppresses early cancer cachexia by regulating the adipose tissue metabolism and gut microbiota dysregulation 43
A. Introduction 43
B. Materials and Methods 45
1. Cancer cahceixa mouse model 45
2. Histological analysis 46
3. Serum IL-6, TNF-α and non-esterified fatty acid measurement 46
4. Gut microbiota analysis 46
5. Cell culture and reagents 48
6. CT26 and L-WRN conditioned medium collection 48
7. Differentiation of pre-adipocytes 49
8. Colon cancer organoid culture 50
9. Go-culture system of preadipocytes and colon cancer organoids 51
10. Immunofluorescent staining 51
11. Lipid accumulation measurements 52
12. RNA extraction and RT-qPCR 52
13. Metabolic characteristic measurements 53
14. Lactate, glucose uptake and ATP measurement 54
15. Statistical Analysis 56
C. Results 57
1. Effects of BC on the cachectic phenotypes in CT26 cancer-cachexia mouse model 57
2. Effects of BC on the lipolysis, fat browning, systemic inflammation and hepatic gluconeogenesis in CT26 cancer-cachexia mouse model 65
3.1. Isolation of patient-derived colon cancer organoids 73
3.2. Effects of BC on BODIPY staining in human preadipocytes co-cultured with colon cancer organoids 75
3.3. Effects of BC on mRNA expressions of adipogenesis-related markers in human preadipocytes co-cultured with colon cancer organoids 77
4. Effects of BC on adipogenesis in adipocytes existing in the cancer cachexia condition 79
5. Effects of BC on regulation of energy metabolism in adipocytes existing in the cancer cachexia condition 83
6. Effects of BC on regulation of energy metabolism in colon cancer cells 91
7. Effects of BC on gut microbiota diversity and structure in CT26 cancer-cachexia mouse model and the correlation between microbial profile and cancer cachectic observations 99
D. Discussion 111
Ⅲ. Study 2. BC suppresses late cancer cachexia by regulating the muscle atrophy and PI3K/Akt pathway 123
A. Introduction 123
B. Materials and Methods 126
1. Cancer cachexia mouse model 126
2. Assessment of grip strength 126
3. RNA extraction and RT-qPCR 127
4. Western blotting 127
5. ELISA assay 129
6. Hematoxylin & Eosin (H&E) Staining 129
7. Cell culture and reagents 129
8. LLC conditioned medium (CM) collection 129
9. Differentiation and LLC CM treantment of C2C12 myoblasts 129
10. Myotube length assessment 130
11. Cell viability assay 130
12. Statistical Analysis 130
C. Results 132
1. Effects of BC on the cachectic phenotypes in LLC cancer-cachexia mouse model 132
2. Effects of BC on muscle atrophy in gastrocnemius muscle in LLC-induced cancer cachexia mouse model 144
3. Effects of BC on myogenesis and muscle atrophy in myotubes existing in the cancer cachexia condition 152
D. Discussion 160
Ⅳ. General discussion 165
Ⅴ. General conclusion 167
Bibliography 168
Appendices 16
Appendix 1. Summary of analyzed 16S rRNA gene sequence information 187
Appendix 2. PCoA plot of the bacterial community using weighted UniFrac distance 188
Appendix 3. Spearman's rank correlation analysis showing relationships between measured values of selected features at the genus level 189
Appendix 4. Effects of BC on food intake in CT26 cancer-cachexia mouse model 190
Appendix 5. Effects of BC on food intake in LLC cancer-cachexia mouse model 191
국문초록 192
Figure 1. Effects of BC on body and organ weights in CT26 cancer-cachexia mouse model 58
Figure 2. Effects of BC on tumor volume in CT26 cancer-cachexia mouse model 60
Figure 3. Effects of BC on the size of subcutaneous fat cells in CT26 cancer-cachexia mouse model 64
Figure 4. Effects of BC on lipolysis in subcutaneous fats of cancer-cachexia mouse model 66
Figure 5. Effects of BC on fat browning in subcutaneous fats of cancer-cachexia mouse model 68
Figure 6. Effects of BC on hepatic gluconeogenesis of cancer-cachexia mouse model 70
Figure 7. Effects of BC on systemic inflammation in cancer-cachexia mouse model 72
Figure 8. Isolation of patient-derived colon cancer organoids 74
Figure 9. Effects of BC on BODIPY staining in human preadipocytes co-culture with colon cancer organoids 76
Figure 10. Effects of BC on mRNA expressions of adipogenesis-related markers in human preadipocytes co-culture with colon cancer organoids 78
Figure 11. Effects of BC on Oil Red 0 staining assay in 3T3-L1 cells treated with CT26 CM 80
Figure 12. Effects of BC on mRNA expressions of adipogenesis-related markers in 3T3-L1 cells treated with CT26 CM 82
Figure 13. Effects of BC on mitochondrial basal respiration in 3T3-L1 cells treated with CT26 CM 84
Figure 14. Effects of BC on glycolysis in 3T3-L1 cells treated with CT26 CM 86
Figure 15. Effects of BC on OCR/ECAR ratio in in 3T3-L1 cells treated with CT26 CM 88
Figure 16. Effects of BC on ATP production, lactate excretion, and glucose uptake in 3T3-L1 cells treated with CT26 CM 90
Figure 17. Effects of BC on mitochondrial basal respiration in HCT116 colon cancer cells 92
Figure 18. Effects of BC on glycolysis in HCT116 colon cancer cells 94
Figure 19. Effects of BC on OCR/ECAR ratio in HCT116 colon cancer cells 96
Figure 20. Effects of BC on ATP production, lactate, excretion, and glucose uptake in HCT116 colon cancer cells 98
Figure 21. Effects of BC on gut microbiota alpha diversity in CT26 cancer-cachexia mouse model 100
Figure 22. Effects of BC on gut microbiota beta diversity in CT26 cancer-cachexia mouse model 102
Figure 23. Effects of BC on the relative abundances of specific gut microbiota in CT26 cancer-cachexia mouse model 105
Figure 24. Effects of BC on the correlation between the diversity/structure of fecal microbiota and cancer cachectic observations in CT26 cancer-cachexia mouse model 107
Figure 25. Effects of BC on the analysis of the KEGG pathways in CT26 cancer-cachexia mouse model 110
Figure 26. Effects of BC on the tumor volume in LLC cancer-cachexia mouse model 133
Figure 27. Effects of BC on the body, organ weights, and food intake in LLC cancer-cachexia mouse model 135
Figure 28. Effects of BC on grip strenght in LLC cancer-cachexia mouse model 137
Figure 29. Effects of BC on the systemic inflammation in LLC cancer-cachexia mouse model 139
Figure 30. Effects of BC on hepatic gluconeogenesis in LLC cancer-cachexia mouse model 141
Figure 31. Effects of BC on myofiber size distribution in gastrocnemius muscle of LLC-induced cancer cachexia mouse model 145
Figure 32. Effects of BC on mRNA levels of the muscle atrophy-related marker in gastrocnemius muscle of LLC-induced cancer cachexia mouse model 147
Figure 33. Effects of BC on mRNA levels of the muscle stem cell-related marker in gastrocnemius muscle of LLC-induced cancer cachexia mouse model 149
Figure 34. Effects of BC on protein expressions of the PI3K/Akt pathway in gastrocnemius muscle of LLC-induced cancer cachexia mouse model 151
Figure 35. Effects of BC on the length and transverse diameter of myotube in C2C12 myoblasts treated with LLC CM 153
Figure 36. Effects of BC on the cell viability in C2C12 myoblasts treated with LLC CM 155
Figure 37. Effects of BC on myogenesis and muscle atrophy-related markers in C2C12 myoblasts treated with LLC CM 157
Figure 38. Effects of BC on the levels of pro-inflammatory cytokines in C2C12 myoblasts treated with LLC CM 159
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