Egzersiz ve Üç Tip Diyetle İndüklenen Ülseratif Kolitten Korunma Modelinin Böbrek ve Karaciğer Üzerindeki Histopatolojik İncelenmesi Apoptoz ve Otofaji İndeksleri

Öz

Egzersiz, bireylerin sağlığının korunması ve geliştirilmesinde, çeşitli sitokinlerin, hormonların, büyüme faktörlerinin ve oksidatif stresin konsantrasyonunu etkileyen bir tür fizyolojik strestir. Ek olarak egzersiz, karbonhidratlar ve serbest yağ asitleri gibi yüksek miktarlardaki substratları harekete geçirerek ve metabolize ederek enerji dengesini etkiler. Tüm bu faktörlerin potansiyel olarak apoptoza veya otofaji ile hücresel hayatta kalmaya aracılık ettiği bilinmektedir. İlk kez grubumuz tarafından farklı beslenme uygulamaları (yüksek karbonhidrat (YK+kolit), yüksek protein (YP+kolit) ve yüksek yağlı (YY+kolit) beslenme), yüzme egzersizi ile kombine edilmiş ve egzersizin ülseratif kolit koruyucu etkisi ortaya konmuştur. Yapılan çalışma sonucunda bu çalışmada egzersiz ile farklı diyet bileşenlerinin (YP+kolit, YY+kolit ve YK+kolit) uygulanması sonucu ortaya çıkan metabolik ilişkinin karaciğer, böbrek enzimleri ile sağlığı nasıl etkilediği sorusuna yanıt aranmıştır. Bu çalışmada farklı diyet bileşenlerinin ve egzersizin, karaciğer ve böbrek üzerindeki etkisinin histopatolojik ve biyokimyasal analizler ile ortaya konması amaçlanmıştır. Sonuçlar değerlendirildiğinde tüm grupların karaciğer dokularında portal alan merkezinde mikroveziküler steatoz gözlenmiş ancak egzersiz sonrası gruplar arasında anlamlı azalışlar bulunmuştur. Tüm grupların böbrek histopatolojisi değerlendirildiğinde glomerüler alan, hiyalin madde birikimi, interstisyel inflamasyon, medüller konjesyon ve kortikal konjesyon açısından gruplar arasında anlamlı fark bulunmamıştır. Böbrek histopatolojisinde YP+kolit gruplarında Bowman aralığında artış istatistiksel olarak anlamlı bulunmuştur. Apoptoz (kaspaz 3 ve kaspaz 9) ve otofaji belirteçleri (p62 ve LC3B) immünaktiviteleri egzersiz gruplarında daha yüksek bulunmuştur. YP+kolit, YY+kolit ve YK+kolit gruplarında ALT, AST ve ALP değerlerinin arttığı ancak egzersiz gruplarında düşüş olduğu gözlemlenmiştir. Tüm sonuçlar değerlendirildiğinde E+YK+kolit grubu serum ALT, AST, ALP, BUN, kreatinin, albümin değerleri ve histopatolojisi ile kontrole en yakın grup olarak bulunmuştur.

Anahtar Kelimeler

• apoptoz
• kaspaz 3
• kaspaz 9
• otofaji
• p62
• LC3b
• sıçan
• karaciğer
• böbrek
• yağ
• karbonhidrat ve protein yönünden zengin diyet.

Histopathological Analysis of Kidney and Liver in the Prevention Model of Exercise and Three Types of Diet-Induced Ulcerative Colitis

Öz

Exercise is a type of physiological stress that has an impact on the concentration of different cytokines, hormones in the maintenance and enhancement of people's health. Exercise also influences energy balance by metabolizing large quantities of substrates. For the first time, our lab's combination of high carbohydrate (HC+colitis), high protein (HP+colitis) and high fat (HF+colitis) nutrition with swimming exercise showed a protective effect against the onset of ulcerative colitis. As a consequence of the investigation, an answer to the question of how the metabolic relationship brought about by the application of exercise and various dietary components impacts liver and kidney enzymes and health was sought in this study. Microvesicular steatosis was discovered in the liver tissues of all groups when the data were analyzed, however there were statisticaly significant differences between the groups following exercise. There was no discernible change in the groups kidney histology when the glomerular area, hyaline material deposition, interstitial inflammation, medullary congestion, cortical congestion were assessed. When comparing the HP+colitis groups, a statistically significant increase in Bowman's distance was seen in the kidney histology. The exercise groups had greater levels of immunoactivity for the apoptosis and autophagy markers. In contrast to the exercise groups, it was seen that the ALT, AST, and ALP values rose in the HP+colitis, HF+colitis, and HC+colitis groups. When all the data were analyzed, it was discovered that the E+HC+colitis group had serum ALT, AST, ALP, BUN, creatinine, albumin levels, and histopathology that were the most similar to the control group.

Anahtar Kelimeler

• apoptosis
• cleave caspase 3
• cleave caspase 9
• autophagy
• p62
• LC3b
• rat
• liver
• kidney
• diet rich in fat
• carbohydrates and protein.

Kaynakça

1. 1. Warburton DER, Nicol CW, Bredin SSD. Health benefits of physical activity: the evidence, CMAJ : Canadian Medical Association Journal, 2006, 174(6): 801.
2. 2. Physical activity, https://www.who.int/news-room/fact-sheets/detail/physical-activity (accessed 8 Apr2023).
3. 3. Berryman JW. The art of medicine: Motion and rest: Galen on exercise and health, The Lancet, 2012, 380(9838): 210–211.
4. 4. Ruegsegger GN, Booth FW. Health Benefits of Exercise, Cold Spring Harb Perspect Med, 2018, 8(7): a029694.
5. 5. Exercise and well-being: a review of mental and physical hea... : Current Opinion in Psychiatry, https://journals.lww.com/co-psychiatry/Abstract/2005/03000/Exercise_and_well_being__a_review_of_mental_and.13.aspx (accessed 8 Apr2023).
6. 6. Murphy MH, Blair SN, Murtagh EM. Accumulated versus continuous exercise for health benefit: A review of empirical studies, Sports Medicine, 2009, 39(1): 29–43.
7. 7. Elmagd MA. Benefits, need and importance of daily exercise, International Journal of Physical Education, Sports and Health, 2016, 3(5): 22–27.
8. 8. Seldin MM, Peterson JM, Byerly MS, Wei Z, Wong GW. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis, Journal of Biological Chemistry, 2012, 287(15): 11968–11980.

9. 9. Otaka N, Shibata R, Ohashi K, Uemura Y, Kambara T, Enomoto T et al. Myonectin is an exercise-induced Myokine that protects the heart from ischemia-reperfusion injury, Circ Res, 2018, 123(12): 1326–1338.
10. 10. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease, Nat Rev Immunol, 2011, 11(9): 607–610.
11. 11. O’Gorman DJ, Krook A. Exercise and the Treatment of Diabetes and Obesity, Medical Clinics of North America, 2011, 95(5): 953–969.
12. 12. Jacob N, Novaes JS, Behm DG, Vieira JG, Dias MR, Vianna JM. Characterization of Hormonal, Metabolic, and Inflammatory Responses in CrossFit® Training: A Systematic Review, Front Physiol, 2020, 11(August). doi:10.3389/fphys.2020.01001.
13. 13. Feito Y, Patel P, Redondo AS, Heinrich KM. Effects of eight weeks of high intensity functional training on glucose control and body composition among overweight and obese adults, Sports, 2019, 7(2). doi:10.3390/sports7020051.
14. 14. Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L. Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease, J Am Med Dir Assoc, 2016, 17(9): 789–796.
15. 15. Wolfe RR. The underappreciated role of muscle in health and disease, 2018, (February): 475–482.
16. 16. Meyer C, Dostou JM, Welle SL, Gerich JE. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis, Am J Physiol Endocrinol Metab, 2002, 282(2 45-2): 419–427.
17. 17. Mooren FC, Krüger K. Exercise, Autophagy, and Apoptosis, Prog Mol Biol Transl Sci, 2015, 135: 407–422.
18. 18. Mooren FC, Krüger K. Exercise, Autophagy, and Apoptosis, Prog Mol Biol Transl Sci, 2015, 135: 407–422.
19. 19. Farré JC, Subramani S. Mechanistic insights into selective autophagy pathways: Lessons from yeast, Nat Rev Mol Cell Biol, 2016, 17(9): 537–552.
20. 20. Walter KM, Schönenberger MJ, Trötzmüller M, Horn M, Elsässer HP, Moser AB, Lucas MS, Schwarz T, Gerber PA, Faust PL, Moch H, Köfeler HC, Krek W, Kovacs WJ. Hif-2α Promotes degradation of mammalian peroxisomes by selective autophagy, Cell Metab, 2014, 20(5): 882–897.
21. 21. Wang X, Li S, Liu Y, Ma C. Redox regulated peroxisome homeostasis, Redox Biol, 2015, 4: 104–108.
22. 22. da Rocha AL, Pinto AP, Morais GP, Marafon BB, Rovina RL, Veras ASC, Teixeira GR, Pauli JR, de Moura LP, Cintra DE, Ropelle ER, Rivas DA, da Silva ASR. Moderate, but not excessive, training attenuates autophagy machinery in metabolic tissues, Int J Mol Sci, 2020, 21(22): 1–21.
23. 23. Rocchi A, He C. Regulation of Exercise-Induced Autophagy in Skeletal Muscle, Curr Pathobiol Rep, 2017, 5(2): 177–186.
24. 24. Rusten TE, Stenmark H. P62, an autophagy hero or culprit?, Nat Cell Biol, 2010, 12(3): 207–209.
25. 25. Ichimura Y, Komatsu M. Selective degradation of p62 by autophagy, Semin Immunopathol, 2010, 32(4): 431–436.
26. 26. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy*[S], Journal of Biological Chemistry, 2007, 282(33): 24131–24145.
27. 27. Komatsu M, Waguri S, Koike M, Sou Y shin, Ueno T, Hara T et al. Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice, Cell, 2007, 131(6): 1149–1163.
28. 28. Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Øvervatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death, Journal of Cell Biology, 2005, 171(4): 603–614.
29. 29. Zhu Y, Zhao L, Liu L, Gao P, Tian W, Wang X, Jin H, Xu H, Chen Q. Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis, Protein Cell, 2010, 1(5): 468–477.
30. 30. Allan LA, Clarke PR. Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation, FEBS Journal, 2009, 276(21): 6063–6073.
31. 31. Gobatto CA, De Mello MAR, Sibuya CY, De Azevedo JRM, Dos Santos LA, Kokubun E. Maximal lactate steady state in rats submitted to swimming exercise, Comparative Biochemistry and Physiology - A Molecular and Integrative Physiology, 2001, 130(1): 21–27.
32. 32. Jean C, Rome S, Mathé V, Huneau JF, Aattouri N, Fromentin G, Achagiotis CL, Tomé D. Metabolic Evidence for Adaptation to a High Protein Diet in Rats, J Nutr, 2001, 131(1): 91–98.
33. 33. Gray RS, Olefsky JM. Effect of a glucosidase inhibitor on the metabolic response of diabetic rats to a high carbohydrate diet, consisting of starch and sucrose, or glucose, Metabolism, 1982, 31(1): 88–92.
34. 34. Gollisch KSC, Brandauer J, Jessen N, Toyoda T, Nayer A, Hirshman MF, Goodyear LJ. Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats, Am J Physiol Endocrinol Metab, 2009, 297(2): 495–504.
35. 35. E. Renata Fabia; R. Willén; A. Ar’Rajab; R. Andersson; B. Ahrén; S. Bengmark. Acetic Acid-Induced Colitis in the Rat: A Reproducible Experimental Model for Acute Ulcerative Colitis, European Surgical Research, 1992, 24((4)): 211–215.
36. 36. Elbaz EM, Essam RM, Ahmed KA, Safwat MH. Donepezil halts acetic acid-induced experimental colitis in rats and its associated cognitive impairment through regulating inflammatory/oxidative/apoptotic cascades: An add-on to its anti-dementia activity, Int Immunopharmacol, 2023, 116. doi:10.1016/J.INTIMP.2023.109841.
37. 37. Elmansy RA, Seleem HS, Mahmoud AR, Hassanein EHM, Ali FEM. Rebamipide potentially mitigates methotrexate-induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study, Anatomical Record, 2021, 304(3): 647–661.
38. 38. Elmansy RA, Seleem HS, Mahmoud AR, Hassanein EHM, Ali FEM, Turlin B et al. Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats, Anatomical Record, 2009, 39(3): 1122–1131.
39. 39. Turlin B, Ramm GA, Purdie DM, Lainé F, Perrin M, Deugnier Y, Macdonald GA. Assessment of hepatic steatosis: Comparison of quantitative and semiquantitative methods in 108 liver biopsies, Liver International, 2009, 29(4): 530–535.
40. 40. Akcan G, Alimogullari E, Abu-Issa R, Cayli S. Analysis of the developmental expression of small VCP-interacting protein and its interaction with steroidogenic acute regulatory protein in Leydig cells, Reprod Biol, 2020, 20(1): 88–96.
41. 41. Juraschek SP, Appel LJ, Anderson CAM, Miller ER. Effect of a high-protein diet on kidney function in healthy adults: Results from the omniheart trial, American Journal of Kidney Diseases, 2013, 61(4): 547–554.
42. 42. Cuenca-Sánchez M, Navas-Carrillo D, Orenes-Piñero E. Controversies surrounding high-protein diet intake: Satiating effect and kidney and bone health, Advances in Nutrition, 2015, 6(3): 260–266.
43. 43. Jenkins DJA, Kendall CWC, Vidgen E, Augustin LSA, Van Erk M, Geelen A, Parker T, Faulkner D, Vuksan V, Josse RG, Leiter LA, Connelly PW. High-protein diets in hyperlipidemia: Effect of wheat gluten on serum lipids, uric acid, and renal function, American Journal of Clinical Nutrition, 2001, 74(1): 57–63.
44. 44. van Elswyk ME, Weatherford CA, McNeill SH. A systematic review of renal health in healthy individuals associated with protein intake above the US recommended daily allowance in randomized controlled trials and observational studies, Advances in Nutrition, 2018, 9(4): 404–418.
45. 45. Pierre Amarenco, Julien Bogousslavsky, Alfred Callahan 3rd, Larry B Goldstein, Michael Hennerici, Amy E Rudolph, Henrik Sillesen, Lisa Simunovic, Michael Szarek, K M A Welch, Justin A Zivin SP by AR in CL (SPARCL) I. Comparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates, New England Journal of Medicine, 2011, 365: 687–696.
46. 46. Ko GJ, Rhee CM, Kalantar-Zadeh K, Joshi S. The effects of high-protein diets on kidney health and longevity, Journal of the American Society of Nephrology, 2020, 31(8): 1667–1679.
47. 47. Rouhani MH, Najafabadi MM, Esmaillzadeh A, Feizi A, Azadbakht L. Direct association between high fat dietary pattern and risk of being in the higher stages of chronic kidney disease, https://doi.org/101024/0300-9831/a000260, 2019, 89(5–6): 261–270.
48. 48. Friedman AN. High-protein diets: Potential effects on the kidney in renal health and disease, American Journal of Kidney Diseases, 2004, 44(6): 950–962.
49. 49. Kamper AL, Strandgaard S. Long-Term Effects of High-Protein Diets on Renal Function, Annu Rev Nutr, 2017, 37(June): 347–369.
50. 50. Granqvist AB, Ericsson A, Sanchez J, Tonelius P, William-Olsson L, Dahlqvist U, Andersson AK, Tomic TT, Hudkins K, Alpers CE, Pellegrini G, Söderberg M. High protein diet accelerates diabetes and kidney disease in the BTBR ob/ob mouse, Am J Physiol Renal Physiol, 2020, 318(3): F763–F771.
51. 51. Skov AR, Toubro S, Bülow J, Krabbe K, Parving HH, Astrup A. Changes in renal function during weight loss induced by high vs low-protein low-fat diets in overweight subjects, Int J Obes, 1999, 23(11): 1170–1177.
52. 52. Kalantar-Zadeh K, Fouque D. Nutritional Management of Chronic Kidney Disease, New England Journal of Medicine, 2017, 377(18): 1765–1776.
53. 53. Hashim K, Chin K. The Mechanism of Kelulut Honey in Reversing Metabolic Changes in Rats Fed with High-Carbohydrate High-Fat Diet, Molecules, 2023, : 28.
54. 54. Tay J, Thompson CH, Luscombe-Marsh ND, Noakes M, Buckley JD, Wittert GA, Brinkworth GD. Long-Term effects of a very low carbohydrate compared with a high carbohydrate diet on renal function in individuals with type 2 diabetes: A randomized trial, Medicine (United States), 2015, 94(47): e2181.
55. 55. Juszczak F, Vlassembrouck M, Botton O, Zwakhals T, Decarnoncle M, Tassin A, Caron N, Declèves AE. Delayed exercise training improves obesity-induced chronic kidney disease by activating ampk pathway in high-fat diet-fed mice, Int J Mol Sci, 2021, 22(1): 1–20.
56. 56. De Castro UGM, Dos Santos RAS, Silva ME, De Lima WG, Campagnole-Santos MJ, Alzamora AC. Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats, Lipids Health Dis, 2013, 12(1): 1–11.
57. 57. Park S, Kim CS, Lee J, Kim JS, Kim J. Effect of Regular Exercise on the Histochemical Changes of D-Galactose-Induced Oxidative Renal Injury in High-Fat Diet-Fed Rats, Acta Histochem Cytochem, 2013, 46(4): 111–119.
58. 58. Díaz-Rúa R, Keijer J, Palou A, van Schothorst EM, Oliver P. Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats, J Nutr Biochem, 2017, 46: 39–48.
59. 59. Liu Y, Lu Q, Xi L, Gong Y, Su J, Han D, Zhang Z, Liu H, Jin J, Yang Y, Zhu X, Xie S. Effects of Replacement of Dietary Fishmeal by Cottonseed Protein Concentrate on Growth Performance, Liver Health, and Intestinal Histology of Largemouth Bass (Micropterus salmoides), Front Physiol, 2021, 12: 2308.
60. 60. Mashmoul M, Azlan A, Mohtarrudin N, Mohd Yusof BN, Khaza’ai H, Khoo HE, Farzadnia M, Boroushaki MT. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats, BMC Complement Altern Med, 2016, 16(1): 1–7.
61. 61. French WW, Dridi S, Shouse SA, Wu H, Hawley A, Lee SO, Gu X, Baum JI. A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats, Nutrients 2017, Vol 9, Page 587, 2017, 9(6): 587.
62. 62. Romano N, Fischer H, Rubio-Benito MM, Overtuf K, Sinha AK, Kumar V. Different dietary combinations of high/low starch and fat with or without bile acid supplementation on growth, liver histopathology, gene expression and fatty acid composition of largemouth bass, Micropterus salmoides, Comp Biochem Physiol A Mol Integr Physiol, 2022, 266: 111157.
63. 63. Younossi ZM, Corey KE, Lim JK. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review, Gastroenterology, 2021, 160(3): 912–918.
64. 64. Exercise-induced leukocyte apoptosis - PubMed, https://pubmed.ncbi.nlm.nih.gov/24974724/ (accessed 8 Apr2023).
65. 65. Jamart C, Benoit N, Raymackers JM, Kim HJ, Kim CK, Francaux M. Autophagy-related and autophagy-regulatory genes are induced in human muscle after ultraendurance exercise, Eur J Appl Physiol, 2012, 112(8): 3173–3177.
66. 66. Jamart C, Francaux M, Millet GY, Deldicque L, Frère D, Féasson L. Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running, J Appl Physiol, 2012, 112(9): 1529–1537.
67. 67. Chun SK, Lee S, Yang MJ, Leeuwenburgh C, Kim JS. Exercise-Induced Autophagy in Fatty Liver Disease, Exerc Sport Sci Rev, 2017, 45(3): 181.