Investigation of DNA damage and inflammatory marker profile in patients after bariatric surgery

Year 2024, Volume: 17 Issue: 2, 255 - 263, 01.04.2024

Tugba Sarı , Sevda Yılmaz , Muhammed Raşid Aykota , Selda Şimşek , İbrahim Açıkbaş , Buket Er Urgancı

https://doi.org/10.31362/patd.1408756

Abstract

Purpose: Obesity is a significant risk factor in the development of many serious diseases. The most prominent ones among them are diabetes and coronary heart disease. Elevated blood sugar levels in obese individuals lead to increased susceptibility to infections due to the suppression of the immune response. Moreover, fatty skin folds can cause topical infections, ulcers, and delayed/impaired wound healing. Therefore, inflammatory and pro-inflammatory markers in the serum have gained importance in diseases such as diabetes and obesity. Furthermore, in obesity, reactive oxygen species (ROS) lead to DNA damage. 8-oxo-dG, which is the primary product of DNA oxidation, can be detected in the serum, saliva, and urine, making it an ideal biological marker for DNA damage in large population-based studies. The Comet assay analysis is a method used to demonstrate the double-strand breaks in DNA. Induction of γ-H2AX in tissue indicates the initiation of a well-regulated mechanism to reverse double-strand breaks in DNA. Potential benefits of monitoring the genomic health in obesity include creating a sense of urgency for personalized intervention measures and evaluating their progress. DNA damage in obesity is believed to be a reversible condition. Chronic inflammation is an etiological factor known to support DNA damage and neoplastic transformations in cells. Cytokines secreted from adipose tissue, especially TNF-alpha, IL-6, and IL-1β, promote the accumulation of various cells, including neutrophils, macrophages, and dendritic cells, and it indicates the initiation of an inflammatory process. In this project, it was aimed to investigate possible changes in inflammation markers and DNA damage in individuals undergoing bariatric surgery, who were beginning to improve endocrine and metabolic syndrome markers.
Materials and methods: For this purpose, blood and urine samples were collected from 45 obese patients, who had undergone bariatric surgery and 45 healthy volunteers matched for age and gender. The levels of inflammatory markers (IL-1β, IL-6, IL-8, and TNF-α) and the DNA damage marker γ-H2AX in serum, as well as the amount of 8-oxo-dG in urine, were determined using ELISA. Additionally, the percentage of DNA damage was determined using the Comet assay analysis.
Results: Weight control achieved through bariatric surgery and the subsequent reduction in fat tissue resulted in a significant decrease in the levels of γ-H2AX and 8-oxo-dG, as well as a parallel significant reduction in the percentage of DNA damage in the Comet assay results. The significant decrease in inflammatory markers IL-1β, IL-6, IL-8, and TNF-α levels indicated that bariatric surgery also affects inflammation indirectly.
Conclusion: Although there are numerous studies in the literature on individual parameters related to DNA damage in various diseases and obesity, it is believed that the present study determining DNA damage, oxidation, and repair mechanisms simultaneously with inflammatory marker levels serves as a guiding example for comparing genomic health and stability in pre-obese, post-obese, and non-obese individuals.

Keywords

Obesity, DNA damage, inflammation, bariatric surgery

Obezite ameliyatı sonrası hastaların DNA hasarı ve inflamatuar marker profilinin araştırılması

Abstract

Amaç: Obezite, birçok ciddi hastalığın gelişmesinde önemli bir risk faktörüdür. Bunlar arasında en büyük payı diyabet ve koroner kalp hastalıkları oluşturmaktadır. Yüksek kan şekeri immün yanıtı baskıladığından obezlerde enfeksiyona yatkınlık artmaktadır. Ayrıca yağlı deri katlantıları topikal enfeksiyon, ülser ve gecikmiş-bozulmuş yara iyileşmesi sorunlarına neden olmaktadır. Bu nedenle diyabet ve obezite gibi hastalıklarda serumdaki inflamatuar ve pro-inflamatuar markerlar önem kazanmıştır. Ayrıca obezitede reaktif oksijen türleri (ROS), DNA hasarına neden olur. DNA oksidasyonunun başlıca ürünü olan 8-oxo-dG serum, tükürük ve idrarda tespit edilebilir, bu da büyük popülasyon bazlı çalışmalar için ideal bir DNA hasarı biyolojik belirleyicisidir. Komet assay analizi DNA çift zincir kırıklarının gösterilmesi için kullanılan bir yöntemdir. Dokuda γ-H2AX indüksiyonu, DNA'nın çift iplik kırıklarının tersine çevrilmesi için iyi düzenlenmiş bir mekanizmanın başladığını göstermektedir. Obezitede genom sağlığını izlemenin potansiyel faydaları, kişiselleştirilmiş müdahale önlemlerinin aciliyetini oluşturmak ve ilerlemelerini değerlendirmek için önemlidir. Obezitedeki DNA hasarının, geri dönüşümlü bir durum olduğu düşünülmektedir. Kronik inflamasyon, DNA hasarı ve hücrelerde neoplastik dönüşümlerin destekleyicisi olarak bilinen bir etiyolojik faktördür. Adipoz dokudan salgılanan sitokinler, özellikle TNF-alfa, IL-6 ve IL-1β, nötrofiller, makrofajlar ve dendritik hücreler dahil olmak üzere çeşitli hücrelerin toplanmasını teşvik eder ve bu da inflamatuar bir sürecin başladığını göstermektedir. Biz bu proje ile obezite operasyonu ile endokrin ve metabolik sendrom belirteçleri düzelmeye başlayan bireylerde inflamasyon markerları ve DNA hasarı üzerine olası değişimlerini araştırmayı amaçladık.
Gereç ve yöntem: Bu amaçla 45 adet obezite ameliyatı geçirmiş hasta ve bu hastalarla yaş ve cinsiyet açısından uyumlu olan 45 adet sağlıklı gönüllüden kan ve idrar örnekleri alınmıştır. İnflamatuar marker IL-1β, IL-6, IL-8 ve TNF-α ve DNA hasar markerı γ-H2AX’in serum miktarı ve ayrıca idrarda 8-oxo-dG miktarı ELISA ile tespit edilmiştir. Komet assay analizi ile de DNA hasar yüzdesi tespit edilmiştir.
Bulgular: Obezite ameliyatı ile sağlanan kilo kontrolü ve dolayısı ile yağ dokusundaki azalma, DNA hasarı üzerinde γ-H2AX ve 8-oxo-dG miktarının azalması ve buna paralel olarak komet assay sonuçlarında da DNA hasar yüzdesinin anlamlı derecede azalması ile sonuçlanmıştır. İnflamasyon markerları IL-1β, IL-6, IL-8 ve TNF-α miktarlarının anlamlı derecede azalması obezite ameliyatının dolaylı olarak inflamasyon üzerine de etkili olduğunu göstermiştir.
Sonuç: Literatürde DNA hasarına ilişkin tekil parametrelerle ilgili birçok hastalıkta ve obezitede çalışma bulunmakla birlikte, DNA hasarının, oksidasyonunun ve tamir mekanizmasının belirlenmesi ve inflamasyon markerlarının da eş zamanlı seviyelerinin belirlenmesi sayesinde genom sağlığı ve stabilitesinin obezite öncesi, sonrası ve non-obez bireylerde karşılaştırılması açısından çalışmamızın yol gösterici olduğunu düşünmekteyiz.

Keywords

Obezite, DNA hasarı, inflamasyon, obezite ameliyatı

References

• 1. Hall JE. Guyton & Hall physiology review. Elsevier Health Sciences, 2020.
• 2. WHO. Obesity and Overweight. 2021. Available at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed December 26, 2023
• 3. Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight loss in adults. Cochrane Database Of Systematic Reviews 2014:8. https://doi.org/10.1002/14651858.CD003641.pub4
• 4. Karnak İ. Obezite tedavisinde cerrahinin yeri. Katkı Pediatri Dergisi 2000;21:554-573.
• 5. Sungurtekin U. Obezitenin cerrahi tedavisi. Cerrahinin ilkeleri. Branicordi FC, et al. (Eds. Çev. Geçim İE, Demirkan A). İstanbul: Tarlan Ltd. Şti, 2008:1040-1045.
• 6. Menenakos E, Stamou KM, Albanopoulos K, Papailiou J, Theodorou D, Leandros E. Laparoscopic sleeve gastrectomy performed with intent to treat morbid obesity: a prospective single-center study of 261 patients with a median follow-up of 1 year. Obes Surg 2010;20:276-282. https://doi.org/10.1007/s11695-009-9918-3
• 7. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 1996;313:17-29. https://doi.org/10.1042/bj3130017
• 8. Monzo Beltran L, Vazquez Tarragón A, Cerdà C. One-year follow-up of clinical, metabolic and oxidative stress profile of morbid obese patients after laparoscopic sleeve gastrectomy. 8-oxo-dG as a clinical marker. Redox Biology 2017;12:389-402. https://doi.org/10.1016/j.redox.2017.02.003
• 9. Hofer T, Karlsson H L, Möller L. DNA oxidative damage and strand breaks in young healthy individuals: a gender difference and the role of life style factors. Free Radic Res 2006;40:707-714. https://doi.org/10.1080/10715760500525807
• 10. Kobayashi J. Molecular mechanism of the recruitment of NBS1/hMRE11/hRAD50 complex to DNA double-strand breaks: NBS1 binds to gamma-H2AX through FHA/BRCT domain. J Radiat Res 2005;45:473-478. https://doi.org/10.1269/jrr.45.473
• 11. Eyluel Bankoglu E, Seyfried F, Arnold C. Reduction of DNA damage in peripheral lymphocytes of obese patients after bariatric surgery-mediated weight loss. Mutagenesis 2017;33:61-67. https://doi.org/10.1093/mutage/gex040
• 12. Usman M, Volpi E V. DNA damage in obesity: Initiator, promoter and predictor of cancer. Mutation Research-Reviews in Mutation Research 2018;778:23-37. https://doi.org/10.1016/j.mrrev.2018.08.002
• 13. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 2014;1842:446-462. https://doi.org/10.1016/j.bbadis.2013.05.017
• 14. Jeong SKI, Seo MW, Kim YH, Kweon SS, Nam HS. Does waist indicate dyslipidemia beter than BMI in Korean adult population?. J Korean Med Sci 2005;27:7-12. https://doi.org/10.3346/jkms.2005.20.1.7
• 15. Askarpour M, Khani D, Sheikhi A, Ghaedi E, Alizadeh S. Effect of bariatric surgery on serum inflammatory factors of obese patients: a systematic review and meta-analysis. Obesity Surgery 2019;29:2631-2647. https://doi.org/10.1007/s11695-019-03926-0
• 16. Wlodarczyk M, Jablonowska Lietz B, Olejarz W, Nowicka G. Anthropometric and dietary factors as predictors of DNA damage in obese women. Nutrients 2018;10:578. https://doi.org/10.3390/nu10050578
• 17. Zaki M, Basha W, El Bassyouni HT, El Toukhy S, Hussein T. Evaluation of DNA damage profile in obese women and its association to risk of metabolic syndrome, polycystic ovary syndrome and recurrent preeclampsia. Genes Dis 2018;5:367-373. https://doi.org/10.1016/j.gendis.2018.03.001
• 18. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006;295:1539-1548. https://doi.org/10.1001/jama.295.13.1539
• 19. Puglisi MJ, Fernandez ML. Modulation of C-reactive protein, tumor necrosis factor-alpha, and adiponectin by diet, exercise, and weight loss. J Nutr 2008;138:2293-2296. https://doi.org/10.3945/jn.108.097188
• 20. Chen J. Multiple signal pathways in obesity-associated cancer. Obes Rev 2011;12:1063-1070. https://doi.org/10.1111/j.1467-789X.2011.00917.x
• 21. Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann NY Acad Sci 2011;1229:45-52. https://doi.org/10.1111/j.1749-6632.2011.06096.x
• 22. Riso P, Pinder A, Santangelo A, Porrini M. Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage? Am J Clin Nutr 1999;69:712-718.
• 23. Nemzer B, Chang T, Xie Z, Pietrzkowski Z, Reyes T, Ou B. Decrease of free radical concentrations in humans following consumption of a high antioxidant capacity natural product. Food Sci Nutr 2014;2:647-654. https://doi.org/10.1002/fsn3.146
• 24. Boeing H, Dietrich T, Hoffmann K, et al. Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: The prospective EPIC-study. Cancer Causes Control 2006;17:957-969. https://doi.org/10.1007/s10552-006-0036-4
• 25. Mullner E, Brath H, Pleifer S, et al. Vegetables and PUFA-rich plant oil reduce DNA strand breaks in individuals with type 2 diabetes. Mol Nutr Food Res 2013;57:328-338. https://doi.org/10.1002/mnfr.201200343
• 26. Włodarczyk M, Nowicka G. Obesity, DNA damage, and development of obesity-related diseases. Int J Mol Sci 2019;20:1146. https://doi.org/10.3390/ijms20051146
• 27. Bukhari SA, Rajoka MI, Ibrahim Z, Jalal F, Rana SM, Nagra SA. Oxidative stress elevated DNA damage and homocysteine level in normal pregnant women in a segment of Pakistani population. Mol Biol Rep 2011;38:2703-2710. https://doi.org/10.1007/s11033-010-0413-7
• 28. Sancar A. Excision repair in mammalian cells. J Biol Chem 1995;270:15915-15918. https://doi.org/10.1074/jbc.270.27.15915 29. Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI. Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS ONE 2013;8:e54059. https://doi.org/10.1371/journal.pone.0054059
• 30. Pazmandi K, Agod Z, Kumar BV, et al. Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. Free Radic Biol Med 2014;77:281-290. https://doi.org/10.1016/j.freeradbiomed.2014.09.028
• 31. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 2003;112:1796-1808. https://doi.org/10.1172/JCI19246
• 32. Gao CL, Zhu C, Zhao YP, et al. Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol 2010;320:25-33. https://doi.org/10.1016/j.mce.2010.01.039
• 33. Heo JW, No MH, Park DH, et al. Effects of exercise on obesity-induced mitochondrial dysfunction in skeletal muscle. Korean J Physiol Pharmacol 2017;21:567-577. https://doi.org/10.4196/kjpp.2017.21.6.567
• 34. Setayesh T, Nersesyan A, Mišík M, et al. Impact of obesity and overweight on DNA stability: Few facts and many hypotheses. Mutat Res Rev Mutat 2018;777:64-91. https://doi.org/10.1016/j.mrrev.2018.07.001
• 35. Andreassi MG, Barale R, Iozzo P, Picano E. The association of micronucleus frequency with obesity, diabetes and cardiovascular disease. Mutagenesis 2011;26:77-83. https://doi.org/10.1093/mutage/geq077
• 36. Tyson J, Spiers A, Caple F, et al. Effects of age, body mass index and genotype on nucleotide excision repair in healthy adults. P Nutr Soc 2006;114. https://doi.org/10.1017/S002966510600526X
• 37. Azzarà A, Pirillo C, Giovannini C, Federico G, Scarpato R. Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents. Mutat Res Fund Mol M 2016;789:9-14. https://doi.org/10.1016/j.mrfmmm.2016.05.001