Hesperidin Alleviates Cecal Ligation and Puncture-Induced Lung and Kidney Injuries

Abstract

ABSTRACT Objective: The potential useful features of hesperidin (Hes) was examined against lung and kidney injuries triggered by cecal ligation and puncture (CLP) in rats in current study. Materials and Methods: 32 Wistar Albino male rats were randomly allocated as sham, CLP, Hes 100 mg/kg and Hes 200 mg/kg groups. For the CLP process under anesthesia, the abdominal area was shaved and cleaned. The cecum was tied with a 4.0 suture and pierced by 18-gauge needle. Using this method, the experimental sepsis model was created. The lung and kidney tissues were removed at the end of the experiment. Biochemical and immunohistochemical analyzes were performed. Hes was administered by oral gavage at the doses of 100 and 200 mg/kg for 15 days. Results: Total oxidant status (TOS), malondialdehyde (MDA) and oxidative stress index (OSI) levels, myeloperoxidase (MPO) activity raised significantly while superoxide dismutase (SOD) and total antioxidant status (TAS) values declined in CLP group compared to sham group in lung and kidney tissues. On the contrary, SOD and TAS levels increased while MPO activity, TOS, OSI and MDA levels decreased due to Hes treatments. Caspase-3 and LC3B immunopositivity raised significantly in CLP group compared to sham group in lung and kidney tissues while decreased was observed in Hes treatment groups. Conclusion: In this study, in the light of our biochemical and immunohistochemical results that it has been detected that, Hes demonstrated an effective protection against CLP-induced lung and kidney tissue injuries in rats. Key Words: Sepsis, Hesperidin, Lung, Kidney, Oxidative stress, Autophagy

Keywords

• Sepsis
• Hesperidin
• Lung
• Kidney
• Oxidative stress
• Autophagy

Hesperidin, Çekal Ligasyonu ve Delinmeye Bağlı Akciğer ve Böbrek Yaralanmalarını Hafifletir

Öz

ÖZ Amaç: Bu çalışmada, sıçanlarda çekal ligasyon ve delme (CLP) ile tetiklenen akciğer ve böbrek hasarlarına karşı hesperidinin (Hes) potansiyel yararlı özellikleri incelenmiştir. Gereç ve Yöntemler: 32 adet Wistar Albino erkek rat rastgele olarak sham, CLP, Hes 100 mg/kg ve Hes 200 mg/kg gruplarına ayrıldı. Anestezi altında CLP işlemi için karın bölgesi tıraş edilerek temizlendi. Çekum 4,0 sütür ile bağlandı ve 18' lik iğne ile delindi. Bu metod kullanılarak deneysel sepsis modeli oluşturuldu. Deneyin sonunda akciğer ve böbrek dokuları çıkarıldı. Biyokimyasal ve immünohistokimyasal analizler yapıldı. Hes, 15 gün süreyle 100 ve 200 mg/kg dozlarında oral gavaj ile uygulandı. Bulgular: Sham grubu CLP grubu ile kıyaslandığında akciğer ve böbrek dokularında Total oksidan durum (TOS), malondialdehit (MDA) ve oksidatif stres indeksi (OSI) düzeyleri, miyeloperoksidaz (MPO) aktivitesi anlamlı olarak artarken süperoksit dismutaz (SOD) ve total antioksidan durum (TAS) değerleri azaldı. Bunun aksine, Hes tedavilerine bağlı olarak SOD ve TAS seviyeleri artarken MPO aktivitesi, TOS, OSI ve MDA seviyeleri azalmıştır. Sham grubu CLP grubu ile kıyaslandığında akciğer ve böbrek dokularında Kaspaz-3 ve LC3B immünopozitifliği anlamlı olarak artarken, Hes tedavi gruplarında azalma gözlendi. Sonuç: Bu çalışmada, sunduğumuz biyokimyasal ve immünohistokimyasal bulgularımız ışığında, Hes' in sıçanlarda CLP' ye bağlı akciğer ve böbrek dokusu hasarlarına karşı etkili bir koruma sağladığı belirlenmiştir. Anahtar Sözcükler: Sepsis, Hesperidin, Akciğer, Böbrek, Oksidatif stres, Otofaji

Anahtar Kelimeler

• Sepsis
• Hesperidin
• Akciğer
• Böbrek
• Oksidatif stres
• Otofaji

References

1. 1. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. Bmj 2007; 335(7625): 879-83.
2. 2. Russell JA. Management of sepsis. New Eng J Med 2006; 355(16):1699-713.
3. 3. Babayigit H, Kucuk C, Sozuer E, Yazici C, Kose K, Akgun H. Protective effect of beta-glucan on lung injury after cecal ligation and puncture in rats. Intensive Care Med 2005; 31(6): 865-70.
4. 4. Klosterhalfen B, Bhardwaj R. Septic shock. General Pharmacology: The Vascular System 1998; 31(1): 25-32.
5. 5. Chang B, Nishikawa M, Sato E, Utsumi K, Inoue M. L-Carnitine inhibits cisplatin-induced injury of the kidney and small intestine. Arch Biochem Biophys 2002; 405(1): 55-64.
6. 6. Kaymak C, Basar H, Sardas S. Reactive oxygen species (ROS) generation in sepsis. FABAD J Pharm Sci 2011; 36(1): 41-7.
7. 7. De Jong HK, Van Der Poll T, Wiersinga WJ. The systemic pro-inflammatory response in sepsis. J Innate Immun 2010; 2(5): 422-30.
8. 8. Garg A, Garg S, Zaneveld L, Singla A. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 2001; 15(8): 655-69.

9. 9. Ekinci Akdemir FN, Gulcin I, Karagoz B, Soslu R, Alwasel SH. A comparative study on the antioxidant effects of hesperidin and ellagic acid against skeletal muscle ischemia/reperfusion injury. J Enzyme Inhib Med Chem 2016; 31(4): 114-8.
10. 10. Garg A, Garg S, Zaneveld LJ, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res 2001; 15(8): 655-69.
11. 11. Jin MJ, Kim U, Kim IS, Kim Y, Kim D-H, Han SB, Kim DH, Kwon OS, Yoo HH. Effects of gut microflora on pharmacokinetics of hesperidin: a study on non-antibiotic and pseudo-germ-free rats. J Toxicol Environ Health, Part A. 2010; 73(21-22): 1441-50.
12. 12. Tanyeli A, Ekinci Akdemir FN, Eraslan E, Guler MC, Nacar T. Anti-oxidant and anti-inflamatuar effectiveness of caftaric acid on gastric ulcer induced by indomethacin in rats. Gen Physiol Biophys 2019; 38(2): 175-81.
13. 13. Ekinci Akdemir FN, Tanyeli A. The Antioxidant Effect of Fraxin against Acute Organ Damage in Polymicrobial Sepsis Model induced Cecal Ligation and Puncture. Turk J Sci 2019; 4(1): 22-9.
14. 14. Ohkawa H, Ohishi N, Yagi K. Assay for Lipid Peroxides in Animal-Tissues by Thiobarbituric Acid Reaction. Anal Biochem 1979; 95(2): 351-8.
15. 15. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 1982; 78(3): 206-9.
16. 16. Sun Y, Oberley LW, Li Y. A Simple Method for Clinical Assay of Superoxide-Dismutase. Clin Chem 1988; 34(3): 497-500.
17. 17. Neviere RR, Cepinskas G, Madorin WS, Hoque N, Karmazyn M, Sibbald WJ, Kvietys PR. LPS pretreatment ameliorates peritonitis-induced myocardial inflammation and dysfunction: role of myocytes. Am J Physiol 1999; 277(3): 885-92.
18. 18. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, Iwashyna TJ. Hospital deaths in patients with sepsis from 2 independent cohorts. Jama 2014; 312(1): 90-2.
19. 19. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. Jama 2014; 311(13): 1308-16.
20. 20. Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, Pérez, XL, Sirvent JM, Group ES. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Res Critical Care Med 2009; 180(9): 861-6.
21. 21. Husak L, Marcuzzi A, Herring J, Wen E, Yin L, Capan DD, Cernat G. National analysis of sepsis hospitalizations and factors contributing to sepsis in-hospital mortality in Canada. Healthcare quarterly (Toronto, Ont) 2010; 13: 35-41.
22. 22. Angus DC, van der Poll T. Severe sepsis and septic shock. New Eng J Med 2013; 369(21): 2063.
23. 23. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Critical Care Med 2003; 31(4): 1250-6.
24. 24. Munford RS. Severe sepsis and septic shock: the role of gram-negative bacteremia. Annu Rev Pathol 2006; 1: 467-96.
25. 25. Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock (Augusta, Ga) 2000; 13(2): 110-6.
26. 26. Wichterman KA, Baue AE, Chaudry IH. Sepsis and septic shock--a review of laboratory models and a proposal. J Surg Res 1980; 29(2): 189-201.
27. 27. Howell GM, Gomez H, Collage RD, Loughran P, Zhang X, Escobar DA, Billiar TR, Zuckerbraun BS, Rosengart MR. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PloS one 2013; 8(7): 69520.
28. 28. Zhang X, Guo L, Collage RD, Stripay JL, Tsung A, Lee JS, Rosengart MR. Calcium/calmodulin-dependent protein kinase (CaMK) Ialpha mediates the macrophage inflammatory response to sepsis. J Leukoc Biol 2011; 90(2): 249-61.
29. 29. Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. Brit J Anaesth 2003;90(2):221-32.
30. 30. Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock (Augusta, Ga) 2008; 38(1): 53-9.
31. 31. Sorg O. Oxidative stress: a theoretical model or a biological reality? C R Biol 2004; 327(7): 649-62.
32. 32. McCord JM. The evolution of free radicals and oxidative stress. Am J Med 2000; 108(8): 652-9.
33. 33. Quoilin C, Mouithys-Mickalad A, Lecart S, Fontaine-Aupart MP, Hoebeke M. Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury. Biochimic Biophys Acta 2014; 1837(10): 1790-800.
34. 34. Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Brit J Anaesth 2013; 110(3): 472-80.
35. 35. Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Brit J Anaesth 2011; 107(1): 57-64.
36. 36. Sagy M, Al-Qaqaa Y, Kim P. Definitions and pathophysiology of sepsis. Curr Prob Pediatr AD 2013; 43(10): 260-3.
37. 37. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ (Clinical research ed) 2016; 353: 1585.
38. 38. Chu SJ, Chang DM, Wang D, Hsu K, Chiang CH. Protective effect of lipophilic antioxidants on phorbol-induced acute lung injury in rats. Critical Care Med 2001; 29(4): 819-24.
39. 39. Ortolani O, Conti A, De Gaudio AR, Masoni M, Novelli G. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock (Augusta, Ga) 2000; 13(1): 14-8.
40. 40. Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC, Dal-Pizzol F. Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Critical Care Med 2004; 32(2): 342-9.
41. 41. Zolali E, Hamishehkar H, Maleki-Dizaji N, Majidi Zolbanin N, Ghavimi H, Kouhsoltani M, Asgharian P. Selenium effect on oxidative stress factors in septic rats. Adv Pharm Bull 2014; 4(3): 289-93.
42. 42. Girotti AW. Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res 1998; 39(8): 1529-42.
43. 43. Topdağı Ö, Tanyeli A, Ekinci Akdemir FN, Eraslan E, Güler MC. Barbaloin Attenuates Oxidative Testicular Injury Induced by Ischemia Reperfusion via Antioxidant Effects. Turk J Sci 2020; 5(1): 28-33.
44. 44. Toklu HZ, Tunali Akbay T, Velioglu-Ogunc A, Ercan F, Gedik N, Keyer-Uysal M, Sener G. Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury. J Surg Res 2008; 145(2): 214-22.
45. 45. Koksal GM, Sayilgan C, Aydin S, Oz H, Uzun H. Correlation of plasma and tissue oxidative stresses in intra-abdominal sepsis. J Surg Res 2004; 122(2): 180-3.
46. 46. Funakoshi T, Ishibe Y, Okazaki N, Miura K, Liu R, Nagai S, Minami Y. Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs. Brit J Anaesth 2004; 92(4): 558-63.
47. 47. Gaut JP, Yeh GC, Tran HD, Byun J, Henderson JP, Richter GM, Brennan ML, Lusis AJ, Belaaouaj A, Hotchkiss RS, Heinecke JW. Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis. PNAS USA 2001; 98(21): 11961-6.
48. 48. Tanyeli A, Güzel Erdoğan D, Ekinci Akdemir FN, Eraslan E and Güler MC. The Role of Chlorogenic Acid in Alleviating Intestinal Ischemia/Reperfusion-Induced Lung Injury, New Trend Med Sci 2020; 1(2): 59-64.
49. 49. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40(2): 280-93.
50. 50. Tuncer AA, Bozkurt MF, Koken T, Dogan N, Pektas MK, Baskin Embleton D. The Protective Effects of Alpha-Lipoic Acid and Coenzyme Q10 Combination on Ovarian Ischemia-Reperfusion Injury: An Experimental Study. Adv Med 2016; 2016: 3415046.
51. 51. Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407(6805): 770.
52. 52. Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000; 256(1): 42-9.
53. 53. Eraslan E, Tanyeli A, Güler MC, Ekinci-Akdemir FN, Nacar T, Topdağı Ö, Polat E. Nrf2 inhibitor brusatol ameliorates cecal ligation and puncture-induced lung injury in rats via anti-inflammation and anti-oxidative stress. Turk Hij Den Biyol Derg 2020; 77(4): 467-476.
54. 54. Almasaudi SB, Abbas AT, Al-Hindi RR, El-Shitany NA, Abdel-Dayem UA, Ali SS, Saleh RM, Al Jaouni SR, Kamal MA, Harakeh SM. Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats. Evid Based Complement Alternat Med 2017; 2017: 5413917.
55. 55. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004; 36(12): 2503-18.
56. 56. Qu L, Chen C, Chen Y, Li Y, Tang F, Huang H, He W, Zhang R, Shen L. High-Mobility Group Box 1 (HMGB1) and Autophagy in Acute Lung Injury (ALI): A Review. Med Sci Monit 2019; 25: 1828-37.
57. 57. Wang K, Chen Y, Zhang P, Lin P, Xie N, Wu M. Protective Features of Autophagy in Pulmonary Infection and Inflammatory Diseases. Cells 2019; 8(2).
58. 58. Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4(2): 151-75.
59. 59. Barth S, Glick D, Macleod KF. Autophagy: assays and artifacts. J Pathol 2010;221(2):117-24.
60. 60. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol 2010; 221(1): 3-12.
61. 61. Wu XJ, Yan XT, Yang XM, Zhang Y, Wang HY, Luo H, et al. GTS-21 ameliorates polymicrobial sepsis-induced hepatic injury by modulating autophagy through alpha7nAchRs in mice. Cytokine 2020; 128: 155019.
62. 62. Hsieh CH, Pai PY, Hsueh HW, Yuan SS, Hsieh YC. Complete induction of autophagy is essential for cardioprotection in sepsis. Ann Surg 2011; 253(6): 1190-200.
63. 63. Moulis M, Vindis C. Methods for Measuring Autophagy in Mice. Cells 2017 ;6(2).