Ratlarda Bortezomib Kaynaklı Dalak Hasarı Üzerine Berberinin Etkisinin Arginaz Aktivitesi ve Oksidan-Antioksidan Parametreler ile İncelenmesi

Öz

Bu çalışmanın amacı; kanser tedavisinde yaygın olarak kullanılan bortezomib (BTZ) kaynaklı dalak hasarına karşı doğal bir flavonoid olan berberinin etkileri araştırmaktır. Bu amaçla çalışmada Sprague Dawley cinsi 35 adet erkek rat kontrol, BTZ, berberin 100 mg/kg, BTZ+berberin 50 mg/kg ve BTZ+berberin 100 mg/kg olmak üzere rastlgele 5 gruba ayrıldı. Analiz sonuçları BTZ’nin glutatyon peroksidaz (GPx), süperoksit dismutaz (SOD) ve katalaz (KAT) gibi antioksidan enzim aktivitelerini ve glutatyon (GSH) düzeylerini azaltarak oksidatif strese neden olduğunu ve böylece lipid peroksidasyonunun son ürünü olan malondialdehit (MDA) seviyelerini artırdığını gösterdi. Bununla birlikte berberinin enzimatik ve non-enzimatik antioksidan düzeylerini artırması yoluyla BTZ kaynaklı oksidatif stresi hafiflettiği ve MDA seviyelerini önemli derecede azalttığı belirlendi. BTZ’nin ayrıca toplam antioksidan kapasite (TAK)’yi azalttığı, toplam oksidan kapasite (TOK) ve nitrik oksit (NO) seviyelerini ise arttığı görülürken berberinin bu parametreleri kontrol grubu seviyelerine yaklaştırdığı tespit edildi. Çalışmada ayrıca arginaz aktivitesi ölçüldü. Sonuçlar incelendiğinde BTZ’nin arginaz aktivitesini baskıladığı, BTZ ile birlikte berberin uygulamasının ise dalak dokusunda arginaz aktivitesini geri kazandırdığı görüldü. Birlikte ele alındığında berberinin dalak dokusunda BTZ’nin tetiklediği oksidatif ve nitrosatif stresi hafifleterek önemli derecede koruma sağladığı ve bu sonuçların daha ileri çalışmalar ile desteklendikten sonra berberinin alternatif tedavi seçenekleri arasına girebileceği düşünülmektedir.

Anahtar Kelimeler

• Berberin
• Bortezomib
• Dalak
• Oksidatif Stres
• Rat

Investigation of the Effect of Berberine with Arginase Activity and Oxidant-Antioxidant Parameters on Bortezomib-Induced Spleen Injury in Rats

Abstract

The aim of the study was to investigate the effects of berberine, one of the natural flavonoids, against spleen damage caused by bortezomib (BTZ), which was widely used in the treatment of cancer. Male Sprague-Dawley rats were randomly divided into five groups: a control group, BTZ-treated group, berberine alone treated group 100 mg / kg, , BTZ + berberine 50 mg/kg treated group, and BTZ+berberine 100 mg/kg treated group. Analysis results showed that BTZ caused oxidative stress by reducing antioxidant enzyme activities such as glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) and glutathione (GSH) levels, thereby increasing malondialdehyde (MDA) levels which is the end product of lipid peroxidation. However, by increasing the enzymatic and non-enzymatic antioxidant levels, berberine was found to reduce BTZ-induced oxidative stress and MDA levels significantly. It was also observed that BTZ decreased the total antioxidant capacity (TAC) and increased the total oxidant capacity (TOC) and nitric oxide (NO) levels, while the berberine made these parameters closer to the control group levels. Arginase activity was also measured in the study. When the results were examined, it was seen that BTZ suppressed arginase activity and BTZ and berberine combined administration regained arginase activity. Accordingly, it is thought that the berberine provides significant protection by lessening the oxidative and nitrosative stress triggered by BTZ in the spleen tissue, and after these results are supported by further studies, the berberine can be included among alternative treatment options.

Keywords

• Berberine
• Bortezomib
• Oxidative Stress
• Rat
• Spleen

References

1. Abdelhazer WY, Khalaf HM, El-Hussieny M, Bayoumi AMA, Shehata S, Refaie MMM. Role of nitric oxide donor in methotrexate-induced testicular injury via modulation of proinflammatory mediators, eNOS and P-glycoprotein. Hum Exp Toxicol. 2020; 39(12): 1700-1709.
2. Adil M, Kandhare AD, Dalvi G, Ghosh P, Venkata S, Raygude KS, Bodhankar SL. Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Ren Fail. 2016; 38(6): 996-1006.
3. Aebi H. Catalase in vitro. Methods Enzymol. 1984; 105 121-126.
4. Akaras N, Abuc OO, Koc K, Bal T, Geyikoglu F, Atilay H, Erol HS, Yigit S, Gul M. (1 --> 3)-beta-d-glucan enhances the toxicity induced by Bortezomib in rat testis. J Food Biochem. 2020; 44(3): e13155.
5. Akaras N, Bal T, Atilay H, Selli J, Halici MB. Protective effects of agomelatine on testicular damage caused by bortezomib. Biotech Histochem. 2017; 92(8): 552-559.
6. Akomolafe SF, Olasehinde TA, Oyeleye SI, Aluko TB, Adewale OO, Ijomone OM. Curcumin Administration Mitigates Cyclophosphamide-Induced Oxidative Damage and Restores Alteration of Enzymes Associated with Cognitive Function in Rats’ Brain. Neurotox Res. 2020; 38: 199-210.
7. Aktas MS, Kandemir FM, Kirbas A, Hanedan B, Aydin MA. Evaluation of oxidative stress in sheep infected with Psoroptes ovis using total antioxidant capacity, total oxidant status, and malondialdehyde level. J Vet Res. 2017; 61(2): 197-201.
8. Aksu EH, Kandemir FM, Özkaraca M, Ömür AD, Küçükler S, Çomaklı S. Rutin ameliorates cisplatin-induced reproductive damagevia suppression of oxidative stress and apoptosis in adultmale rats. Andrologia. 2017; 49(1): e12593.

9. Ali EMM, Zeyadi MA. Impact of caffeic acid phenylester on nitric oxide synthase and arginase in rats intoxicated with nitrites. J King Saud Univ Sci. 2020; 32(4): 2454-2461.
10. Al-malky H, Osman AM, Damanhouri ZA, Alkreathy HM, Al Aama JY, Ramadan WS, Al Qahtani AA, Al Mahdi HB. Modulation of doxorubicin‑induced expression of the multidrug resistance gene in breast cancer cells by diltiazem and protection against cardiotoxicity in experimental animals. Cancer Cell Int. 2019; 19: 191. DOI: 10.1186/s12935-019-0912-0
11. Al-Quraishy S, Murshed M, Delic D, Al-Shaebi EM, Qasem MAA, Mares MM, Dkhil MA. Plasmodium chabaudi-infected mice spleen response tosynthesized silver nanoparticles from Indigofera oblongifolia extract. Lett Appl Microbiol. 2020; 71(5): 542-549.
12. Arafa MH, Atteia HH. Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2. Neurotox Res. 2020; 37: 380-396.
13. Araujo M, Welch WJ. Oxidative stress and nitric oxide in kidney function. Curr Opin Nephrol Hy. 2006; 15(1): 72-77.
14. Benzer F, Kandemir FM, Kucukler S, Comakli S, Caglayan C. Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem. 2018a; 124 (5): 448-457.
15. Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C. Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxic. 2018b; 32(2): e22030.
16. Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E, Ileriturk M, Turkmen K. Benefical effects of lycopene against contrast medium-induced oxidative stress, inflammation, autophagy, and apoptosis in rat kidney. Hum Exp Toxicol. 2015; 34(5): 487-496.
17. Celik H, Kandemir FM, Caglayan C, Ozdemir S, Comakli S, Kucukler S, Yardim A. Neuroprotective efect of rutin against colistin‑induced oxidative stress, infammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Mol Biol Rep. 2020a; DOI: 10.1007/s11033-020-05302-z.
18. Celik H, Kucukler S, Comakli S, Caglayan C, Ozdemir S, Yardim A, Karaman M, Kandemir FM. Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats. Neurotoxicology. 2020b; 81: 197-208.
19. Celik H, Kucukler S, Comakli S, Ozdemir S, Caglayan C, Yardim A, Kandemir FM. Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis. Neurotoxicology. 2020c; 76: 126-137.
20. Celik H, Kucukler S, Ozdemir S, Comakli S, Gur C, Kandemir FM, Yardim A. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology. 2020d; 80: 29-40.
21. Chen X, Zhang Y, Zhu Z, Liu H, Guo H, Xiong C, Xie K, Zhang X, Su S. Protective effect of berberine on doxorubicininduced acute hepatorenal toxicity in rats. Mol Med Rep. 2016; 13(5): 3953-3960.
22. Eftekhari A, Hasanzadeh A, Khalilov R, Hosainzadegan H, Ahmadian E, Eghbal MA. Hepatoprotective role of berberine against paraquat-induced liver toxicity in rat. Environ Sci Pollut Res. 2020; DOI: 10.1007/s11356-07232-1.
23. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004; 37(4): 277-285.
24. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005; 38(12): 1103-1111.
25. Erişir M, Benzer F, Özkaya A, Dağ Ü. Kurşun Uygulanan Ratların Bazı Dokularında (Kalp, Akciğer, Beyin, Dalak, Kas) Oksidatif Stress Üzerine Naringeninin Etkisi. Atatürk Üniversitesi Vet Bil Derg. 2018; 13(1): 34-41.
26. Gao C, Liu Y, Ma L, Wang S. Protective effects of ulinastatin on pulmonary damage in rats following scald injury. Burns. 2012; 38(7): 1027-1034.
27. Geyer JW, Dabich D. Rapid Method for Determination of Arginase Activity in Tissue Homogenates. Anal Biochem. 1971; 39(2): 412-417.
28. Hanedan B, Kirbas A, Kandemir FM, Ozkaraca M, Kilic K, Benzer F. Arginase activity and total oxidant/antioxidant capacity in cows with lung cystic echinococcosis. Med Weter. 2015; 71(3): 167-170.
29. Hou M, Erikkson E, Svechnikov K, Jahnukainen K, Söder O, Meinhardt A, Sävendahl L. Bortezomib treatment causes long‐term testicular dysfunction in young male mice. Mol Cancer. 2014; 13(1): 155-165.
30. Hu B, Zhou Q, Hu YY, Zhuang L, Yi LP, Cao JX, Li TQ, Wang J. Efficacy and Safety of Once-Weekly versus Twice-Weekly Bortezomib in Patients with Hematologic Malignancies: A Meta-analysis with Trial Sequential Analysis. Pharmacotherapy. 2019; 39(6): 697-708.
31. Imenshahidi M, Hosseinzadeh H. Berberis Vulgaris and Berberine: An Update Review. Phytother Res. 2016; 30(11): 1745-1764.
32. Kandemir FM, Benzer F, Yildirim NC, Ozdemir N. Compensatory effects of curcumin on cisplatin-induced toxicity in rabbit testis. J Med Plants Res. 2011; 5(3): 456-461.
33. Kandemir FM, Hanedan B, Aktaş MS, Küçükler S, Çağlayan C. Ratlarda Sisplatinden Kaynaklanan Nefrotoksisite Üzerine Rutinin İyileştirici Etkileri. Fırat Univ Vet J Health Sci. 2020; 34(3): 147-151.
34. Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gulcin I. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017a; 41(5): e12398.
35. Kandemir FM, Küçükler S, Çağlayan C. Beneficial effects of silymarin and naringin against methotrexate-induced hepatotoxicity in rats. Atatürk Üniversitesi Vet Bil Derg. 2017b; 12: 167-177.
36. Kandemir, FM, Özdemir, N. L- Lizin ve L- Ornitinin Sığır Böbrek Doku Arginaz Aktivitesi Üzerine İnhibisyon Etkisi. Fırat Üniversitesi Sağ Bil Derg. 2008; 22(1): 1-4.
37. Kandemir FM, Özdemir N. Some Kinetic Properties of Arginase in Sheep Spleen Tissue. Kafkas Univ Vet Fak Derg. 2009; 15(4): 553-559.
38. Kandemir FM, Yüksel M, Özdemir N, Deveci H. A different approach to diagnosis of subclinical mastitis: milk arginase activity. Vet Arhiv. 2013; 83(6): 603-610.
39. Kaya SO, Gur S, Erisir M, Kandemir FM, Benzer F, Kaya E, Turk G, Sonmez M. Influence of vitamin E and vitamin E-selenium combination on arginase activity, nitric oxide level and some spermatological properties in ram semen. Reprod Domest Anim. 2020; 55: 162-169.
40. Keles ON, Can S, Cigsar G, Colak S, Erol HS, Akaras N, Erdemci B, Bilgin BC, Can I, Unal B, Halici MB. Hepatoprotective Effects of B-1,3-(D)-Glucan on Bortezomib-Induced Liver Damage in Rats. Kafkas Univ Vet Fak Derg. 2014; 20(6): 929-938.
41. Kucukler S, Darendelioglu E, Caglayan C, Ayna A, Yildirim S, Kandemir FM. Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci. 2020a; 259: 118382.
42. Kucukler S, Ozdemir S, Comakli S, Kandemir FM. Effects of Chrysin Against Isoniazid-Induced Lung Injury in Rats. Kocatepe Vet J. 2020b; 13(2): 161-171.
43. Kumar A, Ekavali Chopra K, Mukherjee M, Pottabathini R, Dhull DK. Current knowledge and pharmacological profile of berberine: An update. Eur J Pharmacol. 2015; 761: 288-297.
44. Lawrence RA, Burk RF. Glutathione Peroxidase-Activity in Selenium-Deficient Rat-Liver. Biochem Bioph Res Co. 1976; 71(4): 952-958.
45. Li XL, Li HL, Lu NH, Feng YC, Huang Y, Gao ZH. Iron increases liver injury through oxidative/nitrative stress in diabetic rats: Involvement of nitrotyrosination of glucokinase. Biochimie. 2012; 94(12): 2620-2627.
46. Liu L, Ye Q, Lu MG, Lo YC, Hsu YH, Wei MC, Chen YH, Lo SC, Wang SJ, Bain DJ, Ho C. A New Approach to Reduce Toxicities and to Improve Bioavailabilities of Platinum-Containing Anti-Cancer Nanodrugs. Sci Rep-Uk. 2015; 5: 10881.
47. Lowry OH, Rosebrough NJ, Farr AL. Randall, RJ, Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-275.
48. Maharjan S, Oku M, Tsuda M, Hoseki J, Sakai Y. Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition. Sci Rep-Uk. 2014; 4: 5896. DOI: 10.1038/srep05896
49. Moghaddam HK, Baluchnejadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F. Berberine Ameliorate Oxidative Stress and Astrogliosis in the Hippocampus of STZ-Induced Diabetic Rats. Mol Neurobiol. 2014; 49(2): 820-826.
50. Orciuolo E, Buda G, Cecconi N, Galimberti S, Versari D, Cervetti G, Salvetti A, Petrini M. Unexpected cardiotoxicity in haematological bortezomib treated patients. Brit J Haematol. 2007; 138(3): 396-397.
51. Ozdemir S, Kucukler S, Comakli S, Kandemir FM. The protective effect of Morin against ifosfamide-induced acute liver injury in rats associated with the inhibition of DNA damage and apoptosis. Drug Chem Toxicol. 2020; DOI: 10.1080/01480545.2020.1822390
52. Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006; 107(1): 257-264.
53. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966; 16(2): 359-364.
54. Rath M, Müller I, Kropf P, Closs EI, Munder M. Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages. Front Immunol. 2014; 5: 532. DOI: 10.3389/fimmu.2014.00532.
55. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC. Assessment of Proteasome Inhibition for Extending Remissions, I, Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005; 352(24): 2487-2498.
56. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968; 25(1): 192-205.
57. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34(3): 497-500.
58. Sutradhar S, Deb A, Singh SS. Melatonin attenuates diabetes-induced oxidative stress in spleen and suppression of splenocyte proliferation in laboratory mice. Arch Physiol Biochem. 2020; 1-12.
59. Taslimi P, Kandemir FM, Demir Y, Ileriturk M, Temel Y, Caglayan C, Gulcin I. The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide‐induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. J Biochem Mol Toxicol 2019; 33(6): e22313.
60. Temel, Y, Caglayan C, Ahmed BM, Kandemir FM, Ciftci M. The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: biochemical evaluation of some enzyme activities in vivo and in vitro. Naunyn-Schmiedeberg's Arch Pharmacol. 2020; DOI: 10.1007/s00210-020-01987-y
61. Wang M, Xiong Y, Zhu W, Ruze1 R Xu Q,Yan Z,Zhu J,Zhong M,Cheng Y,Hu S,Zhang G. Sleeve Gastrectomy Ameliorates Diabetes-Related Spleen Damage by Improving Oxidative Stress Status in Diabetic Obese Rats. Obes Surg. 2020; DOI: 10.1007/s11695-020-05073-3
62. Xie JD, Chen SR, Chen H, Pan HL. Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord. Neuropharmacology. 2017; 123: 477-487.
63. Yardim A, Kandemir FM, Comakli S, Ozdemir S, Caglayan C, Kucukler S, Celik H. Protective Effects of Curcumin Against Paclitaxel-Induced Spinal Cord and Sciatic Nerve Injuries in Rats. Neurochem Res. 2020a; DOI: 10.1007/s11064-020-03174-0
64. Yardim A, Kandemir FM, Ozdemir S, Kucukler S, Comakli S, Gur C, Celik H. Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology. 2020b; 81: 137-146.
65. Yardim A, Kucukler S, Ozdemir S, Comakli S, Caglayan C, Kandemir FM, Celik H. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene. 2020c; DOI: 10.1016/j.gene.2020.145239.
66. Ye ZQ, Chen J, Xuan ZX, Yang WC, Chen J. Subcutaneous bortezomib might be standard of care for patients with multiple myeloma: a systematic review and meta-analysis. Drug Des Dev Ther. 2019; 13: 1707-1716.
67. Yildiz F, Terzi A, Coban S, Bitiren M, Celik H, Aksoy N, Ozdogan MK, Cakir H. Purified micronized flavonoid fraction ameliorates the injury of spleen and ileum secondary to hepatic ischemia-reperfusion in rats. Dig Dis Sci. 2010; 55(8): 2237-2243.
68. Yilmaz S, Kandemir FM, Kaya E, Ozkaraca M. Chemoprotective Effects of Propolis on Aflatoxin B1-Induced Hepatotoxicity in Rats: Oxidative Damage and Hepatotoxicity by Modulating TP53, Oxidative Stress. Curr Proteomics. 2020; 17(3): 191-199.