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Gezer, Arzu, Karadağ Sari, Ebru. (1401). Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods. , 26(3), 276-284. doi: 10.22038/ijbms.2023.65948.14507
Arzu Gezer; Ebru Karadağ Sari. "Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods". , 26, 3, 1401, 276-284. doi: 10.22038/ijbms.2023.65948.14507
Gezer, Arzu, Karadağ Sari, Ebru. (1401). 'Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods', , 26(3), pp. 276-284. doi: 10.22038/ijbms.2023.65948.14507
Gezer, Arzu, Karadağ Sari, Ebru. Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods. , 1401; 26(3): 276-284. doi: 10.22038/ijbms.2023.65948.14507

Investigation of apoptotic and autophagic effects of chronic roflumilast use on testicular tissue in rats by immunohistochemical and immunofluorescence methods

Iranian Journal of Basic Medical Sciences
مقاله 3، دوره 26، شماره 3، خرداد 2023، صفحه 276-284    اصل مقاله (965.96 K)
نوع مقاله: Original Article
شناسه دیجیتال (DOI): 10.22038/ijbms.2023.65948.14507
نویسندگان
Arzu Gezer* 1؛ Ebru Karadağ Sari2
1Vocational School of Health Services, Atatürk University, Erzurum, Turkey
2Department of Histology and Embryology, Faculty of Veterinary Medicine, Kafkas University, Kars, Turkey
چکیده
Objective(s): The present study aims to determine how various dosages of chronic roflumilast affect testicular tissue and testosterone levels in healthy rats. 
Materials and Methods: Biochemical tests, along with histopathological, immunohistochemical, and immunofluorescence studies, were carried out.
Results: Loss of tissue in the seminiferous epithelium, degeneration in the interstitial area, a separation between cells, desquamation, interstitial edema, and degenerative alterations in testicular tissue were observed in roflumilast groups when compared with the other groups. While apoptosis and autophagy were statistically negligible in the control and sham groups, the roflumilast groups had significantly higher apoptotic and autophagic alterations, as well as immunopositivity. Serum testosterone levels in the 1 mg/kg roflumilast group were lower than those in the control, sham, and 0.5 mg/kg roflumilast groups.
Conclusion: Analyses of the research findings revealed that continuous usage of the broad-spectrum active component roflumilast exerted unfavorable effects on the testicular tissue and testosterone levels of rats.
کلیدواژه‌ها
Apoptosis؛ Autophagy؛ Rat؛ Roflumilast؛ Testis؛ Testosterone
مراجع
1. Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, et al. The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010;23:235-256.
2. Drobnis EZ, Nangia AK. Phosphodiesterase inhibitors (PDE inhibitors) and male reproduction. Adv Exp Med Biol 2017;1034: 29-38.
3. Ouyang P, Feng Y, Xiong G, Liu R, Fan W, Wang K, et al. Potential mechanism of the PDE camp-related network action on hepatopancreatic necrosis syndrome of chinese mitten crab (eriocheir sinensis). Aquaculture 2021;531:735982.
4. Nabavi SM, Talarek S, Listos J, Nabavi SF, Devi KP, De Oliveira MR, et al. Phosphodiesterase inhibitors say NO to Alzheimer’s Disease. Food Chem Toxicol 2019;134:110822.
5. Giembycz MA, Field SK. Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther 2010;4:147-158.
6. Wedzicha JA. Dual PDE 3/4 inhibition: A novel approach to airway disease? Lancet Respir Med 2013;1:669-670.
7. Fala L. Otezla (Apremilast). An Oral PDE4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis. Am Health Drug Benefits Spec Feature 2015;8:105-110.
8. Fleming P, Yang YB, Lynde C, O’Neill B, Lee KO. Diagnosis and management of atopic dermatitis for primary care providers. J Am Board Fam Med 2020;33:626-635.
9. Zheng CX, Lu M, Guo YB, Zhang FX, Liu H, Guo F, et al. Electroacupuncture ameliorates learning and memory and improves synaptic plasticity via activation of the PKA/CREB signaling pathway in cerebral hypoperfusion. Evid Based Complement Alternat Med 2016;2016:7893710.
10. Voss AK, Strasser A. The essentials of developmental apoptosis. F1000Res 2020;9:F1000. 
11. Yu Q, Lu Z, Tao L, Yang L, Guo Y, Yang Y, et al. ROS-dependent neuroprotective effects of nahs in ischemia brain injury involves the PARP/AIF pathway. Cell Physiol Biochem 2015;36:1539-1551.
12. Garcia-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, et al. Autophagy maintains stemness by preventing senescence. Nature 2016;529:37-42.
13. Herb M, Gluschko A, Schramm M. LC3-Associated phagocytosis-the highway to hell for phagocytosed microbes. Semin Cell Dev Biol 2020;101:68-76. 
14. Murad HA, Habib HS, Rafeeq MM, Sulaiman MI, Abdulrahman AS, Khabaz MN. Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. Exp Biol Med 2017;242:516-526.
15. FDA. 2011. Center for drug evaluatıon and research. [accessed 2021 May 31]: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000PharmR.pdf.
16. Botros SS, El-Lakkany NM, El-Din SHS, William S, Sabra AN, Hammam OA, et al. The phosphodiesterase-4 p inhibitor roflumilast impacts schistosoma mansoni ovipositing in vitro but displays only modest antischistosomal activity in vivo. Exp Parasitol 2020;208:107793. 
17. Johnsen SG. Testicular biopsy score count-a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1970;1:2-25.
18. Erboga M, Kanter M, Aktas C, Donmez YB, Erboga ZF, Aktas E, et al. Anti-apoptotic and anti-oxidant effects of caffeic acid phenethyl ester on cadmium-induced testicular toxicity in rats. Biol Trace Elem Res 2016;171:176-184.
19. Belhan, S, Özkaraca M, Özdek U, Kömüroğlu AU. Protective role of chrysin on doxorubicin‐induced oxidative stress and DNA damage in rat testes. Andrologia 2020;52:e13747.
20. Mouro VGS, Menezes TP, Lima GDA, Domingue RR, Ana Souza CF, Oliveira JA, et al. How bad is aluminum exposure to reproductive parameters in rats? Biol Trace Elem Res 2018;183:314–324.
21. Rasband WS, Imagej US, National Institutes of Health, Bethesda, Maryland, USA, Imagej. Nih. Gov/İj/, 1997-2012. JMP versión. 2014;7, 1989-2007.
22. Baye J. Roflumilast (daliresp): A novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Pharmacy and Therapeutics 2012;37:149-150.
23. Sugin LJS, Murugesan A, Bindu M, Sunil KN. Roflumilast: A potential drug for the treatment of cognitive impairment?  Neurosci Lett 2020;736:135281.
24. Prickaerts J, Heckman PR, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for alzheimer’s disease. Expert Opin Investig Drugs 2017;26:1033-1048. 
25. Yu H, Zou Z, Zhang X, Peng W, Chen C, Ye Y, et al. Inhibition of phosphodiesterase 4 by FCPR03 alleviates lipopolysaccharide-induced depressive-like behaviors in mice: Involvement of P38 and JNK signaling pathways. Int J Mol Sci 2018;19: 513.
26. Wang H, Zhang FF, Xu Y, Fu HR, Wang L, Chen W, et al. The phosphodiesterase-4 inhibitor roflumilast, a potential treatment for the comorbidity of memory loss and depression in alzheimer’s disease: A preclinical study in APP/PS1 transgenic mice. Int J Neuropsychopharmacol 2020;23:700-711.
27. Ansari MN, Aloliet RI, Ganaie MA, Khan TH, Najeeb-Ur-Rehman Imam F, Hamad AM. Roflumilast, a phosphodiesterase 4 inhibitor, attenuates cadmium-induced renal toxicity via modulation of NF-Κb activation and induction of NQO1 in rats. Hum Exp Toxicol 2019;38: 588-597. 
28. Aydemir Y. Comparative clinical pharmacology of asthma, chronic obstructive pulmonary disease and fibrosis diseases. turkish clinics. J Pharmacol-Special Topics 2018;6:118-125.
29. Cilli A, Bal H, Gunen H. Efficacy and safety profile of roflumilast in a real-world experience. J Toraks Dis 2019;11:1100. 
30. Kızılay F, Altay B. Fosfodiesteraz Tip-5 inhibitörlerinin semen parametrelerine etkisi. Androl Bul 2018;20: 54-60.
31. Wedzicha JA, Calverley PM, Rabe KF. Roflumilast: A review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 2016;11: 81.
32. Kyung SY, Kim YJ, Son ES, Jeong SH, Park JW. The phosphodiesterase 4 inhibitor roflumilast protects against cigarette smoke extract-ınduced mitophagy-dependent cell death in epithelial cells. Tuberc Respir Dis (Seoul) 2018;81:138-147.
33. Essam RM, Ahmed LA, Abdelsalam RM, El-Khatib AS. Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of camp/CREB/TLR4 ınflammatory and fibrogenic pathways. Life Sci 2019;222: 245-254.
34. Wu Q, Qi L, Li H, Mao L, Yang M, Xie R, et al. Roflumilast reduces cerebral inflammation in a rat model of experimental subarachnoid hemorrhage. Inflammation 2017;40:1245-1253. 
35. Xu X, Liao L, Hu B, Jiang H, Tan M. Roflumilast, A Phosphodiesterases-4 (PDE4) inhibitor, alleviates sepsis-induced acute kidney injury. Med Sci Monit 2020;26:921319-921321. 
36. Akdeniz E, Dengiz GÖ, Yılmaz Z. Effects of the phosphodiesterase 4 enzyme inhibitor rolipram on testicular ischemia reperfusion injury in rats. Bulent Ecevit University/Institute of Health Sciences. Turkish 2018.
37. Visconti PE, Moore GD, Bailey JL, Leclerc P, Connors SA, Pan D, et al. Capacitation of mouse spermatozoa. II. protein tyrosine phosphorylation and capacitation are regulated by a camp-dependent pathway. Development 1995;121:1139-1150. 
38. Lefievre L, JHA KN, De Lamırande EVE, Vıscontı PE, Gagnon C. Activation of protein kinase a during human sperm capacitation and acrosome reaction. J Androl 2002;23:709-716.
39. Luconi M, Porazzi I, Ferruzzi P, Marchiani S, Forti G, Baldi E. Tyrosine phosphorylation of the a kinase anchoring protein 3 (AKAP3) and soluble adenylate cyclase are involved in the increase of human sperm motility by bicarbonate. Biol Reprod 2005;72: 22-32. 
40. Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod 2009;16: 3-13.
41. Kumar V, Abba AK, Aster JC. Cell injury, cell death, and adaptations. Robbins Basic Pathol  2018;2:31-56.
42. Qian YC, Xie YX, Wang CS, Shi ZM, Jiang CF, Tang YY, et al. Mkrn2 deficiency induces teratozoospermia and male infertility through P53/PERP-mediated apoptosis in testis. Asian J Androl 2020;22: 414.
43. Liu ML, Wang JL, Wei J, Xu LL, Yu M, Liu XM, et al. Tri-ortho-cresyl phosphate induces autophagy of rat spermatogonial stem cells. Reproduction 2015;149:163-170.
44. Wang Y, Zheng W, Bian X, Yuan Y, Gu, J, Liu X, et al. Zearalenone induces apoptosis and cytoprotective autophagy in primary leydig cells. Toxicol Lett 2014;226:182-191.
45. Zgair A, Dawood Y, Ibrahem SM, Lee JB, Fen W, Fischer PM, et al. Strawberry decreases intraluminal and intestinal wall hydrolysis of testosterone undecanoate. Molecules 2021;26:233.
46. Dym M, Raj HG. Response of adult rat Sertoli cells and Leydig cells to depletion of luteinizing hormone and testosterone. Biol Reprod 1977;17: 676–696. 
47. Sokanovic SJ, Capo I, Medar MM, Andric SA, Kostic TS. Long-term inhibition of PDE5 ameliorates aging-induced changes in rat testis. Exp Gerontol 2018;108:139-148.
48. Weckmann K, Diefenthäler P, Baeken MW, Yusifli K, Turck CW, Asara JM, et al. Metabolomics profiling reveals differential adaptation of major energy metabolism pathways associated with autophagy upon oxygen and glucose reduction. Sci Rep 2018;8:2337.
49. Golkowski M, Shimizu-Albergine M, Suh HW, Beavo JA, Ong SE. Studying mechanisms of cAMP and cyclic nucleotide phosphodiesterase signaling in Leydig cell function with phosphoproteomics. Cell Signal 2016;28:764-778.
50. Shimizu-Albergine M, Van Yserloo B, Golkowski MG, Ong SE, Beavo JA, Bornfeldt KE. SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci USA 2016;113:E5685-E5693.

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