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Salvia miltiorrhiza Bunge Ameliorates Benign Prostatic Hyperplasia through Regulation of Oxidative Stress via Nrf-2/HO-1 Activation

  • Young-Jin Choi (Department of Food Science and Nutrition, Dong-A University) ;
  • Nishala Erandi Wedamulla (Department of Food Science and Nutrition, Dong-A University) ;
  • Seok-Hee Kim (Department of Food Science and Nutrition, Dong-A University) ;
  • Mirae Oh (Grassland and Forages Division, National Institute of Animal Science, Rural Development Administration) ;
  • Kang Sik Seo (Curome Bioscience Co., Ltd.) ;
  • Jeong Su Han (Curome Bioscience Co., Ltd.) ;
  • Eun Joo Lee (Healthism Corporation) ;
  • Young Ho Park (Healthism Corporation) ;
  • Young Jin Park (Department of Family Medicine, Dong-A University College of Medicine) ;
  • Eun-Kyung Kim (Educational Major, Graduate School of Education, Dong-A University)
  • Received : 2023.09.02
  • Accepted : 2023.10.23
  • Published : 2024.05.28

Abstract

Oxidative stress is a key factor in the pathogenesis of benign prostatic hyperplasia (BPH) that leads to inflammation. This study aimed to evaluate the ameliorative effects of Salvia miltiorrhiza Bunge extract (HLT-101) on BPH through the regulation of oxidative stress and inflammation. A testosterone propionate (TP)-induced BPH rat model was orally administered HLT-101 (20, 40, or 80 mg/kg), and its effects on oxidative stress- and inflammation-related gene expression were examined. Further, HLT-101 was assessed for its effect on reactive oxygen species (ROS) levels and Nrf-2/HO-1 signaling pathways in BPH-1 cells. HLT-101 decreased testosterone-induced excessive free radical production and inflammatory factor activation. Moreover, HLT-101 treatment significantly decreased the intracellular ROS level in the TNF-α and IFN-γ treated BPH-1 cells through the activation of Nrf-2. In addition, HLT-101 treatment inhibited the NF-κB pathway and androgen receptor (AR) signaling, which is highly linked to the pathogenesis of BPH. Therefore, HLT-101 has the potential to be an effective treatment reagent for BPH because of its ability to reduce inflammation and oxidative stress via Nrf-2/HO-1 signaling.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2020R1A2C1014798), the Research Program for Agricultural Science & Technology Development (PJ016130), National Academy of Agricultural Science, Rural Development Administration, and the Technology Development Program (S3289574) funded by the Ministry of SMEs and Startups (MSS) Republic of Korea.

References

  1. Woodard TJ, Manigault KR, McBurrows NN, Wray TL, Woodard LM. 2016. Management of benign prostatic hyperplasia in older adults. Consult. Pharm. 31: 412-424. https://doi.org/10.4140/TCP.n.2016.412
  2. Shimizu S, Tsounapi P, Shimizu T, Honda M, Inoue K, Dimitriadis F, et al. 2014. Lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction: are these conditions related to vascular dysfunction? Int. J. Urol. 21: 856-864. https://doi.org/10.1111/iju.12501
  3. Vital P, Castro P, Ittmann M. 2015. Oxidative stress promotes benign prostatic hyperplasia. Prostate 76: 58-67. https://doi.org/10.1002/pros.23100
  4. Castro-Diaz D, Callejo D, Cortes X, Perez M. 2014. Study of quality of life in patients with benign prostatic hyperplasia under treatment with silodosin. Actas. Urol. Esp. 38: 361-366. https://doi.org/10.1016/j.acuro.2013.10.002
  5. Tanguay S, Awde M, Brock G, Casey R, Kozak J, Lee J, et al. 2013. Diagnosis and management of benign prostatic hyperplasia in primary care. Can. Urol. Assoc. J. 3: 92.
  6. Kim EH, Brockman JA, Andriole GL. 2018. The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia. Asian J. Urol. 5: 28-32. https://doi.org/10.1016/j.ajur.2017.11.005
  7. Barkin J. 2003. Alpha-Blocker Therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5α-reductase inhibitor dutasteride. Eur. Urol. 44: 461-466. https://doi.org/10.1016/S0302-2838(03)00367-1
  8. Gravas S, Oelke M. 2010. Current status of 5alpha-reductase inhibitors in the management of lower urinary tract symptoms and BPH. World J. Urol. 28: 9-15. https://doi.org/10.1007/s00345-009-0493-y
  9. Csoka A, Bahrick A, Mehtonen O. 2008. Persistent sexual dysfunction after discontinuation of Selective serotonin reuptake inhibitors. J. Sex. Med. 5: 227-233. https://doi.org/10.1111/j.1743-6109.2007.00630.x
  10. The Finasteride SG. 1993. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate 22: 291-299. https://doi.org/10.1002/pros.2990220403
  11. Roehrborn CG. 2008. Pathology of benign prostatic hyperplasia. Int. J. Impotence Res. 20: S11-S18. https://doi.org/10.1038/ijir.2008.55
  12. Kyprianou N, Tu H, Jacobs SC. 1996. Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum. Pathol. 27: 668-675. https://doi.org/10.1016/S0046-8177(96)90396-2
  13. Kullisaar T, Turk S, Punab M, Mandar R. 2011. Oxidative stress-cause or consequence of male genital tract disorders? Prostate 72: 977-983. https://doi.org/10.1002/pros.21502
  14. Minciullo PL, Inferrera A, Navarra M, Calapai G, Magno C, Gangemi S. 2014. Oxidative stress in benign prostatic hyperplasia: a systematic review. Urol. Int. 94: 249-254. https://doi.org/10.1159/000366210
  15. Steers WD. 2001. 5α-reductase activity in the prostate. Urology 58: 17-24. https://doi.org/10.1016/S0090-4295(01)01299-7
  16. Bartsch G, Rittmaster R, Klocker H. 2002. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. World J. Urol. 19: 413-425. https://doi.org/10.1007/s00345-002-0248-5
  17. Fujita K, Nonomura N. 2019. Role of androgen receptor in prostate cancer: a review. World J. Mens Health 37: 288-295. https://doi.org/10.5534/wjmh.180040
  18. Shang Y, Myers M, Brown M. 2002. Formation of the androgen receptor transcription complex. Mol. Cell 9: 601-610. https://doi.org/10.1016/S1097-2765(02)00471-9
  19. Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR. 2007. Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev. 21: 2005-2017. https://doi.org/10.1101/gad.1564207
  20. Abdel-Aziz AM, Fathy N, Atta M, Mohammed M, Ali A, Ibrahim Y. 2020. Amelioration of testosterone-induced benign prostatic hyperplasia using febuxostat in rats: the role of VEGF/TGFβ and iNOS/COX-2. Eur. J. Pharmacol. 889: 173631.
  21. D'Amico R, Genovese T, Cordaro M, Siracusa R, Gugliandolo E, Alessio FP, et al. 2021. Palmitoylethanolamide/baicalein regulates the androgen receptor signaling and NF-κB/Nrf2 pathways in benign prostatic hyperplasia. Antioxidants 10: 1014.
  22. Li Y, Shi B, Dong F, Zhu X, Liu B, Liu Y. 2019. Effects of inflammatory responses, apoptosis, and STAT3/NF-κB- and Nrf2-mediated oxidative stress on benign prostatic hyperplasia induced by a high-fat diet. Aging (Albany NY) 11: 5570-5578.
  23. Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. 2017. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 1863: 585-597. https://doi.org/10.1016/j.bbadis.2016.11.005
  24. He F, Ru X, Wen T. 2020. NRF2, a transcription factor for stress response and beyond. Int. J. Mol. Sci. 21: 4777.
  25. Cardozo LFMF, Pedruzzi LM, Stenvinkel P, Stockler-Pinto M, Daleprane JB, Leite M, et al. 2013. Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie 95: 1525-1533. https://doi.org/10.1016/j.biochi.2013.04.012
  26. El-Sherbiny M, El-Shafey M, El-din El-Agawy MS, Mohamed AS, Eisa N.H, Elsherbiny NM. 2021. Diacerein ameliorates testosterone-induced benign prostatic hyperplasia in rats: effect on oxidative stress, inflammation and apoptosis. Int. Immunopharmacol. 100: 108082.
  27. El-Sahar A, Bekhit N, Eissa NM, Abdelsalam RM, Essam RM. 2023. Targeting HMGB1/PI3K/Akt and NF-κB/Nrf-2 signaling pathways by vildagliptin mitigates testosterone-induced benign prostate hyperplasia in rats. Life Sci. 322: 121645.
  28. SU C, MING Q, RAHMAN K, HAN T, QIN L. 2015. Salvia miltiorrhiza: traditional medicinal uses, chemistry, and pharmacology. Chin. J. Nat. Med. 13: 163-182. https://doi.org/10.1016/S1875-5364(15)30002-9
  29. Pan X, Niu G, Liu H. 2002. Comparison of microwave-assisted extraction and conventional extraction techniques for the extraction of tanshinones from Salvia miltiorrhiza Bunge. Biochem. Eng. J. 12: 71-77. https://doi.org/10.1016/S1369-703X(02)00039-6
  30. Zhou X, Chan K, Yeung JHK. 2012. Herb-drug interactions with Danshen (Salvia miltiorrhiza): a review on the role of cytochrome P450 enzymes. Drug Metabol. Drug Interact. 27: 9-18. https://doi.org/10.1515/dmdi-2011-0038
  31. Wu C, Hong C, Klauck SM, Lin Y, Efferth T. 2015. Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells. J. Ethnopharmacol. 176: 55-68. https://doi.org/10.1016/j.jep.2015.10.020
  32. Ma P, Liu J, Zhang C, Liang Z. 2013. Regulation of water-soluble phenolic acid biosynthesis in Salvia miltiorrhiza Bunge. Appl. Biochem. Biotechnol. 170: 1253-1262. https://doi.org/10.1007/s12010-013-0265-4
  33. Gao H, Sun W, Zhao J, Wu X, Lu J, Chen X, et al. 2016. Tanshinones and diethyl blechnics with anti-inflammatory and anti-cancer activities from Salvia miltiorrhiza Bunge (Danshen). Sci. Rep. 6: 33720.
  34. Jiang Y, Wang L, Zhang L, Wang T, Yu L, Ding C, et al. 2014. Characterization, antioxidant and antitumor activities of polysaccharides from Salvia miltiorrhiza Bunge. Int. J. Biol. Macromol. 70: 92-99. https://doi.org/10.1016/j.ijbiomac.2014.06.036
  35. Sung B, Hye SC, Kim M, Kang Y, Dong HK, Soo HH, et al. 2015. Cytotoxic effects of solvent-extracted active components of Salvia miltiorrhiza Bunge on human cancer cell lines. Exp. Ther. Med. 9: 1421-1428. https://doi.org/10.3892/etm.2015.2252
  36. Ribal MJ. 2013. The link between benign prostatic hyperplasia and inflammation. Eur. Urol. Suppl. 12: 103-109. https://doi.org/10.1016/j.eursup.2013.08.001
  37. Calogero AE, G. Burgio, R.A. Condorelli, R. Cannarella, S. La Vignera. 2018. Epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction. Aging Male 22: 12-19. https://doi.org/10.1080/13685538.2018.1434772
  38. Limon-Pacheco J, Gonsebatt ME. 2009. The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat. Res. 674: 137-147. https://doi.org/10.1016/j.mrgentox.2008.09.015
  39. Rao PS, Kalva S, Yerramilli A, Mamidi S. 2011. Free radicals and tissue damage: role of antioxidants. Free Radic. Antioxid. 1: 2-7. https://doi.org/10.5530/ax.2011.4.2
  40. Aydin A, Arsova-Sarafinovska Z, Sayal A, Eken A, Erdem O, Erten K, et al. 2006. Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostatic hyperplasia. Clin. Biochem. 39: 176-179. https://doi.org/10.1016/j.clinbiochem.2005.11.018
  41. Nomiya M, Andersson K, Yamaguchi O. 2014. Chronic bladder ischemia and oxidative stress: new pharmacotherapeutic targets for lower urinary tract symptoms. Int. J. Urol. 22: 40-46. https://doi.org/10.1111/iju.12652
  42. Eid BG, Abdel-Naim A. 2020. Piceatannol attenuates testosterone-induced benign prostatic hyperplasia in rats by modulation of Nrf2/HO-1/NFκB axis. Front. Pharmacol. 11: 614897.
  43. Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, Sikka SC, et al. 2014. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells. PLoS One 9: e87204.
  44. Krajka-Kuzniak V, Baer-Dubowska W. 2021. Modulation of Nrf2 and NF-κB signaling pathways by naturally occurring compounds in relation to cancer prevention and therapy. Are combinations better than single compounds? Int. J. Mol. Sci. 22: 8223.
  45. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. 2011. NF-κB in aging and disease. Aging Dis. 2: 449-465.
  46. Khurana N, Sikka S. 2018. Targeting crosstalk between Nrf-2, NF-κB and androgen receptor signaling in prostate cancer. Cancers 10: 352.
  47. Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. 1998. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA 95: 4997-5002. https://doi.org/10.1073/pnas.95.9.4997
  48. Yang J. 1997. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275: 1129-1132.  https://doi.org/10.1126/science.275.5303.1129