Nutr Res Pract.  2018 Oct;12(5):378-386. 10.4162/nrp.2018.12.5.378.

Corni Fructus attenuates testosterone-induced benign prostatic hyperplasia by suppressing 5α-reductase and androgen receptor expression in rats

• Hwangbo H
• Kwon DH
• Choi EO
• Kim MY
• Ahn KI
• Ji SY
• Kim JS
• Kim KI
• Park NJ
• Kim BH
• Kim GY
• Hong SH
• Park C
• Jeong JS
• Choi YH

• KMID: 2446997
• DOI: http://doi.org/10.4162/nrp.2018.12.5.378

Abstract

BACKGROUND/OBJECTIVES
Benign prostatic hypertrophy (BPH) is a major cause of abnormal overgrowth of the prostate mainly in the elderly. Corni Fructus has been reported to be effective in the prevention and treatment of various diseases because of its strong antioxidant effect, but its efficacy against BPH is not yet known. This study was designed to evaluate the therapeutic efficacy of Corni Fructus water extract (CF) in testosterone-induced BPH rats.
MATERIALS/METHODS
To induce BPH, rats were intraperitoneal injected with testosterone propionate (TP). Rats in the treatment group were orally administered with CF with TP injection, and finasteride, which is a selective inhibitor of 5α-reductase type 2, was used as a positive control.
RESULTS
Our results showed that the increased prostate weight and histopathological changes in BPH model rats were suppressed by CF treatment. CF, similar to the finasteride-treated group, decreased the levels of testosterone and dihydrotestosterone by TP treatment in the serum, and it also reduced 5α-reductase expression and concentration in prostate tissue and serum, respectively. In addition, CF significantly blocked the expression of the androgen receptor (AR), AR co-activators, and proliferating cell nuclear antigen in BPH rats, and this blocking was associated with a decrease in prostate-specific antigen levels in serum and prostate tissue.
CONCLUSIONS
These results suggest that CF may weaken the BPH status through the inactivation of at least 5α-reductase and AR activity and may be useful for the clinical treatment of BPH.

Keyword

Benign prostatic hyperplasia; corni fructus; dihydrotestosterone; androgen receptor; prostate-specific antigen

MeSH Terms

Aged
Animals
Antioxidants
Cornus*
Dihydrotestosterone
Finasteride
Humans
Proliferating Cell Nuclear Antigen
Prostate
Prostate-Specific Antigen
Prostatic Hyperplasia*
Rats*
Receptors, Androgen*
Testosterone
Testosterone Propionate
Water
Antioxidants
Dihydrotestosterone
Finasteride
Proliferating Cell Nuclear Antigen
Prostate-Specific Antigen
Receptors, Androgen
Testosterone
Testosterone Propionate
Water

Figure

• 

  Fig. 1 Flow diagram of the experimental procedure: a rat model of BPH. Control, corn oil-injected and PBS-treated rats; BHP, TP (3 mg/kg)- and PBS-treated rats; CF-250, TP (3 mg/kg)- and CF (250 mg/kg)-treated rats; CF-500, TP (3 mg/kg)- and CF (500 mg/kg)-treated rats; CF-750, TP (3 mg/kg)- and CF (750 mg/kg)-treated rats; FINA, TP (3 mg/kg)- and finasteride (5 mg/kg)-treated rats. BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; TP, testosterone propionate; FINA, finasteride.

• 

  Fig. 2 Effects of CF administration on prostate weights in TP-induced BPH rats. Changes in the prostate total weight (A) and relative prostate weight ratio (B) were assessed for the control, BPH-induced, CF-, and FINA (finasteride)-treated groups. The data shown represent the mean ± SEM of six rats per group (P < 0.05). BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride.

• 

  Fig. 3 Effects of CF administration on the histological changes in the prostate tissues of TP-induced BPH rats. Representative photomicrographs of the H&E-stained prostate tissues are presented (magnification, 200X). Control, corn oil-injected and PBS-treated rats; BHP, TP (3 mg/kg)- and PBS-treated rats; CF-250, TP (3 mg/kg)- and CF (250 mg/kg)-treated rats; CF-500, TP (3 mg/kg)- and CF (500 mg/kg)-treated rats; CF-750, TP (3 mg/kg)- and CF (750 mg/kg)-treated rats; FINA, TP (3 mg/kg)- and finasteride (5 mg/kg)-treated rats. BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride.

• 

  Fig. 4 Effects of CF administration on testosterone and DHT in serum of TP-induced BPH rats. The serum concentrations of testosterone (A) and DHT (B) were examined by ELISA. The data shown represent the mean ± SEM of six rats per group (P < 0.05). BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride; DHT, dihydrotestosterone.

• 

  Fig. 5 Effects of CF administration on 5α-reductase type 2 in TP-induced BPH rats. (A) The serum concentrations of 5α-reductase type 2 were examined by ELISA. The data shown represent the mean ± SEM of six rats per group (P < 0.05). (B) Representative photomicrographs of prostate tissues immunostained with an anti-5α-reductase type 2 are presented (magnification, 200X). Control, corn oil-injected and PBS-treated rats; BHP, TP (3 mg/kg)- and PBS-treated rats; CF-250, TP (3 mg/kg)- and CF (250 mg/kg)-treated rats; CF-500, TP (3 mg/kg)- and CF (500 mg/kg)-treated rats; CF-750, TP (3 mg/kg)- and CF (750 mg/kg)-treated rats; FINA, TP (3 mg/kg)- and finasteride (5 mg/kg)-treated rats. (C and D) The expression levels of 5α-reductase type 2 in prostate tissues were determined by Western blotting. The experiment was repeated three times among different experimental groups, and all the results were similar (C). Actin was used as an internal control. Values are mean ± SD of data from three separate experiments (P < 0.05) (D). BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride.

• 

  Fig. 6 Effects of CF administration on AR expression in TP-induced BPH rats. (A) Representative photomicrographs of prostate tissues immunostained with an anti-AR are presented (magnification, 200X). Control, corn oil-injected and PBS-treated rats; BHP, TP (3 mg/kg)- and PBS-treated rats; CF-250, TP (3 mg/kg)- and CF (250 mg/kg)-treated rats; CF-500, TP (3 mg/kg)- and CF (500 mg/kg)-treated rats; CF-750, TP (3 mg/kg)- and CF (750 mg/kg)-treated rats; FINA, TP (3 mg/kg)- and finasteride (5 mg/kg)-treated rats. (B and C) The expression levels of AR, AR co-activators (ARA70 and SRC1) and PCNA were determined by Western blotting. The experiment was repeated three times among different experimental groups, and all the results were similar (B). Actin was used as an internal control. Values are mean ± SD of data from three separate experiments (P < 0.05) (C). BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride; DHT, dihydrotestosterone; AR, androgen receptor; ARA70, AR-associated protein 70; SRC1, steroid receptor coactivator-1; PCNA, proliferating cell nuclear antigen.

• 

  Fig. 7 Effects of CF administration on PSA in TP-induced BPH rats. (A) The serum concentrations of PSA were examined by ELISA. The data shown represent the mean ± SEM of six rats per group. The ***P < 0.001 vs. Control group; ##P < 0.005, ###P < 0.001 vs. BPH group. (B and C) The expression levels of PSA in prostate tissues were determined by Western blotting. The experiment was repeated three times among different experimental groups, and all the results were similar. Actin was used as an internal control. Values are mean ± SD of data from three separate experiments (P < 0.05) (C). BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; FINA, finasteride; PSA, prostate-specific antigen.

• 

  Fig. 8 A suggested schematic model for the inhibitory effect of CF on pathogenesis of BPH. BPH, benign prostatic hyperplasia; CF, Corni Fructus water extract; DHT, dihydrotestosterone; AR, androgen receptor; ARA70, AR-associated protein 70; SRC1, steroid receptor coactivator-1;PAS, prostate-specific antigen.

Reference

1. Cornu JN, Ahyai S, Bachmann A, de la Rosette J, Gilling P, Gratzke C, McVary K, Novara G, Woo H, Madersbacher S. A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol. 2015; 67:1066–1096.

2. Pyo JS, Cho WJ. Systematic review and meta-analysis of prostatic artery embolisation for lower urinary tract symptoms related to benign prostatic hyperplasia. Clin Radiol. 2017; 72:16–22.

3. Aaron L, Franco OE, Hayward SW. Review of prostate anatomy and embryology and the etiology of benign prostatic hyperplasia. Urol Clin North Am. 2016; 43:279–288.

4. Strand DW, Costa DN, Francis F, Ricke WA, Roehrborn CG. Targeting phenotypic heterogeneity in benign prostatic hyperplasia. Differentiation. 2017; 96:49–61.

5. Vignozzi L, Rastrelli G, Corona G, Gacci M, Forti G, Maggi M. Benign prostatic hyperplasia: a new metabolic disease? J Endocrinol Invest. 2014; 37:313–322.

6. Steers WD. 5alpha-reductase activity in the prostate. Urology. 2001; 58:17–24.

7. Nicholson TM, Ricke WA. Androgens and estrogens in benign prostatic hyperplasia: past, present and future. Differentiation. 2011; 82:184–199.

8. Andriole G, Bruchovsky N, Chung LW, Matsumoto AM, Rittmaster R, Roehrborn C, Russell D, Tindall D. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol. 2004; 172:1399–1403.

9. Azzouni F, Mohler J. Role of 5α-reductase inhibitors in benign prostatic diseases. Prostate Cancer Prostatic Dis. 2012; 15:222–230.

10. Gharaee-Kermani M, Macoska JA. Promising molecular targets and biomarkers for male BPH and LUTS. Curr Urol Rep. 2013; 14:628–637.

11. Ho CK, Habib FK. Estrogen and androgen signaling in the pathogenesis of BPH. Nat Rev Urol. 2011; 8:29–41.

12. Thorner DA, Weiss JP. Benign prostatic hyperplasia: symptoms, symptom scores, and outcome measures. Urol Clin North Am. 2009; 36:417–429.

13. Smith RD, Patel A. Transurethral resection of the prostate revisited and updated. Curr Opin Urol. 2011; 21:36–41.

14. Traish AM, Melcangi RC, Bortolato M, Garcia-Segura LM, Zitzmann M. Adverse effects of 5α-reductase inhibitors: what do we know, don't know, and need to know? Rev Endocr Metab Disord. 2015; 16:177–198.

15. Lepor H. Alpha-blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am. 2016; 43:311–323.

16. Chang JS, Chiang LC, Hsu FF, Lin CC. Chemoprevention against hepatocellular carcinoma of Cornus officinalis in vitro. Am J Chin Med. 2004; 32:717–725.

17. Kang DG, Moon MK, Lee AS, Kwon TO, Kim JS, Lee HS. Cornuside suppresses cytokine-induced proinflammatory and adhesion molecules in the human umbilical vein endothelial cells. Biol Pharm Bull. 2007; 30:1796–1799.

18. Jiang WL, Chen XG, Zhu HB, Hou J, Tian JW. Cornuside attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons. Pharmacology. 2009; 84:162–170.

19. Jeong EJ, Kim TB, Yang H, Kang SY, Kim SY, Sung SH, Kim YC. Neuroprotective iridoid glycosides from Cornus officinalis fruits against glutamate-induced toxicity in HT22 hippocampal cells. Phytomedicine. 2012; 19:317–321.

20. Telang NT, Li G, Sepkovic DW, Bradlow HL, Wong GY. Antiproliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor-positive clinical breast cancer. Mol Med Rep. 2012; 5:22–28.

21. Zhang QC, Zhao Y, Bian HM. Antiplatelet activity of a novel formula composed of malic acid, succinic acid and citric acid from Cornus officinalis fruit. Phytother Res. 2013; 27:1894–1896.

22. Sun X, Kong L, Zhou L. Protective effect of Fructus corni polysaccharide on hippocampal tissues and its relevant mechanism in epileptic rats induced by lithium chloride-pilocarpine. Exp Ther Med. 2018; 16:445–451.

23. Hwang KA, Hwang YJ, Song J. Antioxidant activities and oxidative stress inhibitory effects of ethanol extracts from Cornus officinalis on raw 264.7 cells. BMC Complement Altern Med. 2016; 16:196.

24. Park JY, Han AR, Kil YS, Kang U, Kim SH, Nam SJ, Seo EK. A new secoiridoid glycoside from the fruits of Cornus officinalis (Cornaceae). Nat Prod Res. 2016; 30:1504–1510.

25. Yoon JH, Youn K, Ho CT, Karwe MV, Jeong WS, Jun M. p-Coumaric acid and ursolic acid from Corni fructus attenuated β-amyloid(25-35)-induced toxicity through regulation of the NF-κB signaling pathway in PC12 cells. J Agric Food Chem. 2014; 62:4911–4916.

26. Ma W, Wang KJ, Cheng CS, Yan GQ, Lu WL, Ge JF, Cheng YX, Li N. Bioactive compounds from Cornus officinalis fruits and their effects on diabetic nephropathy. J Ethnopharmacol. 2014; 153:840–845.

27. Minciullo PL, Inferrera A, Navarra M, Calapai G, Magno C, Gangemi S. Oxidative stress in benign prostatic hyperplasia: a systematic review. Urol Int. 2015; 94:249–254.

28. Bostanci Y, Kazzazi A, Momtahen S, Laze J, Djavan B. Correlation between benign prostatic hyperplasia and inflammation. Curr Opin Urol. 2013; 23:5–10.

29. Keam SJ, Scott LJ. Dutasteride: a review of its use in the management of prostate disorders. Drugs. 2008; 68:463–485.

30. Traish AM. 5α-reductases in human physiology: an unfolding story. Endocr Pract. 2012; 18:965–975.

31. Pihlajamaa P, Sahu B, Jänne OA. Determinants of receptor- and tissue-specific actions in androgen signaling. Endocr Rev. 2015; 36:357–384.

32. Robins DM. Androgen receptor and molecular mechanisms of male-specific gene expression. Novartis Found Symp. 2005; 268:42–52.

33. Prins GS. Molecular biology of the androgen receptor. Mayo Clin Proc. 2000; 75:Suppl. S32–S35.

34. Watanabe M, Yamada Y, Kato H, Imai H, Nakano H, Araki T, Shiraishi T. Malignant phyllodes tumor of the prostate: retrospective review of specimens obtained by sequential transurethral resection. Pathol Int. 2002; 52:777–783.

35. Cunha GR, Wang YZ, Hayward SW, Risbridger GP. Estrogenic effects on prostatic differentiation and carcinogenesis. Reprod Fertil Dev. 2001; 13:285–296.

36. Huang J, Zhang Y, Dong L, Gao Q, Yin L, Quan H, Chen R, Fu X, Lin D. Ethnopharmacology, phytochemistry, and pharmacology of Cornus officinalis Sieb. et Zucc. J Ethnopharmacol. 2018; 213:280–301.

37. Park CH, Noh JS, Park JC, Yokozawa T. Beneficial effect of 7-O-galloyl-D-sedoheptulose, a polyphenol isolated from Corni fructus, against diabetes-induced alterations in kidney and adipose tissue of type 2 diabetic db/db mice. Evid Based Complement Alternat Med. 2013; 2013:736856.

38. Vareed SK, Schutzki RE, Nair MG. Lipid peroxidation, cyclooxygenase enzyme and tumor cell proliferation inhibitory compounds in Cornus kousa fruits. Phytomedicine. 2007; 14:706–709.

39. Wang W, Sun F, An Y, Ai H, Zhang L, Huang W, Li L. Morroniside protects human neuroblastoma SH-SY5Y cells against hydrogen peroxide-induced cytotoxicity. Eur J Pharmacol. 2009; 613:19–23.

40. Xu H, Shen J, Liu H, Shi Y, Li L, Wei M. Morroniside and loganin extracted from Cornus officinalis have protective effects on rat mesangial cell proliferation exposed to advanced glycation end products by preventing oxidative stress. Can J Physiol Pharmacol. 2006; 84:1267–1273.

41. Xu YD, Cui C, Sun MF, Zhu YL, Chu M, Shi YW, Lin SL, Yang XS, Shen YQ. Neuroprotective effects of loganin on MPTP-induced Parkinson's disease mice: neurochemistry, glial reaction and autophagy studies. J Cell Biochem. 2017; 118:3495–3510.