Nutr Res Pract.  2023 Feb;17(1):32-47. 10.4162/nrp.2023.17.1.32.

Mixture of Corni Fructus and Schisandrae Fructus improves testosterone-induced benign prostatic hyperplasia through regulating 5α-reductase 2 and androgen receptor

• Hwangbo H
• Kim MY
• Ji SY
• Park BS
• Kim T
• Yoon S
• Kim H
• Kim SY
• Jung H
• Kim T
• Lee H
• Kim GY
• Choi YH

• KMID: 2539451
• DOI: http://doi.org/10.4162/nrp.2023.17.1.32

Abstract

BACKGROUND/OBJECTIVES
Benign prostatic hyperplasia (BPH) characterized by an enlarged prostate gland is common in elderly men. Corni Fructus (CF) and Schisandrae Fructus (SF) are known to have various pharmacological effects, including antioxidant and anti-inflammatory activities. In this study, we evaluated the inhibitory efficacy of CF, SF, and their mixture (MIX) on the development of BPH using an in vivo model of testosteroneinduced BPH.
MATERIALS/METHODS
Six-week-old male Sprague-Dawley rats were randomly divided into seven groups. To induce BPH, testosterone propionate (TP) was injected to rats except for those in the control group. Finasteride, saw palmetto (SP), CF, SF, and MIX were orally administered along with TP injection. At the end of treatment, histological changes in the prostate and the level of various biomarkers related to BPH were evaluated.
RESULTS
Our results showed that BPH induced by TP led to prostate weight and histological changes. Treatment with MIX effectively improved TP-induced BPH by reducing prostate index, lumen area, epithelial thickness, and expression of BPH biomarkers such as 5α-reductase type 2, prostate-specific antigen, androgen receptor, and proliferating cell nuclear antigen compared to treatment with CF or SF alone. Moreover, MIX further reduced levels of elevated serum testosterone, dihydrotestosterone, and prostate-specific antigen in BPH compared to the SP, a positive control. BPH was also improved more by MIX than by CF or SF alone.
CONCLUSIONS
Based on the results, MIX is a potential natural therapeutic candidate for BPH by regulating 5α-reductase and AR signaling pathway.

Keyword

3-Oxo-5-alpha-steroid 4-dehydrogenase; androgen receptor; prostatic hyperplasia; Cornus; Schisandra

Figure

• 

  Fig. 1 Effects of ethanol extracts of CF and SF, and their mixture (MIX) on prostate weight and volume in TP-induced BPH rats. The rats with BPH induced by TP (3 mg/kg) were treated with SP(45 mg/kg), finasteride (Fina, 5 mg/kg) as a PC, CF (50 mg/kg), SF (50 mg/kg), and MIX (50 mg/kg). Changes in prostate weight (A), prostate index (B), and width of VP (C). Data are expressed as the mean ± SD (n = 6). (D) Representative photographs of prostate tissue in each group.Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; AP, anterior prostate lobe; DP, dorsal prostate lobe; VP, ventral prostate lobe; TP, testosterone propionate; DW, distilled water.***P < 0.001 compared to the control group. ##P < 0.01 and ###P < 0.001 compared to the BPH group.

• 

  Fig. 2 Effects of CF, SF, and MIX on histological changes in TP-induced BPH rats. Representative images of hematoxylin and eosin-stained prostate (A) and testis (B) tissue are shown. Scale bar = 100 μm. (C) The lumen area of the prostate tissue in each group was measured. (D) The thickness of epithelium tissue from prostate in each group was evaluated. Each value indicates the mean ± SD (n = 6).Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; TP, testosterone propionate; DW, distilled water.***P < 0.001 compared to the control group. ##P < 0.01 and ###P < 0.001 compared to the BPH group.

• 

  Fig. 3 Effects of CF, SF, and MIX on the expression and concentration of 5α-reductase type 2 in TP-induced BPH rats. (A) Expression of 5α-reductase type 2 in prostate tissues of each group was determined by immunohistochemistry. Scale bar = 100 μm. (B) 5α-reductase type 2 expression was quantified in the regions of each group. The levels of SRD5A2 (C), testosterone (D) and DHT (E) in serum of each group were detected through ELISA analysis. Each value indicates the mean ± SD (n = 6).Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; SRD5A2, 5α-reductase type 2; DHT, dihydrotestosterone; TP, testosterone propionate; DW, distilled water.***P < 0.001 compared to the control group. #P < 0.05, ##P < 0.01 and ###P < 0.001 compared to the BPH group.

• 

  Fig. 4 Effects of CF, SF and MIX on the expression of PSA and PCNA in TP-induced BPH rats. (A) The serum concentrations of PSA in each group were examined by ELISA. (B and C) The expression of PSA and PCNA in prostate tissues of each group examined by immunohistochemistry. Scale bar = 50 μm. (D and E) The expression of PSA and PCNA in prostate tissues was quantified. Data are expressed as the mean ± SD (n = 6).Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; PSA, prostate-specific antigen; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; PCNA, proliferating cell nuclear antigen; TP, testosterone propionate; DW, distilled water.***P < 0.001 compared to the control group. ##P < 0.01 and ###P < 0.001 compared to the BPH group.

• 

  Fig. 5 Effects of CF, SF, and MIX on AR and its co-activators in prostate tissues of TP-induced BPH rats. To evaluate the expression of AR, ARA70, and SRC1, paraffin blocks of prostate tissue of each group were sectioned into 4 μm in thickness and stained with specific antibodies (n = 6). Representative images of prostate tissues immunostained with an anti-AR (A), ARA70 (B), SRC1 (C), and α-SMA (D) are presented. Scale bar = 50 μm. Quantifications of immunohistochemistry staining of AR (E), ARA70 (F), SRC1 (G), and α-SMA (H). Data are expressed as the mean ± SD (n = 6).Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; AR, androgen receptor; ARA70, AR coactivator 70; SRC1, steroid receptor coactivator 1; α-SMA, α-smooth muscle actin; TP, testosterone propionate; DW, distilled water.***P < 0.001 compared to the control group. ##P < 0.01 and ###P < 0.001 compared to the BPH group.

• 

  Fig. 6 Effects of CF, SF, and MIX on expression of growth factors, Bax, and Bcl-2 in prostate tissues of TP-induced BPH rats. After treatment with TP and/or chemicals for 7 wk, the prostate tissues were obtained and their paraffin blocks of prostate tissues were sectioned into 4 μm in thickness and stained with specific antibodies. The prostatic expression levels of epidermal growth factor, basic fibrosis growth factor, Bax, and Bcl-2 were detected by immunohistochemistry (n = 6). Scale bar = 50 μm. Quantifications of IHC staining of EGF (E), bFGF (F), Bax (G), and Bcl-2 (H). Data are expressed as the mean ± SD (n = 6).Con group, corn oil injection and DW fed group; BPH group, TP injection and DW fed group; SP group, TP injection and saw palmetto fed group; PC group, TP and finasteride injection group; CF group, TP injection and CF fed group; SF group, TP injection and SF fed group; MIX group, TP injection and SF/CF mixture fed group; BPH, benign prostatic hyperplasia; SP, saw palmetto; PC, positive control; CF, Corni Fructus; SF, Schisandrae Fructus; TP, testosterone propionate; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; DW, distilled water.***P < 0.001 compared to the control group. ##P < 0.01 and ###P < 0.001 compared to the BPH group.

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