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A herbal formula, comprising panax ginseng and bee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male wistar rats


King Saud University Saudi Journal of Biological Sciences A herbal formula, comprising Panax ginseng andbee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male Wistarrats Hyun Kyung Park , Su Kang Kim ,, Sang Won Lee , Joo-Ho Chung Byung-Cheol Lee , Sae Won Na , Chun Gun Park Young Ock Kim a Kohwang Medical Research Institute, School of Medicine, Seoul 130-701, Republic of Koreab Development of Ginseng and Medical Plants Research Institute, Rural Administration, Eumseong 369-873, Republic of Koreac Department of Internal Medicine, College of Oriental Medicine, Seoul 130-702, Republic of Koread Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea Received 8 September 2015; revised 24 October 2015; accepted 30 October 2015 recent study reported that Panax ginseng (P. ginseng) has a protective effect on the development of benign prostatic hyperplasia (BPH). KH053 is used as a new herbal prescription consisting of P. ginseng and bee-pollen. The present study aimed to investigate whether the Benign prostatic hyperplasia; KH053 has inhibition effects on the development of benign prostatic hyperplasia (BPH) using an animal model with testosterone induced BPH. The experiment was carried out in forty male Wistar7 week old rats that were divided into four groups (control group, BPH group, positive group, andKH053 group). One group was used as the control and the three groups received subcutaneousinjections of testosterone 20 mg/kg for 4 weeks to induce BPH. One of them received KH053 byoral gavage daily at doses of 200 mg/kg concurrently with the testosterone. The positive groupreceived finasteride at a dose of 1 mg/kg with testosterone. After 4 weeks, all rats were sacrificedand analyzed for prostate weight, and growth factors. Results revealed that, compared to rats inthe BPH group, KH053 showed that the prostate weight and dihydrotestosterone (DHT) levelsin serum were significantly decreased and the decreases in hyperplasia in prostate were alsoobserved. In addition, immunohistochemistry (IHC) also revealed that the protein expressions of * Corresponding author.
E-mail address: (Y.O. Kim).
1 These authors contributed equally to this research work.
Peer review under responsibility of King Saud University.
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1319-562X Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license ).
Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015), H.K. Park et al.
growth factors [transforming growth factor b1 (TGF-b1) and vascular endothelial growth factor(VEGF)] in prostate tissue were decreased in the KH053 group. In conclusion, these results suggestthat KH053, comprising P. ginseng and bee-pollen, inhibits the development of BPH in Wistar ratmodel and might be used as functional food for BPH.
Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This isan open access article under the CC BY-NC-ND license ( nolic compounds However, the specificchemical composition of bee pollen depends strongly on the prostatic hyperplasia (BPH) is one of the urological bees' species, botanical and geographic origin diseases in old men. The incidence of BPH shows about 50– ). Several studies reported that it has various effects to 60% in men at ages 40–60 and greater than 90% in men over strengthen the resistance of the body to diseases. 80 (). BPH is characterized by an showed that date palm pollen treatment reduced enlargement of the prostate surrounding the urethra leading the number of prostatic acini in the BPH rat model and to constriction of the urethra ). And also decreased the production of pro-inflammatory cytokines. In BPH is characterized by hyper-proliferation of the epithelium the present study, the mixture of P. ginseng and bee pollen is and stromal region ). These characters of designed as formula KH053. The effect of KH053 on a BPH result in voiding problems manifested by difficulty of uri- testosterone-induced BPH rat model was determined.
nation and irritative symptoms respectively (). Although the etiology of BPH has been exactly 2. Materials and methods unknown, it was suggested that sex hormones namely andro-gen, testosterone, and dihydrotestosterone (DHT) might con- 2.1. Plant material tribute to prostatic enlargement in BPH. The a1-adrenergicreceptor (a1-AR) antagonists are the initial drugs for treating The dried roots of P. ginseng and bee pollen were used (Dong- BPH (And the 5-alpha-reductase inhibitors sung Pharmaceuticals, Seoul, Republic of Korea). They were block the action of 5-alpha-reductase, the enzyme that con- identified by Dr. Sang-Won Lee in National Institute of Hor- verts from testosterone into DHT ( ticultural and Herbal Science (NIHHS), and voucher speci- mens (numbers KH13 and H14) were deposited with activity of 5-alpha-reductase inhibitors results in an Department of Medicinal Crop Research Institute, NIHHS, increased testosterone level and decreased DHT level. 5- Eumsung. We selected P. ginseng for this research. P. ginseng alpha-reductase inhibitors are used to treat baldness, BPH is sensitive to high heat. As P. ginseng grows the precious and prostate cancer. However, the drug has limitations plants are taken great care daily to insure the highest quality.
because of its side effects, such as decreased libido, erectile dys- The P. ginseng garden is covered with straw to control weeds function, and nasal congestion ).
and protect the sensitive young plants from the long cold Thus, alternative herbal-based therapy has been investigated Medicinal plants have various applica-tions in the treatment of diseases (Recentstudies showed that a commonly used medicinal plant has an 2.2. Preparation of KH053 effective effect on the treatment of BPH or an inhibited effecton the development of BPH. showed that The dried roots of P. ginseng and bee pollen were extracted Panax ginseng has an inhibited effect on BPH in the animal separately with 100% water for 6 h in a reflux apparatus. After BPH model. Another research also reported that Red ginseng refluxing, the extracts were filtered, the filtrates were evapo- and 20(S)-Rg3 regulated testosterone-induced prostate hyper- rated in a rotary evaporator, and the samples were lyophilized plasia by deregulating androgen receptor signaling ( in a freeze dryer (Operon, Gyeonggi, Republic of Korea). The Ginseng has been known as the name of the root extract yields of P. ginseng, was 21%. Each herb of KH053 of P. ginseng. It is variously used to treat specific diseases, as was mixed in the following ratio: P. ginseng:A. japon- traditional medicine in East Asia. And numerous studies ica = 12:28. The KH053 was dissolved in distilled water and showed that P. ginseng has protective effects against degener- sequentially passed through 0.22-lm filters for sterilization.
ative and aging diseases, such as neurodegenerative diseases), anti lipid accumulation ), dia- betic nephropathy (), osteoporosis (), regulating the inflammatory response ( Seven-week-old male Wistar rats with an average body weight ischemia, oxidative stress (), and of 250 ± 10 g were brought from animal company (Central potential chemopreventive effects Lab Animal Inc., Seoul, Korea). The animal room was always regulated at 22 ± 2 °C and at 40–70% relative humidity with a pollen is an apicultural product. It includes 12-h light/dark cycle. All experiments were performed accord- nutritionally valuable substances and considerable amounts ing to the protocols approved by the Animal Care Committee of biologically active substances (It is also of the Animal Center at Kyung Hee University [KHUASP rich in carbohydrates, crude fibers, lipids, vitamins, and phe- Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015), Panax ginseng and bee-pollen for inhibition of hyperplasia in rats 2.4. Induction of BPH and treatments Statistical analyses Firstly, the testis organ of the rats was removed to exclude the the values are presented as mean avera ± standard error.
influence of intrinsic testosterone except for the rats in the con- The differences of values between the groups were statistically trol group. The spermatic cord and blood vessels were ligated analyzed by a one-way analysis of variance (ANOVA), fol- with Silkam sutures 3/8–16 mm (B. Braun Surgical SA, Rubi, lowed by a nonparametric post hoc Tukey test. All P-values Spain) and the testis organ was resected. In order to induce are two-tailed and significance was considered as P < 0.05.
BPH in rats, a subcutaneous injection of testosterone All statistical analyses were performed using PASW Statistics (20 mg/kg; Wako chemicals, Tokyo, Japan) for 4 weeks after ver. 22.0 (SPSS Inc., Chicago, IL, USA).
castration was carried out. And, next day, rats were dividedinto 4 groups (each group, n = 10): (1) control group, (2)testosterone-induced (subcutaneous) BPH group, and (3)KH053 treated group (200 mg/kg oral administration). (4)Finasteride (Sigma–Aldrich, St. Louis, MO, USA) treat group Body weight gains in each group.
as positive group. Based on a previous study, we treated rats Total body weight with 200 mg/kg of KH053 ( gains for 30 days (g) All materials were administered to the animals in the morning for 30 days.
2.5. Blood collection and biochemical analysis After 4 weeks, all rats were fasted overnight. Blood was Values are presented as mean ± standard error (n = 10).
obtained from the heart of the rat. Blood was collected in a Control, not treated group; BPH, testosterone induced BPH group; serum separating tube (SST tube). Blood samples were cen- KH053, testosterone induced BPH with KH053 (200 mg/kg) group; trifuged at 3000g for 15 min. The serum was separated from finasteride, testosterone induced BPH with finasteride (1 mg/kg. p.
blood and stored at 20 °C. The total protein, glutamic oxa- loacetic transaminase (GOT, AST), glutamic pyruvic transam-inase (GPT, ALT), and DHT levels were analyzed by Greenlab (Seoul, Korea). After the animals were sacrificed, the tissueof prostate was stored in formaldehyde solution in order toevaluate pathological change and expression of growth factors.
Total protein, AST and ALT serum level in each 2.6. Histopathological examination Total protein (g/dL) Prostate tissues embedded in paraffin wax were cut into 10-lm-thick sections using a microsection machine. Staining with hematoxylin and eosin was firstly performed. The stained pros- tate tissues were mounted and cover slipped using mounting solution and then examined under a microscope.
Values are presented as mean ± standard error (n = 10).
2.7. Immunohistochemistry (IHC) Control, not treated group; BPH, testosterone induced BPH group;KH053, testosterone induced BPH with KH053 (200 mg/kg) group;finasteride, testosterone induced BPH with finasteride (1 mg/kg. p.
After deparaffinization in prostate tissues, immune histochem- istry (IHC) was performed on 10-lm-thick sections. Antigenretrieval was performed using citrate buffer, pH 6.0, for10 min prior to peroxide quenching with 3% H2O2 in phos-phate buffered saline (PBS) for 15 min. The prostate tissueswere then washed in PBS and preblocked with normal goat Prostate weight in each group.
or rabbit serum for 10 min. For reaction with primary anti- body, slides were incubated with anti-transforming growth fac-tor – b1 (TGF-B1) (Santa Cruz Biotechnology, Santa Cruz, CA, USA) in a 1:200 dilution and then anti-vascular endothe- lial growth factor (VEGF) (Santa Cruz Biotechnology) in a 1:500 dilution overnight at 4 °C. The sections were then incu-bated with biotinylated secondary antibodies (1:1000) for 1 h.
Values are presented as mean ± standard error (n = 10).
Following a washing step with PBS, streptavidin–horseradish Control, not treated group; BPH, testosterone induced BPH group;KH053, testosterone induced BPH with KH053 (200 mg/kg) group; peroxidase was applied. Finally, the sections were rinsed in finasteride, testosterone induced BPH with finasteride (1 mg/kg.
PBS and developed with diaminobenzidine tetrahydrochloride p.o.) group.
substrate for 10 min. At least three random fields of each sec- ### P < 0.001 compared with the control group.
tion were examined at 100 ).
** P < 0.01 compared with the BPH group.
Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015),



H.K. Park et al.
3.1. Effect of KH053 on weight change Body weight gains in each group are presented in . Thefinal body weight was measured after 4 weeks. Each groupshowed an increase compared to that of the initial body weight(control group, 111.00 ± 8.59; BPH group, 105.57 ± 5.04;KH053 group, 107.86 ± 19.75; finasteride group; 106.33± 11.84). The differences in weight change among the groupsdid not show any significant (P > 0.05).
3.2. Effect of KH053 on total protein, AST, and ALT levels inserum In order to evaluate toxicity in the liver, AST and ALT were Effects of KH053 on the DHT levels in serum. Control, tested. The AST and ALT levels in serum were not signifi- not treated group; BPH, testosterone induced BPH group; cantly different among groups (KH053 did not pro- KH053, testosterone induced BPH with KH053 (200 mg/kg) mote the activity of the serum toxicity marker enzymes, such group; finasteride, testosterone induced BPH with finasteride as AST and ALT. It is indicated that rats of each group had (1 mg/kg. p.o.) group. ###P < 0.001 compared with the control a normal function of livers. Total protein levels in the serum group. *P < 0.05 compared with the BPH group.
of the BPH group were slightly increased compared to thatof the control group. However, the differences among thegroups did not show any significance (P > 0.05). The total Histological examination. Control, not treated group; BPH, testosterone induced BPH group; KH053, testosterone induced BPH with KH053 (200 mg/kg) group; finasteride, testosterone induced BPH with finasteride (1 mg/kg. p.o.) group. ###P < 0.001compared with the control group. **P < 0.01 and ***P < 0.01 compared with the BPH group.
Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015),


Panax ginseng and bee-pollen for inhibition of hyperplasia in rats protein levels of the KH053 group were slightly elevated com- Effect of KH053 on the histopathology of the prostate tissue pared to those of the control (P > 0.05).
shown in , there was no change in the histoarchitec- 3.3. Effect of KH053 on the prostate ture of prostate gland in the control group. The prostate tissuewas tightly packed; epithelium was cuboidal and regular in Prostate weights of rats in the BPH group (1.94 ± 0.07 g) size. However, the prostate of the BPH group showed prostatic showed a significant increase compared to those of rats in epithelial hyperplasia (P < 0.001). The epithelial cell layer and the control group (0.84 ± 0.03 g; P < 0.001) ( stromal cell space in the BPH group were larger. KH053- KH053 treated groups (1.63 ± 0.06 g, P < 0.01) showed sig- treated rats significantly showed a reduction in both epithelial nificant decreases in prostate weights compared with those of size and thickness of epithelial layer compared with that of the the BPH group. Prostate weights in the finasteride group were BPH group, which was similar to the reduction in finasteride also decreased markedly compared with the BPH group. These results were similar to those for the KH053-treated group.
3.4. Measurement of DHT levels in the serum Expression of VEGF and TGF-b1 in prostate tissue The BPH group showed a significant increase in serum DHTlevel (345 ± 8.17 pg/mL, P < 0.01) compared with the con- order to examine the effects of the administration of KH053 trol group (159 ± 8.34 pg/mL; ). In contrast, the on the expression of growth factors in prostate tissue, In finasteride-treated group showed a significantly reduced serum the protein expressions of growth factors (VEGF and TGF-b1) DHT level (250.57 ± 25.68 pg/mL, P < 0.01) compared with in the BPH group were increased than those of the control the BPH group. Similarly to finasteride-treated group, the group (P < 0.05). These protein expressions of VEGF and KH053-treated groups showed significant reduction in DHT TGF-b1 in both the KH053 group and the finasteride group (249.86 ± 35.07 pg/mL observed a decrease compared with those of the BPH group P < 0.05) compared with the BPH group.
(P < 0.05).
The expressions of TGF-b1 and VEGF immunohistochemistry of prostate tissue from the rats (100). Control, not treated group; BPH, testosterone induced BPH group; KH053, testosterone induced BPH with KH053 (200 mg/kg) group; finasteride,testosterone induced BPH with finasteride (1 mg/kg. p.o.) group. To determinate a mechanism which could explain the effects of KH053on BPH, the expression of TGF-b1 and VEGF in the rat prostates were examined. As shown in immunohistochemical resultsshowed TGF-b1 and VEGF are rarely expressed in normal prostate, weak labeling observed in prostatic tissues in control group.
Immunohistochemical detection also revealed an increase in TGF-b1 and VEGF expression in prostatic epithelial cells in the BPH modelgroup. A moderate expression of TGF-b1 and VEGF was also observed in the BPH model group. Immunohistochemical result shows thatthe level of VEGF was significantly higher in the BPH group, while no significant difference was seen in the KH053 group as comparedwith the finasteride group.
Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015), H.K. Park et al.
main objective of this study was to evaluate whether a This study was supported by grants from the ‘‘Cooperative KH053 could prevent the development of BPH in an animal Research Program for Agriculture Science & Technology model. BPH showed enlargement of the prostate through a Development (Project No. PJ0095582015)" Rural Develop- proliferative process of the stromal and epithelial elements.
ment Administration, Republic of Korea.
KH053 significantly reduced the pathology in inhibiting pros-tate growth in our results. KH053 treated animals showed sig- nificant reductions in prostate weights, DHT, and decreasedprostatic epithelial hyperplasia with decreased TGF-b1 and VEGF expression.
are two drugs used for BPH therapy. They are 5a-reductase inhibitors (5-ARIs) and a-adrenergic receptor blockers (). Thea 1-adrenergic receptor (a1-ARs) antagonists are the initial drugs for treating BPH ). 5-ARIs are related to metabolic transformations of a variety of endogenous ster- oids. 5-ARIs generally prevent conversion of testosterone, DHT in androgen-associated disorders. So, 5-ARIs are used to the treatment of BPH and androgenetic alopecia ). However, the drug has unfavorable side effects, such as orthostatic hypotension, decreased libido, and erectile dysfunction ( connects to nuclear androgen receptors (ARs) on the surface of stromal and epithelial cells. It activates the transcription of various growth factors that are mitogenic for the epithelial and stromal cells of the prostate ( ). Thus, an increased DHT level could contribute to the development of BPH. In our results, KH053 significantly showed a decreased DHT level.
b1 has been known as multifunctional cytokine. It plays an important role in numerous pathways, such as extra- cellular matrix production and degradation, cell differentia- tion, proliferation, and apoptosis ).
VEGF plays a major role in metastasis and angiogenesis.
VEGF is a major factor in angiogenesis as it influences endothelial cell growth () and acts in prostate stimulating the secretion of extracellular matrix ele- ments, proliferation and angiogenesis, and also contributing to the glandular hyperplasia. A previous study reported that DHT could increase the transcription of VEGF and the secre- tion of biologically active VEGF from human prostatic stroma ). In our results, KH053 significantly showed decreased expressions of TGF-b1 and VEGF.
this study, KH053, comprising P. ginseng and bee- pollen, treatment in rats induced BPH effectively reduced pros- tate weight, both epithelial size and thickness of epithelial layer, DHT level compared to those of rats induced BPH. In addition, we observed that KH053 contributed to decreased expressions of TGF-b1 and VEGF in prostate tissues. These results indicate that KH053 has inhibited effects on the devel- opment of BPH in an animal model and may be effective strategies for clinical application of KH053 to BPH. In further studies, clinical trials need to investigate whether KH053 is safe, effective for humans and/or BPH patients.
potential conflict of interest relevant to this article wasreported.
Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015), Panax ginseng and bee-pollen for inhibition of hyperplasia in rats Please cite this article in press as: Park, H.K. et al., A herbal formula, comprising Panax ginseng and bee-pollen, inhibits development of testosterone-induced benignprostatic hyperplasia in male Wistar rats. Saudi Journal of Biological Sciences (2015),

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