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. 2024 Dec 31;11(1):e70184. doi: 10.1002/vms3.70184

Portulaca oleracea Extract Ameliorates Testosterone Propionate‐Induced Benign Prostatic Hyperplasia in Male Sprague‐Dawley Rats

Young‐Ju Lim 1, Hye Rim Kim 2, Seul Bi Lee 2, Sang Back Kim 2, Dong‐Hee Kim 3, Jae‐Hyun So 3, Kyung‐Ku Kang 4, Soo‐Eun Sung 4, Joo‐Hee Choi 4, Minkyoung Sung 4, Yeon‐Ji Lee 4, Wook‐Tae Park 1, Gun Woo Lee 1, Seul‐Ki Kim 5, Min‐Soo Seo 6,✉
PMCID: PMC11687364  PMID: 39739367

ABSTRACT

Benign prostatic hyperplasia (BPH) is a distressing health problem that can cause serious complications in aging men. Androgens are implicated in the causation of BPH. Portulaca oleracea (PO) is a natural product with diverse pharmacological effects. The objective of this study was to investigate the effect of PO in a rat model of testosterone propionate (TP)‐induced BPH and explore the underlying mechanisms. Thirty‐five Sprague‐Dawley (SD) rats were divided into the following equal groups (n = 7): normal control (NC) group, TP (3 mg/kg) group, finasteride (10 mg/kg) group, 25 and 50 mg/kg PO groups.

At the end of the experiment, the body weights (BWs) of the rats were measured before they were euthanized to the establishment obtain serum and prostate weight (PW). TP‐induced levels of androgen‐related proteins in the prostate were also investigated. In the TP group, prostate size, BW, serum DHT level, prostate epithelial cell thickness and androgen‐related protein level were higher than those in the NC group (p < 0.001). PO reversed TP‐induced BPH in a dose‐dependent manner (p < 0.01) and its effect was similar to that of finasteride. A similar effect of PO on the androgen‐related protein level was also observed. We successfully established a TP‐induced BPH rat model. This is the first study to demonstrate that inhibition of androgen‐related proteins using PO can alleviate BPH.

Keywords: androgen‐related proteins, benign prostatic hyperplasia, Portulaca oleracea, testosterone propionate

Portulaca oleracea (PO) ameliorates BPH by inhibiting AR and SRD5A2 in the testosterone propionate‐induced BPH rat model.

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1. Introduction

Benign prostatic hyperplasia (BPH) is an enlargement of the prostate caused by accelerated proliferation of stromal and epithelial cells but which does not lead to tumourigenesis (Zhang et al. 2016). Histological changes in BPH include increased epithelial thickness and infiltration of epithelial tissue into the luminal area (Elsherbini et al. 2022; Youn et al. 2017). The typical symptoms are lower urinary tract symptoms, acute urinary retention and bladder outlet obstruction (Alawamlh, Goueli, and Lee 2018; Lloyd, Marks, and Ricke 2019; Vande Griend and Linnebur 2012). Most symptomatic patients with BPH are over the age of 50 years, and symptoms of intermittent urinary frequency, incomplete urination and nocturia impair their quality of life (Calogero et al. 2019; Fine and Ginsberg 2008). The cumulative prevalence of BHP has been shown to range from 50% in men aged 50 years to 80% in men aged ≥80 years, with a decadal increment of 10% from the fifth decade of life (Sathianathen et al. 2019). The interplay between hormonal disturbances and cell proliferation is one of the hotspots in BPH research (McVary 2003).

Summary

  • Testosterone propionate induces benign prostatic hyperplasia (BPH) in rats.

  • The imbalance between testosterone and dihydrotestosterone (DHT) is a key element in the pathophysiology of BPH.

  • Portulaca oleracea (PO) is known as the global panacea, as mentioned by the World Health Organization (WHO).

  • Portulaca oleracea alleviated BPH by inhibiting AR and SRD5A2.

  • Portulaca oleracea also alleviated TP‐induced prostate histopathology.

The imbalance between testosterone and dihydrotestosterone (DHT) is a key element in the pathophysiology of BPH (Baig et al. 2019; Csikós et al. 2021). Testosterone, an androgen, is instrumental in the development of the male reproductive system (Welén and Damber 2022; Williams et al. 2001). It is converted to DHT by the action of Type 1 or Type 2 5α‐reductase (Batista and Mendonca 2020). Prostate hyperplasia is caused by DHT‐activating androgen receptor (AR)‐mediated prostate cell proliferation (Mohler et al. 2011). In addition, inflammation has also been implicated in the causation of BPH (Nicholson and Ricke 2011). The prostate of BPH patients exhibits several pro‐inflammatory mediators. IL‐17 is considered an important cytokine in BPH development and progression. Although it is negligible in normal prostate, it is amplified in BPH tissue and secreted mainly by prostate cells. IL‐17, which activates the NFκB pathway, regulates the expression of IL‐6, IL‐8 and IL‐1 in epithelial, endothelial and stromal cells. This triggers the release of TNFα. Interestingly, in mouse models, secretion of IL‐17 increases with aging, a process often associated with BPH (De Nunzio, Presicce, and Tubaro 2016; Jahan et al. 2021; Song et al. 2023). Studies have found increased levels of nuclear factor kappa‐light chain enhancer of activated B cells (NF‐kB) in the prostate tissue of patients with BPH (Vickman et al. 2020).

To date, pharmacological treatment of BPH has focused on alleviating symptoms and reducing prostate growth using α‐1 adrenergic receptor antagonists (α1‐blockers) and 5α‐reductase inhibitors (5ARIs) (Tarter and Vaughan 2006). Finasteride, one of the medications used to treat BPH, blocks the conversion of testosterone to DHT by inhibiting Type 2 5α‐reductase activity (Anitha, Inamadar, and Ragunatha 2009). However, long‐term finasteride treatment may cause side effects such as erectile dysfunction, depression and decreased libido (Ganzer, Jacobs, and Iqbal 2015).

Herbal medicines are used across the world owing to their good safety profile (Csikós et al. 2021). The use of phytotherapy has increased significantly in the United States. Some herbs are a rich source of antioxidants. Portulaca oleracea (PO), mentioned by the WHO as one of the most widely used medicinal plant, is known as the ‘global panacea’ (Sadeghi et al. 2019; Zhou et al. 2015). It is an annual succulent plant that is considered an excellent food supplement due to its high nutritional and antioxidant properties (Al‐Quwaie et al. 2023; Hadjzadeh et al. 2022; Qian et al. 2023). Various parts of this plant are rich in pectin, proteins, carbohydrates, unsaturated fatty acids, iron, copper, potassium, calcium and melatonin (Park, Kim, and Bae 2011). The antioxidant, analgesic, anti‐inflammatory, neuroprotective, hepatoprotective and anti‐tumour properties of PO have been extensively studied (Chen et al. 2012; Qiao et al. 2019; Samarghandian, Borji, and Farkhondeh 2017). The objective of this study was to investigate the PO extract that improves testosterone propionate (TP)‐induced BPH in rats and to explore the underlying mechanisms.

2. Materials and Methods

2.1. Chemicals and Reagents

TP was purchased from Wako Pure Chemicals (TCI, Japan, Cat# T0028, CAS RN 57‐85‐2). Finasteride was supplied by Merck & Co. Inc. (Kenilworth, NJ, USA). Antibodies against AR (1:500; Abcam, Cambridge, UK), SRD5A2 (1:500; Invitrogen, Carlsbad, CA, USA) and β‐actin (1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) were also procured.

2.2. Animals and Grouping

Thirty‐five specific‐pathogen‐free male Sprague‐Dawley (SD) rats (weight: 230–270 g; age: 6 weeks) were purchased from the ORIENT BIO Inc. (Seoul, Korea). The rats were divided into the following five groups: normal control (NC) group (n = 7), TP(3 mg/kg) only (n = 7), finasteride (10 mg/kg) group as the positive control group (n = 7) and two experimental BPH‐treated groups with PO 25 mg/kg and PO 50 mg/kg, (Sigma‐Aldrich) groups (n = 7 each) (Table 1). Each group received oral administration (P.O.).

TABLE 1.

Animal grouping (oral administration).

Number Group N
1 Normal control 7
2 Testosterone propionate (3 mg/kg) 7
3 Testosterone propionate (3 mg/kg) + Finasteride (10 mg/kg) 7
4 Testosterone propionate (3 mg/kg) + Portulaca oleracea (25 mg/kg) 7
5 Testosterone propionate (3 mg/kg) + Portulaca oleracea (50 mg/kg) 7
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Five to seven animals were housed together in polypropylene cages (200 × 260 × 130 mm3) in a controlled environment (room temperature: 22°C ± 2°C; humidity: 50% ± 5%; and 12/12 h day/night cycle). After a 7 day acclimatization period, the rats were assigned to various groups. All rats received treatment once a day for 28 days (Chaudhari and Nampoothiri 2017; Solanki et al. 2021). All animals were weighed twice a week. At the end of the study, rats were weighed and anaesthetized using 3% isoflurane (Hana Pharm, Seoul, Korea). The prostate was rapidly dissected, and the ventral area was examined and weighed. Portions of prostate tissue were fixed in 10% neutral buffered formalin for histological studies.

2.3. Induction and Confirmation of TP‐BPH Rat Model

As shown in Figure 1A, we established a rat model of TP‐induced BPH. After the acclimatization period, the rats were divided into groups. Samples were administered to each experimental group for 28 days.

FIGURE 1.

FIGURE 1

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Effect of Portulaca oleracea on prostatic hypertrophy in TP‐induced BPH rat model. A testosterone propionate‐induced BPH model was established. (A) Experimental schedule showing that each experimental group was administered simultaneously. (B) Representative images showing changes in prostate tissue in each experimental group on Day 28 (Scale bar = 1 cm). NC, normal control; TP, testosterone propionate.

2.4. Analysis of Levels of DHT

The serum level of DHT was determined using an enzyme‐linked immunosorbent assay kit (Biovision, E4604‐100) according to the manufacturer's instructions.

2.5. Histological Examination

The prostate samples fixed in 10% neutral buffered formalin were trimmed after 48 h at 4°C. Specimens were dehydrated by passage through a graded ethanol series, permeabilized with xylene and embedded in paraffin. Paraffin‐embedded specimens were cut into 4‐µm‐thick sections using a microtome (Leica RM2235, Leica Microsystems, Nussloch, Germany) mounted on a Superfrost Plus microscope slide (Fisher Scientific, Pittsburgh, PA, USA). Serial sections were stained with haematoxylin & eosin (H&E) using Dako CoverStainer (Agilent, Santa Clara, CA, USA). Immunohistochemical (IHC) staining was also performed to determine the expression of androgen‐related proteins. The prostate sections were stained with antibodies against AR (1:500; Abcam, Cambridge, UK) and SRD5A2 (1:500; Invitrogen, Carlsbad, CA, USA) using Dako EnVision+System‐HRP (Agilent) according to the manufacturer's instructions. After staining, prostate sections were scanned with a panoramic scan II scanner (3DHISTECH Kft., Budapest, Hungary). Prostate epithelial thickness was quantified using ImageJ software version 1.53a (NIH, Bethesda, MD, USA).

2.6. Western Blot

Western blotting was used to determine protein expressions of androgen‐related markers. Snap‐frozen prostate tissue was homogenized in RIPA buffer containing M‐PER and Halt Protease and phosphatase inhibitor cocktail (Thermo Fisher Scientific). Sample concentration was determined using the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific) according to the manufacturer's instructions. Lysates were centrifuged at 3000 g for 10 min at 4°C to remove solid tissue and debris. The supernatant was then centrifuged at 14,000 g for 20 min at 4°C to obtain soluble cytosolic proteins. Protein samples (100 g/well) were loaded on 8%–12% SDS‐polyacrylamide gels and transferred to polyvinylidene fluoride (PVDF) membranes (Invitrogen). The membranes were then blocked with TBS‐T supplemented with 5% skim milk for 1.5 h at room temperature. After blocking, membranes were incubated overnight with AR (1:500; Abcam, Cambridge, UK), SRD5A2 (1:500; Invitrogen, Carlsbad, CA, USA) and β‐actin (1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) at 4°C. After washing, the membranes were incubated with secondary antibodies for 2 h at room temperature. Signals were detected using the ECL reagent (Advansta, Menlo Park, CA, USA) according to the manufacturer's protocol. Analysis was performed using ImageQuant LAS 4000 (GE Healthcare, Buckinghamshire, UK).

2.7. PO L. Bioconversion Extraction Method

To establish the method and reaction conditions for bioconversion of 70% alcohol extract of purslane (PO L. from China, Human Herb), Aspergillus crude enzyme solution was used to verify enzyme titre, review production conditions for carbohydrate hydrolytic enzyme and bioconversion. The optimal reaction conditions (reaction temperature, pH, enzyme concentration, substrate concentration) of carbohydrase were set. Purslane (200 g) was extracted and concentrated in 70% ethanol for 24 h; then, 2 g of the freeze‐dried powder was dissolved in 20 mL of distilled water, followed by the addition of 20 mL of crude enzyme solution derived from Aspergillus kawachii. The resultant mixture was shaken at 200 rpm at 30°C for 24 h. Bioconversion was carried out during the period. Subsequently, an equal amount of ethyl acetate was added and re‐extracted for 24 h while shaking at 200 rpm. Then, vacuum decompression was performed to remove ethyl acetate, and freeze‐drying was performed to obtain a sample in powder form for experimental use (Abdullah and Kusumaningtyas 2020; He et al. 2021; Yang et al. 2016).

2.8. Statistical Analysis

The data were analysed by Student's t‐test using Excel software (Microsoft, Redmond, WA, USA) and expressed as the mean ± standard error. Statistically significant data are indicated by asterisks (***p < 0.001, **p < 0.01, *p < 0.05, ###p < 0.001).

3. Results

3.1. PO Attenuated Prostatic Hypertrophy in a Dose‐Dependent Manner in TP‐Induced BPH Rat Model

We dissected TP‐induced BPH rats. First, we evaluated the macroscopic features of BPH. Administration of TP to rats for 28 days led to significantly larger prostates compared to those in the NC group, indicating the establishment of the BPH model. However, the finasteride group (positive control group) showed significantly lower prostate enlargement compared to the TP group. Moreover, the PO groups (25 and 50 mg/kg) showed reduced prostate hypertrophy in a dose‐dependent manner (Figure 1B).

3.2. PO Improved Prostate Weight (PW) in a Dose‐Dependent Manner in TP‐Induced BPH Rat Model

As shown in Figure 2, the PW to body weight (BW) ratio was significantly increased in the TP group compared to the NC group. Unlike rats in the TP group, rats in the finasteride group showed a significant decrease in the PW/BW ratio. In addition, the PW/BW ratio was also decreased in the PO groups (25 and 50 mg/kg).

FIGURE 2.

FIGURE 2

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Effect of Portulaca oleracea on prostate weight of TP‐induced BPH rat model. Analysis of the changes in the prostate weight to body weight (PW/BW) ratio in the TP group, finasteride group, PO 25 and PO 50 mg/kg group. Data expressed as mean ± SD. Statistical significance assessed by One‐way ANOVA followed by post hoc Dunnett's test: ###p < 0.001 versus normal control group; **p < 0.01 versus TP group. NC, normal control; TP, testosterone propionate.

3.3. PO Regulated DHT Levels in Serum of TP‐Induced BPH Rat Model

In this study, rats in the TP group had significantly higher DHT levels compared to rats in the control group. In the finasteride group, the serum DHT concentration was significantly lower than that in the TP group. PO groups (25 and 50 mg/kg) showed lesser reduction in DHT levels compared to that in the finasteride group; however, the serum DHT levels in the PO groups were lower than those in the TP group (Figure 3).

FIGURE 3.

FIGURE 3

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Effect of Portulaca oleracea on DTH levels in serum of TP‐induced BPH rat model. Results of ELISA showing serum DHT levels in TP‐induced BPH rats. Data expressed as mean ± SD. Statistical significance assessed by One‐way ANOVA followed by post hoc Dunnett's test: ###p < 0.001 versus normal control group; *p < 0.05 versus TP group. NC, normal control; TP, testosterone propionate.

3.4. PO Alleviated the Histological Changes in Prostate Tissue of TP‐Induced BPH Rat Model

As shown in Figure 4, rats in the TP group had a thickened muscle layer compared to the NC group. There was decreased multilayered epithelium and decreased glandular lumen in BPH group. The expression of AR in the TP group was higher than that in the NC group. However, administration of finasteride and PO at various concentrations (25 and 50 mg/kg) decreased AR expression. This phenomenon was also observed in the expression of SRD5A2 in prostate tissue. The expression of SRD5A2 increased in the TP group and significantly decreased in the finasteride and PO (25, 50 mg/kg) groups.

FIGURE 4.

FIGURE 4

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Effect of Portulaca oleracea on histological changes in prostate tissue of TP‐induced BPH rat model. Representative photomicrographs of H&E‐stained prostate tissue (panel magnification × 100). Representative photos of AR and SRD5A2 stained sections examined under a light microscope (panel magnification × 100) (Scale bar = 100 µm). AR, androgen receptor; H&E, haematoxylin & eosin; NC, normal control; TP, testosterone propionate.

3.5. PO Reduced the Thickness in Prostate Epithelial Tissue of TP‐Induced BPH Rat Model

The thickness index of the TP group was significantly higher compared to the NC group. In contrast, the finasteride group showed a significantly decreased thickness index. The PO groups (25 and 50 mg/kg) also showed a significant decrease in thickness index in a dose‐dependent manner (Figure 5).

FIGURE 5.

FIGURE 5

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Effect of Portulaca oleracea on prostate epithelial thickness of TP‐induced BPH rat model. Measurement of prostate epithelial tissue thickness in a rat model of testosterone‐induced benign prostatic hyperplasia (BPH). Epithelial thickness of prostate tissue. Data expressed as mean ± SD. Between‐group difference assessed using Student t‐test: ###p < 0.001 versus normal control group; **p < 0.01, ***p < 0.001 versus TP group. NC, normal control; TP, testosterone propionate.

3.6. PO Decreased Protein Expression of AR and Steroid 5‐Alpha Reductase Type II (SRD5A2) of TP‐Induced Rat Model

IHC staining demonstrated the increased expression of AR and SRD5A2 in the BPH model. The protein expression of AR and SRD5A2 in prostate tissue was significantly increased in the TP group compared to the NC group. The protein expression in the finasteride group was significantly lower than that in the TP group. Furthermore, both PO groups (25 and 50 mg/kg) showed a decrease in the protein expression of AR and SRD5A2 (Figure 6A,B).

FIGURE 6.

FIGURE 6

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Effect of Portulaca oleracea on protein expression of AR and SRD5A2 in prostate tissue of TP‐induced BPH rats. (A) Western blots showing protein expression bands of AR and SRD5A2 in each experimental group; (B) Measurements using Image J software. Data expressed as mean ± SD. Between‐group difference assessed using Student t‐test: ###p < 0.001 versus normal control group; **p < 0.01, ***p < 0.001 versus TP group. AR, androgen receptor; NC, normal control; TP, testosterone propionate.

4. Discussion

PO is a medicinal plant used in traditional medicine (Iranshahy et al. 2017). Many studies have demonstrated its anti‐inflammatory, antioxidant and antibacterial properties (Dan 2006; Malek et al. 2004; Wang et al. 2007). However, the potential role of PO in the treatment of BPH has not been studied. The androgen/AR axis plays an important role in the development and function of the prostate and influences prostate‐related pathogenesis (Kim, Jin, and An 2021; Park, Youn, and Um 2019; Wang et al. 2021). Androgens such as testosterone and DHT, which act as ligands, bind to AR. Androgens and AR undergo dimerization, phosphorylation and nuclear translocation and then regulate protein expression through various mechanisms. Increased expression of AR has been observed in benign and malignant prostate diseases (Izumi et al. 2013; Jin et al. 2019), suggesting the role of AR in the development of BPH. Indeed, androgen/AR signalling is considered an important therapeutic target. Androgen deprivation therapy, which reduces androgen levels and blocks the action of AR, is the cornerstone of pharmacological treatment for BPH. Administration of finasteride reduces prostate size in BPH patients, and the therapeutic effect is closely related to the inhibition of androgen conversion (Tempany et al. 1993; Thompson et al. 2003). However, there has been a recent impetus on focusing on the use of natural products for treatment of BPH (Jin et al. 2023; Kim et al. 2023; Park et al. 2022). Many patients use dietary supplements as a long‐term, effective and safe strategy to treat BPH, but their effectiveness and safety are still limited. Therefore, this study investigated the potential effect of PO on BPH and its underlying molecular mechanism in a rat model.

Considering that BPH is characterized by hormonal disturbances and pathological proliferation, we established a TP‐induced rat model of BPH. The prostates of model rats showed pathological changes, including swelling, increased PW index and increased DHT levels compared to normal rats. However, the administration of finasteride and PO suppressed prostate hypertrophy through androgen regulation. We determined the therapeutic effect of PO on pathologically activated epithelial cell proliferation in the prostate tissue of rats with BPH. To determine the underlying mechanism by which PO inhibits prostatic hypertrophy, we investigated the expression of AR and SRD5A2. The results showed overexpression of AR and SRD5A2 in the TP group. However, administration of finasteride and PO (25 and 50 mg/kg) inhibited it. These results indicated that the effects of PO were associated with androgen/AR‐ and SRD5A2‐dependent proliferation (Cao et al. 2019; Jin et al. 2019; Li et al. 2020; Wang et al. 2008). IHC analysis showed that PO administration significantly reduced AR and SRD5A2 compared to the TP group. This suggests that the therapeutic effect of PO on BPH may depend on the inhibition of AR and SRD5A2 regulation.

Some additional considerations in this study need to be discussed. First, PO was not found to be toxic in either high‐concentration extract using saline solution or extract using ethanol (Chen et al. 2009; da Silva et al. 2023). For this reason, we added our fermentation technique to the usual ethanol‐based extraction method to obtain PO extract. As PO is not toxic irrespective of the extraction method, its long‐term administration is not likely to cause side effects in future experiments. Second, this study used 6‐week‐old male rats to induce BPH. As BPH is known as a disease of older men, there may be concerns regarding the extrapolation of our results to humans. However, the mechanisms underlying the development of BPH with age are not fully understood. Many studies have discussed the link among BPH, age and inflammation (Fibbi et al. 2010; Madersbacher, Sampson, and Culig 2019). The BPH‐induced rat model showed a significant increase in urinary frequency and a decrease in urinary volume. This is similar to the clinical symptoms experienced by BPH patients, and recent studies have reported that older rats have an increased incidence of BPH compared to younger rats (Bespalov et al. 2021).

5. Conclusion

In conclusion, PO exerted an inhibitory effect on BPH in the rat model by regulating androgen‐induced proliferative responses. The effect of PO on BPH is likely associated with decreased expression of AR and SRD5A2. Our findings suggest that PO may alleviate BPH by inhibiting AR and SRD5A2.

Author Contributions

All authors were financially involved in the research and/or preparation of the manuscript. Y.‐J.L., H.R.K., M.‐S.S. and S.‐K.K. conceived and designed the study. Y.‐J.L., H.R.K., S.B.L., S.B.K., D.‐H.K., J.‐H.S., K.‐K.K., S.‐E.S., J.‐H.C., M.S., Y.‐J.L., W.‐T.P., G.W.L. acquired and analysed the data. Y.‐J.L. and H.R.K. wrote the article. Y.‐J.L., H.R.K., S.B.L., S.B.K., D.‐H.K., J.‐H.S., K.‐K.K., S.‐E.S., J.‐H.C., M.S., Y.‐J.L. drafted and critically revised the article and were responsible for polishing the manuscript. All the authors have discussed the results and approved the final manuscript.

Ethics Statement

Ethical approval was obtained from the Institutional Animal Care and Use Committee at ORIENT BIO Inc. (Seoul, Korea) before the animal experiment (Approval No. IACUC2202‐017‐01).

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/vms3.70184.

Acknowledgements

This research was supported by Kyungpook National University Research Fund, 2022.

Funding: This research was supported by Kyungpook National University Research Fund, 2022.

Young‐Ju Lim and Hye Rim Kim contributed equally to this work as the first authors.

Seul‐Ki Kim and Min‐Soo Seo contributed equally to this work as the corresponding authors.

Data Availability Statement

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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