Research Progress in Traditional Chinese Medicine Treatment Of Benign Prostatic Hyperplasia Ⅱ

Table 1 Mechanisms of active ingredients of traditional Chinese medicine in treatment of benign prostatic hyperplasia (BPH)

2.2 Single Chinese medicine

2.2.1 Organ-tonifying Chinese medicine

Organ-tonifying Chinese medicine exerts its therapeutic effect by regulating the endocrine environment, enhancing immunity, improving microcirculation, and promoting cell repair and regeneration. Rhodiola rosea is sweet and cold in nature, and has the effect of invigorating qi and activating blood circulation. Studies have shown that its water extract can reduce the levels of 5αR mRNA, DHT, α-SMA, cytokeratin and prostate weight (PW) index, thereby inhibiting BPH cell proliferation[27].

Licorice has multiple functions such as invigorating the spleen and qi, clearing away heat and detoxifying, and relieving pain. Studies have shown that its ethanol extract exhibits anti-proliferative, anti-inflammatory and pro-apoptotic effects in the treatment of BPH. The mechanism is related to downregulating the expression of AR, PSA, 5AR2, DHT, and Bcl-xL, and upregulating the levels of caspase-3, Bax, and poly (ADP-ribose) polymerase[28]. Cordyceps sinensis has the effects of nourishing the lungs and kidneys, stopping bleeding and resolving phlegm, and in modern pharmacology, it has anti-tumor, anti-arrhythmic, and renal function improvement effects. Studies have shown that its water extract exerts an anti-proliferative effect by reducing the expression of T and DHT and upregulating the level of transmembrane protease serine 2[29]. Psoralea corylifolia has multiple effects such as warming the kidney and supporting yang, consolidating semen and reducing urine. Studies have found that its water extract plays an important role in the treatment of BPH by inhibiting BPH cell proliferation, anti-inflammation, and promoting apoptosis. The mechanism may be related to downregulating the expression of Bcl-2, 5AR2 mRNA, AR, PSA, PCNA, and upregulating Bax levels[30]. Studies have shown that the ethanol extract of Cornus officinalis can inhibit cell cycle function, promote proliferation, and promote apoptosis by down-regulating the expression of CDK4, 5AR, Bcl-2, DHT, fibroblast growth factor (FGF)-2, AR, EGF, cyclin D1, and cyclin E, reducing the phosphorylation level of MAPK, and up-regulating the expression of P21, P27, Bax, and Akt phosphorylation, thus playing a role in treating BPH[31]. Astragalus has many functions such as replenishing qi and raising yang, promoting diuresis and reducing swelling, and relieving stagnation and relieving numbness. It is clinically used to treat qi deficiency and fatigue, chronic diarrhea and prolapse of the anus, edema, and proteinuria in chronic nephritis. Zhou Huan et al.[32] found that the water extract of Astragalus has the effects of promoting BPH cell apoptosis, anti-angiogenesis, and anti-inflammatory, and its mechanism is related to down-regulating the expression of Akt1 and VEGF. It has been reported that ginseng can effectively improve brain function, immune function and male erectile dysfunction, and has anti-cancer, antioxidant and anti-aging effects. Its aqueous extract also has an important effect on BPH. The mechanism may be related to downregulating the expression of AR, 5AR2, DHT, ROS, and Bcl-xL, and upregulating the levels of caspase-3 and Bax[33].

2.2.2 Heat-clearing, detoxifying and diuretic 

Chinese medicines regulate the body's water metabolism, improve the local damp-heat environment of the prostate, and reduce inflammatory reactions, thereby relieving symptoms such as frequent urination, urgency, and pain in BPH patients. Kushen has the effects of clearing heat and detoxifying, diuresis and swelling reduction, and exerts anti-infection, anti-inflammatory, immunomodulatory and anti-cancer effects. Studies have shown that the anti-proliferation effect of its ethyl acetate extract on BPH cells is related to the inhibition of 5αR expression [34]. Tianhu Cilantro is mainly used to treat jaundice, dysentery, edema and other diseases. It is well-known for its anti-inflammatory properties in pharmacology. Studies have found that its methanol extract plays a role in treating BPH through anti-proliferation, anti-inflammatory and pro-apoptosis pathways. The mechanism is related to downregulating the expression of PCNA, NF-κB, COX-2 and inducible nitric oxide synthase (iNOS), 5αR mRNA, DHT, T, TNF-α, IL-6, and upregulating Bax and caspase-3 levels [35]. Studies have shown that Plantain ethanol extract exerts antioxidant, anti-inflammatory, and anti-proliferative effects by downregulating the expression of PSA, C-reactive protein (CRP), SOD, and malondialdehyde [36]. Pharmacological studies of dandelion have revealed that it has antioxidant, anti-cancer, diuretic, anti-inflammatory, and immune-protective effects, which are attributed to its bioactive components, such as dandelion glycosides, chlorogenic acid, quercetin, and dandelion. Studies have confirmed that its ethanol extract plays an anti-proliferative and pro-apoptotic role in the treatment of BPH by downregulating the expression of AR, serum T, DHT, and Bcl-2, and upregulating the expression of Bax [37]. Scutellaria baicalensis is considered to be a good medicine for treating dysuria, fever, atherosclerosis, allergies and inflammation. This is closely related to baicalin, the main component of Scutellaria baicalensis. Some studies believe that its ethanol extract exerts anti-proliferative and anti-inflammatory effects by downregulating the expression of DHT, 5αR, AR, and PCNA, regulating the balance of Bax/Bcl-2[38].

In recent years, a large number of studies have confirmed the good effects of many Chinese herbal extracts on BPH using BPH cells and testosterone propionate-induced rats as experimental models. For the treatment of BPH, plantain, dandelion, etc. are mainly used for diuresis and stranguria, cordyceps, rhodiola, psoralea, ginseng, licorice, etc. are mainly used for tonifying the internal organs, and bitter herb, scutellaria, radix scoparia, etc. are mainly used for clearing heat, detoxifying and removing dampness. In addition, dandelion and licorice can clear heat and detoxify, and psoralea can astringe and consolidate. It plays a role in treating BPH through anti-inflammatory, anti-oxidative, anti-angiogenic, anti-cell proliferation, and pro-apoptotic pathways. Its main mechanisms include regulating the expression of pro-inflammatory factors (NF-κB, IL-6, LOX-5, COX-2, etc.), cell proliferation factors (PSA, PCNA, 5αR, etc.), oxidation-related proteins (SOD, ROS, etc.), EGF, cell cycle-related proteins (cyclinD1, cyclin E, etc.), and pro-apoptotic factors (Bax), and blocking pathways such as NF-κB and AR. However, different extraction methods and purification degrees may lead to differences in the types, contents, and biological activities of the extracted active ingredients, affecting the comparability of the experiments. In addition, the differences in dosage and administration methods in different studies will also affect the evaluation of the therapeutic effect, thereby causing deviations in the results, as shown in Table 2.

  Table 2 Mechanisms of single traditional Chinese medicines in treatment of benign prostatic hyperplasia (BPH)

2.3 Chinese herbal compound and Chinese patent medicine

2.3.1 Chinese herbal compound

Chinese herbal compound has shown excellent integrative medical advantages in the treatment of BPH. Its characteristics are the combination of personalized syndrome differentiation and treatment with multi-component and multi-target synergistic effects. It achieves a safe and efficient treatment effect by regulating prostate cell proliferation, improving local blood circulation, regulating endocrine balance, strengthening anti-inflammatory immunity and promoting diuresis and stranguria. The Bushen Tongluo prescription is composed of 6 Chinese herbs: earthworm, earthworm, dodder seed, mistletoe, and phellodendron. Gong Guoyu et al. [39] found that this prescription can reduce the levels of T, DHT, TGF-β1, and vimentin, and upregulate the expression of caspase-3, thereby regulating energy metabolism in prostate tissue and inhibiting EMT, achieving a therapeutic effect on BPH.

Danzhiqing'e prescription is composed of four Chinese medicinal herbs: Danshen, Psoralea corylifolia, Eucommia ulmoides, and Anemarrhena asphodeloides. It has the effects of nourishing yin and yang, promoting blood circulation and removing blood stasis, and is widely used to treat estrogen and androgen-related diseases. Liu Yang et al. [40] pointed out that this prescription inhibits M2 macrophage-induced prostate cell proliferation and inflammation-related BPH by inactivating the ERK1/2 pathway. Kangquan prescription is composed of six Chinese herbs: Morinda officinalis, earthworm, Eupolyphaga sinensis, rhubarb, Trachelospermum officinale, and cinnamon bark. Chen Wenfan et al. [41] pointed out that this prescription inhibits TGF-β/Smad pathway conduction by upregulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) protein and reversing EMT in rat prostate tissue. Its mechanism may be related to downregulating the mRNA and/or protein expression of TGF-β, TGF-βR1, TGF-βR2, p-Smad2, p-Smad3 and N-cadherin protein, and increasing the mRNA and protein expression of BAMBI and E-cadherin protein. Zishen Pill is a compound prescription composed of Anemarrhena asphodeloides, Phellodendron chinense, and Cinnamon bark, which is commonly used to treat BPH. Wang Yao et al. [42] found that this prescription can reduce the expression of VEGF, TNF-α, CCL5, IL, etc., thereby treating BPH through inflammation/immunity and cell apoptosis/proliferation related pathways. Jiawei Guizhi Fuling Wan (Guizhi Fuling Wan plus Wangbuliuxing, leech, and Linderae serrata) is a common prescription used by Academician Wang Qi to treat BPH. Liu Dan et al. [43] pointed out that the main ingredients of this prescription, such as β-sitosterol, quercetin, baicalin, and ellagic acid, regulate the expression of Bax, Bcl-2, TNF, IL-6, VEGF, EGFR, etc., and then regulate the PI3K-Akt, VEGF and other pathways, thus playing an anti-inflammatory, anti-angiogenic, and pro-apoptotic role in the treatment of BPH. Yiqi Huoxue Xiaozheng Fang is composed of 8 herbs such as Astragalus and Atractylodes macrocephala. Zhu Wenxiong et al. [44] found that this prescription can reduce the prostate acinar area and interstitial area and improve the pathological changes of prostate tissue. Its mechanism is related to regulating the spasmolytic polypeptide (TFF)/Wnt pathway and downregulating the expression of TFF2, Wnt4, and Wnt6. Xianjia Decoction formulated by Professor Zhou Anfang is composed of 11 herbs including Epimedium and Lycium barbarum. It has the effects of invigorating the kidney and promoting blood circulation, clearing away heat and detoxifying, and resolving phlegm and dispersing nodules. It is used to treat kidney deficiency and blood stasis type BPH. Liu Qi et al. [45] found that this prescription exerts anti-inflammatory effects by downregulating the expression of IL-6, p-STAT3, p-JAK2, JAK2, and STAT3 mRNA, and then inhibiting the IL-6/JAK2/STAT3 pathway. Qianliexiao is mainly composed of 17 herbs including Epimedium and Cuscuta australis. Jiang Xingyu et al. [46] pointed out that this prescription inhibits prostate proliferation in rats by downregulating the expression of platelet-endothelial cell adhesion molecule (CD31), HIF1-α, VEGFR, and caspase-9, and regulating the HIF1-α/VEGFR pathway.

2.3.2 Chinese patent medicine

Chinese patent medicine combines scientific compatibility with modern pharmaceutical technology, achieving standardization and quality control of active ingredients. It also has good safety and tolerability, reducing the loss of efficacy and adverse reactions that may occur during the decoction process of traditional Chinese medicine. Shuangshitonglin capsule is derived from Cheng's Dixiefenqingyin, which is composed of Dixie, Phellodendron, Patrinia, Indigo, Talc, Plantago, Acorus, Poria, Atractylodes, and Salvia. Mao Qian et al. [47] pointed out that this prescription can improve prostate tissue hyperplasia in rats, which may be related to downregulating the expression of EGFR, VEGFA, p-P38, and p-Akt. Wang Xitao et al. [48] confirmed that the therapeutic effect of Guizhi Fuling capsule on BPH is mainly achieved by reducing the prostate index (PI) and downregulating the expression of DHT, VEGF, and TGF-β1. Compound Anise Granules is an empirical prescription of Professor Wang Shimin for the treatment of BPH. It is mainly composed of five herbs: red tannins, kudzu root, hawthorn, wolfberry, and American ginseng. Li Huifeng et al. [49] pointed out that this prescription reduces prostate wet weight and PI, downregulates the expression of T, DHT, PI3K, Akt, Bcl-2, VEGFA, EGFR, and ERK1/2 proteins, and plays an anti-proliferative, anti-angiogenic, and pro-apoptotic role. Kelong Capsule is composed of Jinkui Shenqi Pills plus Astragalus, soybean isoflavones, and pumpkin seed oil. Song Guanhui et al. [50] confirmed that it plays an anti-proliferative and anti-inflammatory role by downregulating the levels of T, DHT, TNF-α, IL-1β, and IL-6 mRNA, upregulating the expression of estradiol and Nrf2 mRNA, and then activating the Nrf2 pathway.

Ningmitai capsule is composed of four seasons red, Imperata root, Rhizoma Cyperi, Tripterygium wilfordii, Herba Agrimoniae, Hibiscus mutabilis leaf, and Forsythia suspensa. Liu Shengjing et al. [51] pointed out that this prescription can downregulate the expression of PCNA, AR, EGF, IL-6, and TNF-α to reduce PI, improve the structure of hyperplastic glands, and relieve interstitial fibrosis. Qizhitongqiao capsule (astragalus, leech, dodder seed, lindera scutellariae, alpinia oxyphylla, cinnamon bark, and Rhizoma Cyathulae) is a perfected version of Professor Zhang Chunhe's Qianlie granule. It has the effects of invigorating qi and activating blood circulation, tonifying the kidney and opening the orifices. Zhao Fan et al. [52] pointed out that this prescription inhibits the expression of Bcl-2, PCNA, hypoxia-inducible factor 1-α (HIF1-α), and VEGF, upregulates Bax/Bcl-2, inhibits prostate hyperplasia in rats, and improves tissue pathological changes.

In summary, traditional Chinese medicine formulas and Chinese patent medicines, as important means of TCM treatment of BPH, effectively inhibit prostate cell proliferation, induce cell apoptosis, regulate sex hormone metabolism, improve prostate blood circulation and microcirculation, reduce tissue edema and congestion, and strengthen anti-inflammatory immune response to reduce the damage of inflammatory response to prostate tissue through the synergistic effect of multiple components and multiple targets. Its mechanism is mainly related to the regulation of ERK1/2, TGF-β/Smad, MAPK, PI3K/Akt, Nrf2, FF/Wnt, IL-6/JAK2/STAT3, HIF1-α/VEGFR and other pathways, as shown in Table 3. However, the characteristics of multiple components and multiple targets make its mechanism complex and difficult to fully analyze, the interaction between different components in the compound may enhance or weaken the efficacy of certain components, and some efficacy evaluation depends on the subjective judgment of researchers, which are potential deviations in the above studies.

Table 3 Mechanisms of traditional Chinese medicine formulas/Chinese patent medicines in treatment of benign prostatic hyperplasia (BPH)