目的 探討桂枝茯苓膠囊對(duì)大鼠良性前列腺增生（BPH）的作用機(jī)制。方法 72只雄性SPF級(jí)SD大鼠隨機(jī)分為6組：對(duì)照組、模型組、非那雄胺（陽性藥，2 mg·kg^-1）組和桂枝茯苓膠囊低、中、高劑量（0.87、1.74、3.47 g·kg^-1）組，每組12只；除對(duì)照組外，其余5組sc雌、雄激素（0.05 mg·kg^-1苯甲酸雌二醇和4 mg·kg^-1丙酸睪酮），每天1次，連續(xù)28 d，建立BPH模型。同時(shí)ig給予藥物，每天給藥1次，連續(xù)給藥28 d。HE染色觀察前列腺組織病理變化；ELISA法檢測(cè)血清中雙氫睪酮（DHT）、雌二醇（E₂）和前列腺中DHT、E₂、轉(zhuǎn)化生長(zhǎng)因子β1（TGF-β1）、表皮生長(zhǎng)因子（EGF）的水平；Western blotting檢測(cè)前列腺中增殖細(xì)胞核抗原（PCNA）、雄激素受體（AR）、雌激素受體α（ERα）、胰島素樣生長(zhǎng)因子（IGF-1）、成纖維細(xì)胞生長(zhǎng)因子7（FGF-7）、缺氧誘導(dǎo)因子1α（HIF-1α）和血管內(nèi)皮生長(zhǎng)因子（VEGF）蛋白表達(dá)水平；實(shí)時(shí)熒光定量PCR（qRT-PCR）法檢測(cè)前列腺中PCNA、FGF-7、IGF-1和VEGF mRNA表達(dá)水平。結(jié)果 與對(duì)照組比較，模型組前列腺指數(shù)顯著增加（P<0.01），前列腺上皮厚度顯著增加（P<0.01），前列腺顯著增生，間質(zhì)充血、水腫；血清中DHT和前列腺中DHT、E₂、EGF水平顯著升高（P<0.05、0.01）；前列腺中TGF-β1水平顯著降低（P<0.05），PCNA、AR、ERα、FGF-7、IGF-1、HIF-1α和VEGF蛋白表達(dá)水平及PCNA、FGF-7、IGF-1和VEGF mRNA表達(dá)水平顯著升高（P<0.05、0.01）。與模型組比較，桂枝茯苓膠囊高劑量顯著降低前列腺指數(shù)（P<0.05），各劑量均顯著減小前列腺上皮厚度（P<0.01），減輕間質(zhì)充血、水腫；桂枝茯苓膠囊低劑量顯著升高前列腺中TGF-β1水平，顯著降低EGF水平（P<0.05）以及PCNA、FGF-7、VEGF mRNA的表達(dá)（P<0.01），顯著下調(diào)前列腺中AR蛋白表達(dá)水平（P<0.05）；中劑量能顯著升高前列腺中TGF-β1水平，顯著降低EGF水平（P<0.05、0.01）以及PCNA、VEGF mRNA的表達(dá)水平（P<0.01），顯著下調(diào)IGF-1蛋白表達(dá)水平（P<0.05）；高劑量顯著升高前列腺中TGF-β1水平，顯著降低血清中DHT水平、前列腺中DHT、E₂、EGF水平（P<0.05、0.01）以及PCNA、FGF-7、IGF-1和VEGF mRNA的表達(dá)水平（P<0.01），顯著下調(diào)PCNA、AR、ERα、FGF-7、IGF-1、HIF-1α和VEGF蛋白表達(dá)（P<0.05、0.01）。結(jié)論 桂枝茯苓膠囊對(duì)BPH有明顯的治療作用，其作用機(jī)制可能包括降低DHT、E₂水平，抑制E₂與ERα結(jié)合及AR信號(hào)通路；并且升高TGF-β1水平、降低EGF水平，抑制細(xì)胞增殖、誘導(dǎo)細(xì)胞凋亡，下調(diào)FGF-7、IGF-1、HIF-1α和VEGF生長(zhǎng)因子的表達(dá)，抑制細(xì)胞增殖與血管生成。

Objective To explore the mechanism of Guizhi Fuling capsule on benign prostatic hyperplasia (BPH) in rats.Methods 72 male SPF SD rats were randomly divided into six groups:control group, model group, finasteride (positive drug, 2 mg·kg^-1) and Guizhi Fuling Capsules low-dose, medium-dose and high-dose (0.87, 1.74, 3.47 g·kg^-1) groups, with 12 rats in each group. Except the control group, the other five groups were given male and female hormones (0.05 mg·kg^-1 estradiol benzoate and 4 mg·kg^-1 testosterone propionate), once a day for 28 d, and the BPH model was established. At the same time, the therapeutic drug was given by ig, with a volume of 10 mL·kg^-1, once a day, for 28 d. The pathological changes of prostate tissue were observed by HE staining. The contents of DHT and E₂ in serum, DHT, E₂, TGF-β1 and EGF in prostate tissue were detected by ELISA. The protein expressions of PCNA, AR, ERα, IGF-1, FGF-7, HIF-1α and VEGF in prostate were detected by Western blotting. The mRNA expression of PCNA, FGF-7, IGF-1 and VEGF in prostate was detected by qRT-PCR. Results Compared with control group, the prostate index and epithelial thickness of prostate in the model group were significantly increased (P < 0.01), the prostatic hyperplasia, interstitial congestion and edema were significantly increased, and the contents of DHT in serum and DHT, E₂ and EGF in prostate were significantly increased (P < 0.05 and 0.01). The content of TGF-β1 in prostate was significantly decreased (P < 0.05), and the protein expression levels of PCNA, AR, ERα, FGF-7, IGF-1, HIF-1α and VEGF and the mRNA expression levels of PCNA, FGF-7, IGF-1 and VEGF in prostate were significantly increased (P < 0.05 and 0.01). Compared with the model group, the high-dose group of Guizhi Fuling Capsule significantly reduced the prostate index (P < 0.05), while the low-dose, medium, and highdose groups significantly reduced the thickness of the prostate epithelium (P < 0.01), reducing prostate hyperplasia, interstitial congestion, and edema. The low-dose group of Guizhi Fuling Capsule significantly increased TGF-β1 content in the prostate gland, significantly reducing EGF content (P < 0.05) and the expression of PCNA, FGF-7, and VEGF mRNA (P < 0.01), significantly downregulating the expression level of AR protein in the prostate (P < 0.05). The medium dose group of Guizhi Fuling Capsule can significantly increase TGF-β1 content in the prostate gland, significantly reducing EGF content (P < 0.05 and 0.01) and the expression levels of PCNA and VEGF mRNA (P < 0.01), significantly downregulating the expression level of IGF-1 protein (P < 0.05). The high-dose group of Guizhi Fuling Capsule significantly increased TGF-β1 content in the prostate gland, significantly reducing the levels of DHT in serum, DHT, E2, EGF in prostate (P < 0.05 and 0.01), as well as the expression levels of PCNA, FGF-7, IGF-1, and VEGF mRNA (P < 0.01), significantly downregulating PCNA, AR, ERα、FGF-7, IGF-1, HIF-1α and VEGF protein expression (P < 0.05 and 0.01). Conclusion Guizhi Fuling capsule has obvious therapeutic effect on benign prostatic hyperplasia, which may reduce DHT and E₂ content, inhibit E₂ and ERα binding and AR signaling pathway. Moreover, it increased the content of TGF-β1 and decreased the content of EGF, inhibited cell proliferation and induced cell apoptosis, down-regulated the expression of FGF-7, IGF-1, HIF-1α and VEGF growth factors, and inhibited cell proliferation and was related to angiogenesis.

R285.5

2021年國(guó)家中醫(yī)藥管理局岐黃學(xué)者項(xiàng)目（國(guó)中醫(yī)藥人教函［2022］6號(hào)）