目的 探讨桂枝茯苓胶囊对大鼠良性前列腺增生（BPH）的作用机制。方法 72只雄性SPF级SD大鼠随机分为6组：对照组、模型组、非那雄胺（阳性药，2 mg·kg^-1）组和桂枝茯苓胶囊低、中、高剂量（0.87、1.74、3.47 g·kg^-1）组，每组12只；除对照组外，其余5组sc雌、雄激素（0.05 mg·kg^-1苯甲酸雌二醇和4 mg·kg^-1丙酸睾酮），每天1次，连续28 d，建立BPH模型。同时ig给予药物，每天给药1次，连续给药28 d。HE染色观察前列腺组织病理变化；ELISA法检测血清中双氢睾酮（DHT）、雌二醇（E₂）和前列腺中DHT、E₂、转化生长因子β1（TGF-β1）、表皮生长因子（EGF）的水平；Western blotting检测前列腺中增殖细胞核抗原（PCNA）、雄激素受体（AR）、雌激素受体α（ERα）、胰岛素样生长因子（IGF-1）、成纤维细胞生长因子7（FGF-7）、缺氧诱导因子1α（HIF-1α）和血管内皮生长因子（VEGF）蛋白表达水平；实时荧光定量PCR（qRT-PCR）法检测前列腺中PCNA、FGF-7、IGF-1和VEGF mRNA表达水平。结果 与对照组比较，模型组前列腺指数显著增加（P<0.01），前列腺上皮厚度显著增加（P<0.01），前列腺显著增生，间质充血、水肿；血清中DHT和前列腺中DHT、E₂、EGF水平显著升高（P<0.05、0.01）；前列腺中TGF-β1水平显著降低（P<0.05），PCNA、AR、ERα、FGF-7、IGF-1、HIF-1α和VEGF蛋白表达水平及PCNA、FGF-7、IGF-1和VEGF mRNA表达水平显著升高（P<0.05、0.01）。与模型组比较，桂枝茯苓胶囊高剂量显著降低前列腺指数（P<0.05），各剂量均显著减小前列腺上皮厚度（P<0.01），减轻间质充血、水肿；桂枝茯苓胶囊低剂量显著升高前列腺中TGF-β1水平，显著降低EGF水平（P<0.05）以及PCNA、FGF-7、VEGF mRNA的表达（P<0.01），显著下调前列腺中AR蛋白表达水平（P<0.05）；中剂量能显著升高前列腺中TGF-β1水平，显著降低EGF水平（P<0.05、0.01）以及PCNA、VEGF mRNA的表达水平（P<0.01），显著下调IGF-1蛋白表达水平（P<0.05）；高剂量显著升高前列腺中TGF-β1水平，显著降低血清中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的表达水平（P<0.01），显著下调PCNA、AR、ERα、FGF-7、IGF-1、HIF-1α和VEGF蛋白表达（P<0.05、0.01）。结论 桂枝茯苓胶囊对BPH有明显的治疗作用，其作用机制可能包括降低DHT、E₂水平，抑制E₂与ERα结合及AR信号通路；并且升高TGF-β1水平、降低EGF水平，抑制细胞增殖、诱导细胞凋亡，下调FGF-7、IGF-1、HIF-1α和VEGF生长因子的表达，抑制细胞增殖与血管生成。

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年国家中医药管理局岐黄学者项目（国中医药人教函［2022］6号）