Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation,Journal of Advanced Research

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Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2023-04-14 , DOI: 10.1016/j.jare.2023.04.006
Bo-Ram Jin ₁ , Hyo-Jung Kim ₁ , Jung-Hyun Na ₂ , Won-Kyu Lee ₃ , Hyo-Jin An ₄

Affiliation

Introduction

Apocynin (Apo), an NADPH oxidase (NOX) inhibitor, has been widely used to treat various inflammatory diseases. However, the therapeutic effects of Apo on benign prostatic hyperplasia (BPH), a multifactorial disease associated with chronic inflammation and hormone imbalance, remain unknown.

Objectives

The link between androgen signaling, reactive oxygen species (ROS), and prostate cell proliferation may contribute to the pathogenesis of BPH; therefore, the aim of this study was to identify the specific signaling pathway involved and to demonstrate whether the anti-oxidant Apo plays a role in the prevention and treatment of BPH.

Methods

Ingenuity pathway analysis and si-RNA transfection were conducted to demonstrate the androgen receptor (AR) and NOX4 linkage in BPH. Pathological markers of BPH were measured by H&E staining, immunoblotting, ELISA, qRT-PCR, and immunofluorescence to examine the effect of Apo. Rats stimulated with testosterone and BPH-1 cells were used as BPH models.

Results

AR and NOX4 network-mediated oxidative stress was upregulated in the BPH model. Next, we examined the effects of Apo on oxidative stress and chronic prostatic inflammation in BPH mouse models. In a testosterone-induced BPH rat model, Apo alleviated pathological prostate enlargement and suppressed androgen/AR signaling. Apo suppressed the upregulation of proinflammatory markers and promoted the expression of anti-oxidant factors. Furthermore, Apo regulated the TGF-β/Glut9/activin pathway and macrophage programming. In BPH-1 cells, Apo suppressed AR-mediated proliferation and upregulation of TGFB and NOX4 expression by alleviating oxidative stress. Apo activated anti-oxidant and anti-inflammatory systems and regulated macrophage polarization in BPH-1 cells. AR knockdown partially abolished the beneficial effects of Apo in prostate cells, indicating AR-dependent effects of Apo.

Conclusion

In contrast with existing BPH therapies, Apo may provide a new application for prostatic disease treatment, especially for BPH, by targeting the AR/TGF-β/NOX4 signaling pathway.

中文翻译：

靶向良性前列腺增生治疗：罗布麻素抑制 AR/TGF-β/NOX4 抑制炎症和增殖

介绍

罗布麻宁 (Apo) 是一种 NADPH 氧化酶 (NOX) 抑制剂，已广泛用于治疗多种炎症性疾病。然而，Apo 对良性前列腺增生（BPH）（一种与慢性炎症和激素失衡相关的多因素疾病）的治疗作用仍不清楚。

目标

雄激素信号传导、活性氧 (ROS) 和前列腺细胞增殖之间的联系可能与 BPH 的发病机制有关；因此，本研究的目的是确定所涉及的具体信号通路，并证明抗氧化剂Apo是否在预防和治疗BPH中发挥作用。

方法

Ingenuity 通路分析和 si-RNA 转染证明了 BPH 中雄激素受体 (AR) 和 NOX4 的联系。通过H&E染色、免疫印迹、ELISA、qRT-PCR和免疫荧光检测BPH的病理标志物，以检查Apo的作用。使用睾酮和BPH-1细胞刺激的大鼠作为BPH模型。

结果

AR 和 NOX4 网络介导的氧化应激在 BPH 模型中上调。接下来，我们研究了 Apo 对 BPH 小鼠模型氧化应激和慢性前列腺炎症的影响。在睾酮诱导的 BPH 大鼠模型中，Apo 减轻了病理性前列腺肥大并抑制了雄激素/AR 信号传导。 Apo 抑制促炎标记物的上调并促进抗氧化因子的表达。此外，Apo 调节 TGF-β/Glut9/激活素途径和巨噬细胞编程。在 BPH-1 细胞中，Apo 通过减轻氧化应激来抑制 AR 介导的增殖以及 TGFB 和 NOX4 表达的上调。 Apo 激活 BPH-1 细胞中的抗氧化和抗炎系统并调节巨噬细胞极化。 AR敲低部分消除了 Apo 对前列腺细胞的有益作用，表明 Apo 的 AR 依赖性作用。