4-Methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy for chronic prostatitis
4-Methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy for chronic prostatitis
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4-甲基伞形酮治疗和透明质酸抑制作为慢性前列腺炎的治疗策略
DOI：
10.1002/pros.24205
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发表时间：
2021-07-28
期刊：
影响因子：
2.8
通讯作者：
Liang, Chaozhao
中科院分区：
文献类型：
--
作者：
Chen, Jing;Meng, Jialin;Liang, Chaozhao
背景：透明质酸（HA）是一种细胞外基质成分，在大多数慢性炎症组织中积累。本研究旨在探讨HA在慢性前列腺炎发病机制中的作用。材料与方法首先对慢性前列腺炎/慢性盆腔疼痛综合征（CP/CPPS）患者的人口学特征和外周血血清样本进行分类，以评估外周血血清HA水平与患者炎症严重程度的关系。其次，我们诱导了实验性自身免疫性前列腺炎（EAP）小鼠模型，并用4-甲基伞形酮（4-MU）（200 mg/kg/天）治疗小鼠。处死小鼠后，从小鼠脾脏的Th 1细胞提取RNA用于RNA测序。我们利用加权基因共表达网络分析（WGCNA）来鉴定与EAP发病相关的共表达基因模块和中心基因。通过使用蛋白质印迹分析确认与所鉴定的途径相关的关键基因的表达。结果CP/CPPS患者血清HA水平明显高于正常对照组，且与患者疼痛程度、排尿症状、生活质量呈正相关。此外，HA蛋白在EAP模型的前列腺组织中的表达显著高于对照组。4-MU，一种HA合成的口服抑制剂，减轻了免疫细胞向前列腺的浸润，并显著降低了Th 1细胞的比例。基于WGCNA，我们鉴定了18个共表达模块，并鉴定了Grey 60和brown模块与EAP正相关，与对照组和4-MU处理组负相关。途径富集分析和蛋白质印迹分析证明，HA可能激活细胞周期途径，增加Th 1细胞的比例，促进慢性前列腺炎的发病机制，而这些过程被逆转的4-MU治疗。结论CP/CPPS患者血清HA水平较健康对照组升高，4-MU靶向HA可能通过降低Th 1细胞比例，缓解慢性前列腺炎，从而抑制细胞周期相关通路的活性。本研究结果对慢性前列腺炎的临床治疗有一定的启示。
Background Hyaluronan (HA), an extracellular matrix component, accumulates in most chronic inflammatory tissues. Here, we studied the impact of HA on the pathogenesis of chronic prostatitis. Materials and Methods First, we sorted demographic characteristics and peripheral blood serum samples from patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) to assess the relationship between the levels of HA in peripheral blood serum and the severity of inflammation in patients. Second, we induced an experimental autoimmune prostatitis (EAP) mouse model and treated the mice with 4-methylumbelliferone (4-MU) (200 mg/kg/day). After the mice were sacrificed, RNA from Th1 cells of the mouse spleens was extracted for RNA sequencing. We used weighted gene co-expression network analysis (WGCNA) to identify co-expressed gene modules and hub-gene related to the pathogenesis of EAP. The expression of critical genes associated with the identified pathway was confirmed by using western blot analysis. Results HA was significantly more highly expressed in CP/CPPS patients than in healthy volunteers and positively correlated with the severity of pain, urination symptoms, and quality of life. Besides, the protein expression of HA was significantly higher in prostate tissues derived from EAP models than in those derived from controls. 4-MU, an oral inhibitor of HA synthesis, relieved immunocyte infiltration to the prostate and significantly reduced the proportion of Th1 cells. Based on the WGCNA, we identified 18 co-expression modules and identified that the Grey60 and brown modules were positively associated with the EAP and negatively associated with the Control and 4-MU-treated groups. Pathway enrichment analyses and western blot assays proved that HA potentially activated the cell cycle pathway, increasing the proportion of Th1 cells promoting chronic prostatitis pathogenesis, while these processes were reversed by 4-MU treatment. Conclusions Our results suggest that HA is elevated in patients with CP/CPPS compared with healthy controls and that targeting HA through 4-MU suppresses the activity of the cell cycle-related pathway, potentially by decreasing the proportion of Th1 cells and relieving chronic prostatitis. Our findings might inspire the clinical treatment of chronic prostatitis.