Procyanidin Alleviates Diabetic Retinopathy by Activating the Expression of Activating Transcription Factor 1 Expression to Upregulate Synoviolin 1 and Inhibit the High Mobility Group Box 1/Toll-Like Receptor 4 Pathway

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Limin Zheng, Yaodan Cao, Wuyun Lu, Jinqi Hao, Yanqin Yu, Songtao Yuan
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Abstract

Diabetic retinopathy (DR) remains a major cause of vision loss among working-age individuals, significantly impairing quality of life in diabetic patients. While no definitive cure exists, Procyanidin (PRO), a polyphenolic compound, has shown potential in mitigating diabetes-related complications. However, its mechanism of action in DR remains poorly understood. To explore this, we established an in vitro high glucose (HG) model using human retinal microvascular endothelial cells (hRMECs) and an in vivo diabetic rat model. Cells were cultured in normal glucose (NG, 5 mM) or HG (30 mM) for 48 h, followed by PRO treatment. Techniques including qRT-PCR, Western blotting, flow cytometry, histological staining, Transwell, tube formation, chromatin immunoprecipitation (ChIP), and dual-luciferase assays were employed. PRO treatment conferred protection against DR; however, this effect was reversed upon knockdown of activating transcription factor 1 (ATF1). Mechanistically, ATF1 enhanced transcription of synoviolin 1 (SYVN1), promoting HMGB1 degradation via ubiquitination and suppressing the HMGB1/toll-like receptor 4 (TLR4) signaling pathway. Findings from the in vitro model were validated in vivo. In conclusion, PRO alleviates DR by regulating the ATF1/SYVN1/HMGB1 axis and inhibiting pro-inflammatory signaling. These results provide novel insights into the molecular mechanism of PRO's protective role in DR and support its therapeutic potential.

Abstract Image

原花青素通过激活转录因子1表达上调滑膜拉琴1和抑制高迁移率组盒1/ toll样受体4通路缓解糖尿病视网膜病变
糖尿病视网膜病变(DR)仍然是工作年龄人群视力丧失的主要原因,严重影响糖尿病患者的生活质量。虽然没有明确的治疗方法,原花青素(PRO),一种多酚化合物,已经显示出减轻糖尿病相关并发症的潜力。然而,其在DR中的作用机制仍然知之甚少。为此,我们利用人视网膜微血管内皮细胞(hRMECs)建立了体外高糖模型和体内糖尿病大鼠模型。细胞在正常葡萄糖(NG, 5 mM)或HG (30 mM)中培养48 h,然后进行PRO处理。采用qRT-PCR、Western blotting、流式细胞术、组织学染色、Transwell、试管形成、染色质免疫沉淀(ChIP)和双荧光素酶测定等技术。PRO治疗可预防DR;然而,当激活转录因子1 (ATF1)被敲低时,这种作用被逆转。从机制上讲,ATF1增强了SYVN1的转录,通过泛素化促进HMGB1的降解,并抑制HMGB1/toll样受体4 (TLR4)信号通路。体外模型的结果在体内得到了验证。综上所述,PRO通过调节ATF1/SYVN1/HMGB1轴和抑制促炎信号传导来缓解DR。这些结果为PRO在DR中的保护作用的分子机制提供了新的见解,并支持其治疗潜力。
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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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