Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
Mol Pharm. 2022 Jul 4;19(7):2335-2342. doi: 10.1021/acs.molpharmaceut.2c00143. Epub 2022 May 23.
Alcoholic liver disease (ALD) has a significant impact on human health and is one of the leading causes of liver disease mortality. The early and exact diagnosis of ALD is very important since the early stage of disease progression can be reversible. Although ALD can be evaluated by ultrasound, CT, or MRI, there is still no imaging technique sufficient in the diagnosis of early-stage ALD. Of the current studies, epigenetic modulation plays a significant role in the development and progression of ALD. In this work, we evaluate whether BRDs play a vital role in the early-stage ALD using our new PET imaging probe of BET proteins, [C]CW22. PET/CT imaging of [C]CW22 and [F]FDG was used to identify early-stage lesions of livers and brains in the mice model. We found that the average uptake values of livers and brains in early-stage ALD were significantly increased for [C]CW22 PET/CT imaging but only slightly changed in [F]FDG PET/CT imaging. Consistently, we also found that BRD 3, 4 protein expression levels were significantly higher in the liver and brain tissues of early-stage ALD. Furthermore, through Pmod software, we found that [C]CW22 PET/CT uptakes in the brain stem, cerebellum, and midbrain were significantly up-regulated in the early-stage ALD. In conclusion, BRDs were important mediators of damage in early-stage ALD. [C]CW22 PET/CT imaging can detect the early-phase alcohol-induced damage of livers and brains, which will likely lead to human trials in the future.
酒精性肝病 (ALD) 对人类健康有重大影响，是导致肝病死亡率的主要原因之一。ALD 的早期和准确诊断非常重要，因为疾病进展的早期阶段是可以逆转的。虽然可以通过超声、CT 或 MRI 来评估 ALD，但目前还没有一种影像学技术足以诊断早期 ALD。在目前的研究中，表观遗传调节在 ALD 的发生和发展中起着重要作用。在这项工作中，我们使用我们新的 BET 蛋白 PET 成像探针 [C]CW22 来评估 BRD 是否在早期 ALD 中发挥重要作用。使用 [C]CW22 和 [F]FDG 的 PET/CT 成像来识别小鼠模型中肝脏和大脑的早期病变。我们发现，在早期 ALD 中，[C]CW22 PET/CT 成像的肝脏和大脑的平均摄取值显著增加，但 [F]FDG PET/CT 成像的摄取值仅略有变化。一致地，我们还发现 BRD3、4 蛋白在早期 ALD 的肝脏和脑组织中的表达水平显著升高。此外，通过 Pmod 软件，我们发现早期 ALD 中脑干、小脑和中脑的 [C]CW22 PET/CT 摄取显著上调。总之，BRD 是早期 ALD 损伤的重要介质。[C]CW22 PET/CT 成像可以检测到肝脏和大脑早期阶段的酒精诱导损伤，这可能会导致未来在人类中进行临床试验。
