Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Department of Gastroenterology, The 981st Hospital of PLA, Chengde, 067000, Hebei, China.
J Gastroenterol. 2024 Nov;59(11):1037-1051. doi: 10.1007/s00535-024-02145-4. Epub 2024 Aug 15.
Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. There is a lack of medications that effectively alleviate or reverse pancreatic fibrosis and thus cure chronic pancreatitis.
We screened drugs that could alleviate pancreatic fibrosis from 80 traditional Chinese medicine monomers and verified their efficacy and mechanisms.
We preliminarily identified corynoline as an antifibrotic candidate by drug screening among 80 compounds. In vitro, corynoline dose-dependently reduces collagen I synthesis in pancreatic stellate cells induced by TGF-β1 and inhibits its activation. Furthermore, we found that corynoline could alleviate the morphological disruption, such as acinar cell atrophy, collagen deposition etc., as well as reduced pancreatic weight in mice with chronic pancreatitis. We further validated the antifibrotic effect of corynoline in mRNA and protein levels. We also found that corynoline could inhibit NF-κB signaling pathway in vitro and in vivo. Next, we identified PSMA2 as the binding protein of corynoline by Lip-SMap and validated it using DARTS. Moreover, the siRNA of PSMA2 disrupts the anti-fibrotic effect of corynoline.
In conclusion, corynoline is a promising agent for the treatment of pancreatic fibrosis and chronic pancreatitis.
胰腺纤维化是慢性胰腺炎的主要病理特征。目前缺乏能够有效缓解或逆转胰腺纤维化从而治愈慢性胰腺炎的药物。
我们从 80 种中药单体中筛选出能够缓解胰腺纤维化的药物，并验证其疗效和机制。
通过 80 种化合物的药物筛选，我们初步鉴定出柯里宁是一种抗纤维化候选药物。在体外，柯里宁剂量依赖性地降低 TGF-β1 诱导的胰腺星状细胞中胶原 I 的合成，并抑制其激活。此外，我们发现柯里宁可以减轻慢性胰腺炎小鼠的形态破坏，如腺泡细胞萎缩、胶原沉积等，并减轻胰腺重量。我们进一步在 mRNA 和蛋白水平验证了柯里宁的抗纤维化作用。我们还发现柯里宁可以抑制 NF-κB 信号通路的体外和体内活性。接下来，我们通过 Lip-SMap 鉴定出 PSMA2 是柯里宁的结合蛋白，并通过 DARTS 进行了验证。此外，PSMA2 的 siRNA 破坏了柯里宁的抗纤维化作用。
综上所述，柯里宁是一种有前途的治疗胰腺纤维化和慢性胰腺炎的药物。
