Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002, India.
Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, Telangana, India.
Eur J Pharmacol. 2022 Dec 15;937:175366. doi: 10.1016/j.ejphar.2022.175366. Epub 2022 Nov 12.
Hepatic fibrosis is a progressive consequence of injury to the liver cells. Liver fibrosis causes hepatic dysfunction and also plays a key role in the pathogenesis of other chronic ailments. Dehydrozingerone (DHZ) is a half-structural analogue of curcumin and is known to have several therapeutic benefits. However, the impact of DHZ on liver fibrosis was not investigated. The current investigation attempted to determine the anti-fibrotic effect of DHZ against thioacetamide-induced liver fibrosis in rats and TGF-β-induced differentiation in human HSC-LX2 cells and to uncover the possible mechanisms. In in-vivo, DHZ significantly reduced the TAA-induced liver index and ameliorated the liver functional parameters. TAA elevated the fibrotic marker's expression in TAA control, on the other hand, DHZ treatment significantly mitigated the same in mRNA and protein levels. Additionally, these findings were supported by histological investigations and immunohistochemistry studies of the fibrotic marker's expressions. DHZ treatment effectively reduced oxidative stress by increasing catalase activity and decreased the expression of inflammatory markers (myeloperoxidase and neutrophil-elastase) in liver tissues. Additionally, collagen staining and histological findings confirmed that DHZ administration significantly reduced TAA induced pathological deformities and elevated collagen levels. In-vitro results showed that TGF-β-induced differentiation was suppressed by DHZ treatment in a dose-dependent manner. Mechanistic approaches in HSC-LX2 and liver tissues revealed that DHZ treatment mitigated fibrosis by modulating the MAPK-pathway. Overall, these results show that DHZ exhibited anti-fibrotic action by reducing fibrotic markers and their activities through regulation of the MAPK-pathway, suggesting that DHZ may be a promising therapeutic molecule for liver fibrosis.
肝纤维化是肝脏细胞损伤的一种进行性后果。肝纤维化导致肝功能障碍，也是其他慢性疾病发病机制中的关键因素。脱氢枞酮（DHZ）是姜黄素的半结构类似物，已知具有多种治疗益处。然而，DHZ 对肝纤维化的影响尚未得到研究。本研究试图确定 DHZ 对硫代乙酰胺诱导的大鼠肝纤维化和 TGF-β诱导的人 HSC-LX2 细胞分化的抗纤维化作用，并揭示可能的机制。在体内，DHZ 显著降低 TAA 诱导的肝指数并改善肝功能参数。TAA 增加了 TAA 对照组中纤维化标志物的表达，而 DHZ 处理则显著减轻了纤维化标志物在 mRNA 和蛋白水平上的表达。此外，这些发现得到了组织学研究和纤维化标志物表达的免疫组织化学研究的支持。DHZ 治疗通过增加过氧化氢酶活性有效降低氧化应激，并降低肝脏组织中炎症标志物（髓过氧化物酶和中性粒细胞弹性蛋白酶）的表达。此外，胶原染色和组织学结果证实，DHZ 给药可显著减少 TAA 诱导的病理畸形和胶原水平升高。体外结果表明，DHZ 处理以剂量依赖性方式抑制 TGF-β诱导的分化。在 HSC-LX2 和肝组织中的机制方法表明，DHZ 通过调节 MAPK 通路减轻纤维化。总体而言，这些结果表明，DHZ 通过减少纤维化标志物及其通过调节 MAPK 通路的活性来发挥抗纤维化作用，表明 DHZ 可能是肝纤维化的一种有前途的治疗分子。
