Novel Curcumin Analogue L6H4 in Treating Liver Fibrosis and Type 2 Diabetes

Jun Ma,1,* Deep K Vaishnani,2,* Mansi,2 Jing Zeng,3 Zhenwen Xie,3 Xuanchen Jin,3 Haixia Zhang,3 Khaing Wut Yi Hla,2 Furong Ying4 1Department of Pathology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2School of International Studies, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China; 3School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China; 4Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Furong Ying, Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China, Tel/Fax +86 57755579738, Email 764741293@qq.comPurpose: The objective of this study was to evaluate the therapeutic efficacy of the curcumin analogue L6H4 in attenuating liver fibrosis and alleviating insulin resistance in streptozotocin-induced diabetic rats.Methods: Male Sprague-Dawley rats were fed a high-fat diet to induce insulin resistance, followed by streptozotocin injection to induce diabetes. The rats were then treated with L6H4 for eight weeks. Body weight, metabolic parameters, liver function, and liver histopathology were evaluated. Immunohistochemistry was performed to assess the expression of TGF-β 1, TIMP-2, and MMP-2 in liver tissues. Statistical analysis was conducted using one-way ANOVA and Spearman rank correlation test.Results: L6H4 treatment effectively reversed the weight gain associated with a high-fat diet and improved metabolic parameters in diabetic rats. Liver function markers, such as ALT and AST, were reduced after L6H4 treatment. Histological analysis showed improved liver morphology and reduced fibrosis in L6H4-treated rats. Electron microscopy revealed improved ultrastructural features of hepatocytes. Immunohistochemistry demonstrated downregulation of TGF-β 1 and TIMP-2 expression and restoration of MMP-2 expression in the liver tissue of L6H4-treated rats. Correlation analysis showed a significant positive correlation between TGF-β 1 and TIMP-2 expression.Conclusion: The findings suggest that L6H4 has therapeutic potential in attenuating liver fibrosis and alleviating insulin resistance in streptozotocin-induced diabetic rats. The hepatoprotective effect of L6H4 may be attributed to its anti-inflammatory properties and its ability to target molecules involved in fibrosis. Further research is warranted to explore the potential of L6H4 as a treatment option for nonalcoholic fatty liver disease and type 2 diabetes.Plain Language Summary: The versatile curcumin, derived from turmeric, has shown potential in treating type 2 diabetes (T2D) and its complications. However, its bioavailability is limited. This study evaluated the efficacy of L6H4, a curcumin analogue, in treating T2D-induced hepatic fibrosis in rats. The rats were fed a high-fat diet and injected with streptozotocin to induce T2D. L6H4 treatment for eight weeks reversed weight gain, abnormal liver function, and histological changes. The analogue reduced markers of T2D severity, including blood glucose, insulin levels, and insulin resistance. L6H4 also decreased liver fibrosis by reducing the expression of TGF-β 1 and TIMP-2 and increasing MMP-2 expression. These changes in protein expression were consistent with previous studies on liver fibrosis. The effects of L6H4 on MMP-2 and TIMP-2 expression in the liver of diabetic rats had not been observed before. Additionally, L6H4 exhibited anti-inflammatory properties and regulated the expression of key fibrosis-related proteins. The study suggests that L6H4 has the potential as a therapeutic candidate for treating diabetic hepatopathy. Further research is needed to elucidate the molecular mechanisms of action of L6H4 and other curcumin analogues in T2D and liver fibrosis. In conclusion, L6H4 shows promise as a curcumin analogue with hepatoprotective effects and the ability to modulate protein expression involved in liver fibrosis in T2D.Keywords: type 2 diabetic rats, curcumin analogue, L6H4, TIMP– 2, MMP– 2, TGF-β 1