Date of Award
2026
Document Type
Dissertation
Degree Name
Pharmaceutical Sciences (Ph.D.)
Department
Pharmaceutical Sciences
First Advisor
Xingguo Cheng
Second Advisor
Pengli Bu
Third Advisor
Diane Hardej
Abstract
Rhodanine (RHO) is a 5-membered heterocyclic scaffold with a broad range of biological activities, including antimicrobial, anticancer, and anti-inflammatory properties. Epalrestat (EPS) is a structurally optimized derivative of RHO, with a modified core that enhances its aldose reductase inhibitory activity for the treatment of diabetic neuropathy. Although RHO-derived compounds have been extensively investigated as aldose reductase inhibitors, their clinical translation has been hindered by their metabolic instability and toxicity concerns. In contrast, EPS demonstrated improved pharmacokinetic properties and therapeutic effectiveness during its development. However, post-marketing surveillance indicated that EPS therapy resulted in hepatic dysfunction. We previously reported that EPS induced oxidative stress, inflammation, and fibrogenesis in the mouse liver. This study aimed to further investigate the inflammatory response through which EPS causes liver injury and whether this injury is related to the parent compound RHO. In mouse livers, both EPS and RHO upregulated pro-inflammatory mediators, particularly interleukin (IL)-6. In addition, EPS and RHO increased mRNA and protein levels of acute-phase proteins such as C-reactive protein and serum amyloid A, as well as angiogenic and vasoactive mediators such as vascular endothelial growth factor, inducible nitric oxide synthase, and tumor necrosis factor-alpha. This increased inflammatory response disrupts endothelial cell integrity, tight junctions, and vascular homeostasis, resulting in sinusoidal dilatation. Furthermore, EPS and RHO increased the expression and release of interleukin (IL)-10 and subsequently induced suppressor of cytokine signaling 3 (SOCS3), which provides a critical negative feedback loop that attenuates the effects of IL-6 signaling, thereby maintaining homeostasis and preventing excessive inflammation. In summary, EPS and RHO induced hepatic inflammation and disrupted sinusoidal endothelial integrity through IL-6-mediated signaling cascades.
Recommended Citation
Yarde, Shari, "RHODANINE AND ITS DERIVATIVE EPALRESTAT INDUCE HEPATITIS AND SINUSOIDAL DILATATION VIA ACTIVATION OF THE IL-6 SIGNALING PATHWAY" (2026). Theses and Dissertations. 1020.
https://scholar.stjohns.edu/theses_dissertations/1020