Modulation of interleukins 38 and 1 Beta gene expression by N-(4-benzoylphenyl)-5-nitrofuran-2-carboxamide in Triton...

Atherosclerosis (AS) is characterized by a gradual plaque buildup within the arteries, resulting in hardened and narrowed arteries. Thus, it leads to blood flow limitation and increased risk of critical diseases. Hyperlipidemia is correlated with inflammation, as seen with increased expression of different inflammatory markers including tumor-necrosis factor-alpha (TNF-α), C-reactive protein (CRP), chemokines and interleukins. This current study explores the relationship between novel anti-hyperlipidemic compounds and the expression of specific inflammatory markers in acute hyperlipidemic rats induced by Triton WR-1339.

Male Wistar rats were separated into six different groups including a normal control group, a hyperlipidemic control group, four hyperlipidemic groups administrated with fenofibrate, N-(4-benzoylphenyl)-5-nitrofuran-2-carboxamide (NF4BP), N-(3-benzoylphenyl)-5-nitrofuran-2-carboxamide (NF3BP) and N-(4-acetylphenyl)-5-nitrofuran-2-carboxamide (NF4AP). The rats were sacrificed after 20 h of treatment; RT-PCR was employed to assess the specific inflammatory markers expression levels and protein-protein network was predicted using STRING 11.5 database.

This study demonstrated that the novel compounds significantly reduced total triglyceride levels when compared to the hyperlipidemic group. Two-fold changes in CRP, TNF-α, interleukin-1 beta (IL-1β), interleukin-38 (IL-38), interleukin-6 (IL-6), intercellular adhesion molecule (ICAM-1), chemokine-16 (CXCL-16), and vascular cell adhesion molecule (VCAM-1) were evaluated in comparison to the hyperlipidemic group revealed a significant downregulation of CRP (~ 3 folds), IL-1β (~ 7 folds), IL-6 (~ 5 folds), and TNF-α (~ 4 folds) after administration of NF4AP; the findings also showed a significant downregulation of TNF-α (~ 4 folds), and IL-1β (~ 6 folds) after administration of NF3BP; and there was also a significant downregulation of IL-1β (~ 6 folds). TNF-α (~ 2 folds), and IL-6 (~ 3 folds), expression after administration of NF4BP, suggesting a substantial suppression of pro-inflammatory signaling. It is noteworthy that anti-inflammatory IL-38 was significantly overexpressed after administration of NF4BP (~ 42 folds). STRING 11.5 database predicted that IL-1β down regulation plays an important role among the inflammatory markers tested.

In conclusion, all novel compounds and fenofibrate demonstrated significant antihyperlipidemic properties. Among the three compounds, NF4BP showed the highest elevation in the expression levels of anti-inflammatory marker IL-38 accompanied by down regulation of proinflammatory markers. Understanding the impact of these compounds on inflammatory markers' expression is critical for developing effective therapeutic strategies for managing hyperlipidemia-associated complications. Hence, targeting these inflammatory pathways by these compounds may offer new avenues for the prevention of dyslipidemia complications.