EFFECT OF TRANSCRIPTION FACTOR MODULATORS ON THE NITRIC OXIDE SYSTEM PARAMETERS IN THE BLOOD OF RATS UNDER LIPOPOLYSACCHARIDE-INDUCED SYSTEMIC INFLAMMATORY RESPONSE

The study aimed to investigate the effect of transcription factor modulators on nitric oxide (NO) system parameters in the blood of rats under lipopolysaccharide (LPS)-induced systemic inflammatory response (SIR). The experiment was conducted on 42 male Wistar rats weighing 180–220 g, divided into 6 groups (7 animals per group): Group 1 included intact rats (Control I); Group 2 involved rats, which underwent LPS-induced systemic inflammatory response (SIR) modeling (Control II). In the remaining groups, transcription factor modulators were administered under SIR modeling: Group 3 received the anticancer drug bortezomib (used to treat multiple myeloma and mantle cell lymphoma), an NF-κB inhibitor (via proteasome suppression); Group 4 received the anticancer agent SR 11302 (investigated as a potential treatment for lung cancer), an inhibitor of the transcription factor AP-1; Group 5 received dimethyl fumarate, a specific activator of the Nrf2–ARE signaling pathway; Group 6 was administered with quercetin, a flavonoid that acts as an NF-κB inhibitor and an Nrf2 pathway activator. The results showed that LPS-induced SIR significantly increased total NOS and iNOS activity while reducing cNOS and arginase activity in blood serum. This indicates the development of nitrosative stress and impaired L-arginine metabolism in rats. The use of NF-κB inhibitors (bortezomib) and AP-1 inhibitors (SR 11302), as well as Nrf2 activators (dimethyl fumarate and quercetin) reduced iNOS activity and partially normalized cNOS activity, demonstrating their anti-inflammatory and metabolic effects. The most effective agents for correcting nitrosative stress in SIR were bortezomib and SR 11302, which reduced iNOS activity to near-intact levels and partially restored the functional activity of cNOS. Most transcription factor modulators (bortezomib, dimethyl fumarate, quercetin) partially restored arginase activity, highlighting their potential role in correcting impaired L-arginine metabolism. However, the AP-1 inhibitor (SR 11302) further decreased arginase activity compared to the LPS-induced group, suggesting possible inhibition of compensatory enzyme mechanisms and an exacerbation of metabolic imbalance. The findings confirm the key roles of the NF-κB, AP-1, and Nrf2 signaling pathways in regulating nitrosative stress, offering promising pharmacological targets for correcting inflammatory and metabolic disturbances.