Vesnarinone Suppresses TNFα mRNA Expression by Inhibiting Valosin-Containing Protein

Abstract

Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IkBa to activate nuclear factor (NF)kB. We show that vesnarinone impairs the degradation of IkBa, and that the impairment of the degradation of IkBa is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFkB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IkBa, resulting in the suppression of tumor necrosis factor-a mRNA expression.

Transcriptional Analysis Reveals Distinct Subtypes in Amyotrophic Lateral Sclerosis: Implications for Personalized Therapy

“…Meanwhile, the pharmacological modulation of VCP may reduce motorneuron-toxicity TDP-43-mediate and thus represents a therapeutic strategy for ALS (Supplementary Table 9). In this regard, some VCP inhibitors (Vesnarinone, Xanthohumol) [139,140] have demonstrated to prevent neuroinflammation and apoptosis associated with several neurological diseases [141,142].…”

Signal Transduction of Improving Effects of Ibudilast on Methamphetamine Induced Cell Death

“…Pentoxifylline blocks the TNF-α release in microglia, however, it no effect on the accumulation of nitrites. On the other hand, Vesnarinone inhibits IL-1, IL-6, and TNF-α but no effect on IL-10 (Xie et al, 2002;Chen et al, 2003;Koyama et al, 2010;Hotta et al, 2013). In addition to the above effects, ibudilast also increases IL-10, which also increases IL-1, IL-6, and TNF-α (Stenvinkel et al, 2005) and it seems to have a stronger performance in protecting neurons against damage in neurodegenerative diseases.…”

Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in medicine and chemical biology

“…The beads with a moderately hydrophilic GMA surface exhibit a low non-specific protein binding and a high binding capacity, due to the small size with a diameter of approximately 200 nm. A wide variety of target proteins for pharmaceutical drugs, environmental hormones, and biologically active compounds have been isolated by using FG beads (Hotta et al, 2013;Ito et al, 2012;Kabe et al, 2016Kabe et al, , 2020. CRBN and damaged specific DNA binding protein 1 (DDB1) were isolated from HeLa cell extracts by affinity purification using FG beads to which FR259625, a carboxy derivative of thalidomide, was immobilized (Figure 2).…”