Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.
Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.
Cellular sumoylation processes are proposed targets for anti-viral and anti-cancer therapies. We reported that Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) dysregulates cellular sumoylation processes, contributing to its oncogenic potential in EBV-associated malignancies. Ginkgolic acid and anacardic acid, known inhibitors of sumoylation, inhibit LMP1-induced protein sumoylation; however, both drugs have adverse effects in hosts. Here we test the effects of glycyrrhizic acid, a medicinal botanical extract with anti-inflammatory, anti-carcinogenic, and anti-viral properties, on cellular sumoylation processes. While glycyrrhizic acid is known to inhibit EBV penetration, its affect on cellular sumoylation processes remains to be documented. We hypothesized that glycyrrhizic acid inhibits cellular sumoylation processes and may be a viable treatment for Epstein-Barr virus-associated malignancies. Results showed that glycyrrhizic acid inhibited sumoylation processes (without affecting ubiquitination processes), limited cell growth, and induced apoptosis in multiple cell lines. Similar to ginkgolic acid; glycyrrhizic acid targeted the first step of the sumoylation process and resulted in low levels of spontaneous EBV reactivation. Glycyrrhizic acid did not affect induced reactivation of the virus, but the presence of the extract did reduce the ability of the produced virus to infect additional cells. Therefore, we propose that glycyrrhizic acid may be a potential therapeutic drug to augment the treatment of EBV-associated lymphoid malignancies.
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