Vibsanin B preferentially targets HSP90ß, inhibits interstitial leukocyte migration, and ameliorates experimental autoimmune encephalomyelitis.

Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz-enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90ß. At the molecular level, inactivation of HSP90 can mimic vibsanin B's effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90ß and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway.

BACKGROUND: The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. RESULTS: Cnr2 activation down-regulates 5-lipoxygenase (Alox5) expression by suppressing the JNK/c-Jun activation. CONCLUSION: The Cnr2-JNK-Alox5 axis modulates leukocyte inflammatory migration. SIGNIFICANCE: Linking two important regulators in leukocyte inflammatory migration and providing a potential therapeutic strategy for treating human inflammation-associated diseases. Inflammatory migration of immune cells is involved in many human diseases. Identification of molecular pathways and modulators controlling inflammatory migration could lead to therapeutic strategies for treating human inflammation-associated diseases. The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. Through a chemical genetic screen using a zebrafish model for leukocyte migration, we found that both an agonist of the Cnr2 and inhibitor of the 5-lipoxygenase (Alox5, encoded by alox5) inhibit leukocyte migration in response to acute injury. These agents have a similar effect on migration of human myeloid cells. Consistent with these results, we found that inactivation of Cnr2 by zinc finger nuclease-mediated mutagenesis enhances leukocyte migration, while inactivation of Alox5 blocks leukocyte migration. Further investigation indicates that there is a signaling link between Cnr2 and Alox5 and that alox5 is a target of c-Jun. Cnr2 activation down-regulates alox5 expression by suppressing the JNK/c-Jun activation. These studies demonstrate that Cnr2, JNK, and Alox5 constitute a pathway regulating leukocyte migration. The cooperative effect between the Cnr2 agonist and Alox5 inhibitor also provides a potential therapeutic strategy for treating human inflammation-associated diseases.

Inhibition of the replication of hepatitis B virus in vitro by a novel 2,6-diaminopurine analog, beta-LPA.

Antiviral therapy of chronic hepatitis B remains a major clinical problem worldwide. Like lamivudine, nucleoside analogs have become the focus of investigation of anti-hepatitis B virus (anti-HBV) drugs. Here, beta-LPA is a novel 2,6-diaminopurine analog found to possess potent anti-HBV activity. In HepG2.2.15 cell line, beta-LPA had a 50% effective concentration (EC(50)) of 0.01 microM against HBV, as determined by analysis of secreted and intracellular episomal HBV DNA. Levels of HBV surface antigen (HBsAg) and e antigen (HBeAg) in drug-treated cultures revealed that beta-LPA had no significant inhibitory effects on HBsAg and HBeAg. beta-LPA didn't show any cytotoxicity up to 0.4 microM with a 50% cytotoxic concentration (CC(50)) of 50 microM. Furthermore, treatment with beta-LPA resulted in no apparent inhibitory effects on mitochondrial DNA content. Considering the potent inhibition of HBV DNA synthesis and no obvious toxicity of beta-LPA, this compound should be further explored for development as an anti-HBV drug.

[Research Progress on the Role of Pyroptosis in the Pathogenesis of Myelodysplastic Syndrome -Review].

Pyroptosis is a novel type of programmed cell death, which is closely related with the pathogenesis of myelodysplastic syndromes (MDS). The recent studies showed that all of S100A9/TLR4, S100A9/CD33 and Nox/ROS signaling pathways can activate oxygen-sensitivity NLRP3 inflammasome and then induce the pyroptosis of hematopoeitic stem cells (HSC) / hematopeitic pregenitor cells (HPC), resulting in ineffective hematopoiesis in patients with MDS. Further studies on the role and molecular mechanism of pyroptosis in the pathogenesis of MDS will provide the potential opportunity for the diagnosis and treatment of MDS. Here, the recent advances in the role and mechnism of pyroptosis in the pathogenesis of MDS are reviewed.