Ponalrestat

Objective To investigate the role and mechanism of aldo-keto reductase 1 member B1 (AKR1B1) in regulating microglial cell polarization and thereby regulating the activity of retinal ganglion cells (RGCs). Methods Lipopolysaccharide (LPS) was used to induce BV-2 polarization in microglia cells. AKR1B1 siRNA and inhibitor ponalrestat/Statil were used to treat BV-2 cells, and the effect of AKR1B1 on cell polarization was identified through morphology and inflammatory cytokine expression detection, including tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), cyclooxygenase 2(COX2), and inducible nitric oxide synthase(iNOS). Primary RGCs were cultured with the indicated BV-2 conditional medium. The activity of RGCs was detected by brain-specific homeobox protein 3a (Brn-3a) immunofluorescence staining, and apoptosis was observed by TUNEL staining. The expression of phosphorylated IKK and p65 in the nucleus were detected by Western blotting. Results LPS induced M1-type polarization of BV-2 cells, while its conditioned medium induced decreased RGC activity and increased apoptosis. Inhibition of AKR1B1 blocked M1 type polarization of BV-2 cells and restored RGC activity. Inhibition of AKR1B1 can block LPS-induced IKK phosphorylation and NF-κBp65 nuclear localization. Conclusion AKR1B1 can induce microglial activation by activating NF-κB pathway, which in turn inhibit the activity and promote apoptosis of RGCs.

Plant development is regulated by both synergistic and antagonistic interactions of different phytohormones, including a complex crosstalk between ethylene and auxin. For instance, auxin and ethylene synergistically control primary root elongation and root hair formation. However, a lack of chemical agents that specifically modulate ethylene or auxin production has precluded precise delineation of the contribution of each hormone to root development. Here, we performed a chemical genetic screen based on the recovery of root growth in ethylene-related Arabidopsis mutants with constitutive "short root" phenotypes (eto1-2 and ctr1-1). We found that ponalrestat exposure recovers root elongation in these mutants in an ethylene signal-independent manner. Genetic and pharmacological investigations revealed that ponalrestat inhibits the enzymatic activity of the flavin-containing monooxygenase YUCCA, which catalyzes the rate-limiting step of the indole-3-pyruvic acid branch of the auxin biosynthesis pathway. In summary, our findings have identified a YUCCA inhibitor that may be useful as a chemical tool to dissect the distinct steps in auxin biosynthesis and in the regulation of root development.