Kurarinone, a flavonoid isolated from the roots of Sophora flavescens, was suggested to exert potent antioxidant and immunosuppressive effects. However, the underlying mechanisms remain unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the antioxidant defense system with anti-inflammatory activity. In the present study, we demonstrated that kurarinone activated Nrf2 and increased the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1). Mechanistically, kurarinone downregulated the expression of kelch-like ECH-associated protein 1 (KEAP1), subsequently leading to the activation of Nrf2. Kurarinone also inhibited the expression of the inflammatory cytokine, interleukin (IL)-1β, and inducible nitric oxide synthase (iNos) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The overexpression of HO-1 suppressed the LPS-induced production of inflammatory mediators in RAW264.7 cells, and the immunosuppressive effects of kurarinone were partially inhibited by a treatment with Tin Protomorphyrin IX (TinPPIX), an inhibitor of HO-1. These results indicate that kurarinone activates the KEAP1/Nrf2 pathway to induce HO-1 expression, thereby exerting immunosuppressive effects.

In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.

Two distinct oligomeric structures were obtained by the self-assembly of 4-(diethylboryl)pyridine (1). In the (1)H NMR spectrum of 1 in CDCl3, at least two sets of signals were observed for the pyridyl α- and β-hydrogen atoms. ESI-MS, VPO, and TLC analysis revealed that 1 assembles mainly into a mixture of cyclic pentamers and hexamers in solution via intermolecular boron-nitrogen coordination bonds. Crystallization of 1 in THF by vapor diffusion of EtOH or in CHCl3 afforded the cyclic hexamer incorporating one THF molecule (16·THF) or 1.5 mol equiv of chloroform molecule (16·CHCl3), respectively. Similarly, a solution of 1 in a mixture of benzene and hexane furnished the cyclic pentamer bearing two benzene molecules (15·C6H6). It seems that the solvent differences affected the crystallization of the two distinct cyclic oligomers of 1, either of which was cocrystallized predominantly with the solvent molecule. Thermogravimetric analysis of the crystals and NMR studies of the solution revealed that the noncovalent interactions between the host and guest are not strong enough to hold the guest molecule in the cavity.

Zentangle is a pattern art composed of regular patterns, such as symmetric patterns and self-similarity patterns. We formalized a model of pattern generating processes and conducted computer simulation for generating zentangle patterns automatically. This paper describes three features of zentanlge covered in this research, regularity, ununiformity, and filling process, then presents a model of zentangle. This model premises that zentangle patterns are composed of three classes of patterns. Also, this model deforms the patterns and draws them on empty white regions repeatedly for simulating the features of ununiformity and filling processes. The patterns based on this model have similar features to hand drawn zentangle patterns. Our simulation tool has some functions for interactive pattern composition, as well as auto-generating functions. For example, users can select a sub-pattern to fill a certain target region to compose desired zentangle patterns, or can use gray scale images to define target regions filled with sub-patterns.