Chemical Synthesis of Triazole-Derived Suppressors of Strigolactone Functions.

Triazole is a five-membered heteroring consists of two carbon atoms and three nitrogen atoms and exhibits a wide range of biological activities. The basic heterocyclic rings are 1,2,3-triazole and 1,2,4-triazole. Here we describe the chemical synthetic methods for triazole derivatives that can suppress the function of SL by inhibiting SL biosynthesis pathway or SL perception sites such as D14.

Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.

Arabidopsis FHY3 and FAR1 integrate light and strigolactone signaling to regulate branching.

Branching/tillering is an important parameter of plant architecture and is tightly regulated by both internal factors (such as plant hormones) and external factors (such as light conditions). How the various signaling pathways converge to coordinately regulate branching is not well understood. Here, we report that in Arabidopsis, FHY3 and FAR1, two homologous transcription factors essential for phytochrome A-mediated light signaling, and SMXL6/SMXL7/SMXL8, three key repressors of the strigolactone (SL) signaling pathway, directly interact with SPL9 and SPL15 and suppress their transcriptional activation of BRC1, a key repressor of branching, thus promoting branching. In addition, FHY3 and FAR1 also directly up-regulate the expression of SMXL6 and SMXL7 to promote branching. Simulated shade treatment reduces the accumulation of FHY3 protein, leading to increased expression of BRC1 and reduced branching. Our results establish an integrated model of light and SL coordinately regulating BRC1 expression and branching through converging at the BRC1 promoter.