New 7-Chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums as Promising Fungicide Candidates: Design, Synthesis, and Bioactivity.

As our further research, a series of new 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums were designed and synthesized. Twelve compounds were found with excellent inhibition activity in vitro on three to five out of six phytopathogenic fungi, superior to standard drugs thiabendazole and/or azoxystrobin. Especially, 18 displayed the highest activity against three out of the fungi and the highest comprehensive activity for all of the fungi. The test in vivo revealed that 18 at 50 µg/mL was able to completely control Physalospora piricola infections in apples over 8 days. Scanning/transmission electron microscopic observations found that 18 could damage the hyphal integrity and cell membrane structure of P. piricola. The safety evaluation showed that 18 had no effect on the germination rate of cowpea seed at ≤200 µg/mL. The SAR revealed that the combination of 7-Cl and 2'- or 4'-alkyl is conducive to improvement of the activity. Thus, 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-ium is a promising antifungal lead scaffold.

Unexpected expression of heat-activated transient receptor potential (TRP) channels in winter torpid bats and cold-activated TRP channels in summer active bats.

The ability to sense temperature changes is crucial for mammalian survival. Mammalian thermal sensing is primarily carried out by thermosensitive transient receptor potential channels (Thermo-TRPs). Some mammals hibernate to survive cold winter conditions, during which time their body temperature fluctuates dramatically. However, the underlying mechanisms by which these mammals regulate thermal responses remain unclear. Using quantitative real-time polymerase chain reaction (qRT-PCR) and the Western blotting, we found that Myotis ricketti bats had high levels of heat-activated TRPs (e.g., TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (e.g., TRPM8 and TRPC5) during active states in summer. We also found that laboratory mice had high mRNA levels of cold-activated TRPs (e.g., Trpm8 and Trpc5) under relatively hot conditions (i.e., 40 °C). These data suggest that small mammals up-regulate the expression of cold-activated TRPs even under warm or hot conditions. Binding site analysis showed that some homeobox (HOX) transcription factors (TFs) regulate the expression of hot- and cold-activated TRP genes and that some TFs of the Pit-Oct-Unc (POU) family regulate warm-sensitive and cold-activated TRP genes. The dual-luciferase reporter assay results demonstrated that TFs HOXA9, POU3F1, and POU5F1 regulate TRPC5 expression, suggesting that Thermo-TRP genes are regulated by multiple TFs of the HOX and POU families at different levels. This study provides insights into the adaptive mechanisms underlying thermal sensing used by bats to survive hibernation.