Plasticity of NMDA Receptors at Ventral Hippocampal Synapses in the Infralimbic Cortex Regulates Cued Fear.

The medial prefrontal cortex (mPFC) processes contextual information from the hippocampus to generate appropriate fear responses. In rodents, one path for sending contextual information to the mPFC is via the direct projections from the ventral hippocampus (vHC) to the infralimbic cortex (IL). Plasticity in the synaptic communication from the vHC to the IL could contribute to the behavioral changes produced by the acquisition and extinction of conditioned fear. To examine this possibility, we used optogenetic stimulation of vHC synapses in brain slices from trained rats. We found that fear acquisition reduced NMDA receptor (NMDAR) currents at vHC synapses onto IL pyramidal neurons. The depression of NMDAR currents reversed more efficiently after extinction in the conditioning context than extinction in a novel context. Moreover, a cohort of animals that exhibited poor extinction retrieval failed to reverse the plasticity induced by fear conditioning. In addition, ex vivo application of brain-derived neurotrophic factor (BDNF), which is known to simulate extinction in IL, reversed this conditioning-induced plasticity mimicking extinction. Therefore, we have identified a novel mechanism that modulates conditioned fear via changes in NMDAR current at vHC synapses onto IL pyramidal neurons. Disruption of this mechanism could contribute to the abnormal contextual modulation of fear seen in posttraumatic stress disorder (PTSD).

Para-Substituted Functionalised Ferrocene Esters with Novel Antibacterial Properties.

INTRODUCTION: Bacterial antibiotic resistance is on rise despite advances in the development of new antibiotics. In an attempt to circumvent resistance, scientists are shifting focus from modifying existent antibiotics to identifying new antibiotic compounds. AIM: To assess the potential antibiotic effects of functionalised ferrocenecarboxylates para-substituted on the phenoxy pendant group to form: 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl and 4-(H-pyrrol-1-yl)phenyl. MATERIALS AND METHODS: For this, we employed the Kirby-Bauer disc diffusion method using a collection of nine bacterial species: Staphylococcus aureus, Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Bacillus subtilis, Proteus vulgaris and Enterobacter aerogenes. RESULTS: The results show that all four-halogen substituted ferrocenecarboxylates 4-fluorophenyl (23.33 µM, 11.66 µM, 5.83 µM), 4-chlorophenyl (10.16 µM, 5.08 µM, 2.54 µM), 4-bromophenyl (9.0 µM, 4.5 µM, 2.25 µM), and 4-iodophenyl (17.12 µM, 8.56 µM, 4.28 µM) exhibited an antibacterial effect by reducing proliferation of Bacillus subtilis. Meanwhile, only 4-bromophenyl (9.0 µM) and 4-chlorophenyl (10.16 µM) ferrocenecarboxylates were able to decrease the growth of Micrococcus luteus. CONCLUSION: Hence, functionalised ferrocenecarboxylates para-substituted with small and simple groups represent a novel class of bio-organometallic compounds with the potential to be used as antibacterial agents.

Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.

Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.