An Escherichia coli mutant was isolated and shown to be polymyxin B resistant. Mapping and sequence analysis revealed a missense mutation at codon 53 within the pmrA (basR) gene that results in a G-to-V substitution. Fusions of promoters from the pmrC, yibD, and pmrH genes with the lacZ reporter showed that they were constitutively expressed in pmrA53 cells. In pmrA ؉ strains, these promoters were induced by iron and zinc, while a ⌬pmrA mutation blocked induction. The PmrA regulon regulates genes whose products remodel the composition and charge of lipid A and hence the barrier properties of the outer membrane. Along these lines, the pmrA53 mutant was also found to be hypersensitive to the anionic bile detergent deoxycholic acid.The outer membrane of gram-negative bacteria functions as a barrier to exclude toxic chemicals, such as antibiotics, from entering and killing the cell (18). To meet different environmental challenges, bacteria can physiologically adapt or mutate to remodel the chemical composition of lipopolysaccharides (LPS) and hence the permeability properties of their outer membranes (6, 16). In Salmonella enterica, pmrA constitutive mutants become resistant to the cationic antibiotic polymyxin B with the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) and, to a lesser extent, phosphoethanolamine (pEtN) moieties to lipid A (9, 25). The addition of L-Ara4N partly neutralizes the negative charges on lipid A, a component of LPS, and hence reduces the electrostatic interaction with polymyxin B. Similarly, the PmrAB two-component regulon can be induced in wild-type cells by iron, which in turn leads to lipid A modification and polymyxin resistance (28). PmrAB-dependent remodeling of LPS also confers resistance towards cationic peptides and metal ions (4, 16). In Pseudomonas aeruginosa, polymyxinresistant mutants can be cross resistant to aminoglycosides (12).Inside the human host, LPS (endotoxin) remodeling plays a key role in bacterial fitness and virulence. L-Ara4N LPS modification not only confers resistance to endogenous antibacterial cationic peptides but also helps bacteria evade the innate immune system by making LPS a poor Toll-like receptor 4 agonist (16). To date, Salmonella has been the primary model organism for understanding the role of LPS remodeling in pathogenesis and antibiotic resistance. Here we identify and characterize a pmrA constitutive mutant of Escherichia coli and show that the mutant confers hypersensitivity to the bile detergent deoxycholic acid.Strains. During the course of our studies with novel antibacterial agents, we isolated a spontaneous resistant mutant named DW137 (Table 1) (D. Wall and J. M. Froelich, unpublished data). This mutation was mapped by Hfr crosses (15) to ϳ93 min on the E. coli chromosome. Subsequent bacteriophage P1vir transductions with a set of known Tn10 insertions around 93 min mapped the mutation between zje-2241::Tn10 and cadB2231::Tn10 (15, 17). Because the mutation mapped near the pmrAB (basRS) locus, we tested and found the strain was resistan...
Depression is a serious psychiatric disorder with high prevalence, and the delayed onset of antidepressant effects remains a limitation in the treatment of depression. This study aimed to screen essential oils that have the potential for rapid-acting antidepressant development. PC12 and BV2 cells were used to identify essential oils with neuroprotective effects at doses of 0.1 and 1 µg/mL. The resulting candidates were treated intranasally (25 mg/kg) to ICR mice, followed by a tail suspension test (TST) and an elevated plus maze (EPM) after 30 min. In each effective essential oil, five main compounds were computationally analyzed, targeting glutamate receptor subunits. As a result, 19 essential oils significantly abolished corticosterone (CORT)-induced cell death and lactate dehydrogenase (LDH) leakage, and 13 reduced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). From in vivo experiments, six essential oils decreased the immobility time of mice in the TST, in which Chrysanthemum morifolium Ramat. and Myristica fragrans Houtt. also increased time and entries into the open arms of the EPM. Four compounds including atractylon, α-curcumene, α-farnesene, and selina-4(14),7(11)-dien-8-one had an affinity toward GluN1, GluN2B, and Glu2A receptor subunits surpassed that of the reference compound ketamine. Overall, Atractylodes lancea (Thunb.) DC and Chrysanthemum morifolium Ramat essential oils are worthy of further research for fast-acting antidepressants through interactions with glutamate receptors, and their main compounds (atractylon, α-curcumene, α-farnesene, and selina-4(14),7(11)-dien-8-one) are predicted to underlie the fast-acting effect.
Aromatherapy is one of the most common safer alternative treatments for psychiatric disorders with fewer side effects than conventional drugs. Here, we investigated the effects of cinnamon essential oil (CIEO) inhalation on mouse behaviors by performing different behavioral tests. CIEO inhalation showed anxiolytic effects in the elevated plus maze test, as inferred from increased time spent in open arms and decreased time spent in closed arms. Moreover, the CIEO treatment enhanced social behavior by increasing the total contact number, time spent in the center, distance traveled in the center, and total distance in the social interaction test. However, CIEO inhalation did not have any effect on performance in the open field test, tail suspension test, forced swimming test, and Y maze tests. The microarray analysis indicated that the CIEO treatment downregulated 17 genes and upregulated 15 genes in the hippocampus. Among them, Dcc, Egr2, and Fos are the most crucial genes that are involved in anxiety-related biological processes and pathways, including the regulation of neuronal death and neuroinflammation. Gas chromatography/mass spectrometry analysis revealed that cinnamaldehyde is the main component of CIEO. Cinnamaldehyde recovered MK-801-induced anxiety-related changes in the electroencephalogram power spectrum in zebrafish. Taken together, our findings suggest that CIEO and its main component cinnamaldehyde have an anxiolytic effect through the regulation of the expression of genes related to neuroinflammatory response and neuronal death.
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