(S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression.

Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.

Antimicrobial usage on 72 farrow-to-finish pig farms in Japan from 2015 to 2017.

In Japan veterinary antimicrobials are used most in the pig production sector. However, there is a paucity of data on the quantity of antimicrobials used on pig farms in Japan. This study describes antimicrobial use on Japanese pig farms in 2015, 2016 and 2017 in terms of mg of active ingredient per kg of PCU (population correction unit). Data on antimicrobial use from a total of 72 farrow-to finish farms over these three years were used in the study. The results revealed that the average use of antimicrobials in 2015, 2016 and 2017 was 304.8 (SD = 226.3), 311.2 (SD = 241.0) and 342.9 (SD = 291.3) mg/kg PCU, respectively. Most (97%) of the antimicrobials were administered orally. The most commonly used antimicrobials were tetracyclines, followed by macrolides, penicillins and sulfonamides. Tohoku was the region in which the lowest quantities of antimicrobial were used whilst South Kanto was the region in which the largest amount was used. The use of antimicrobials was on the increase in the North Kanto, South Kanto and Kyushu regions.

mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model.

Growing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examined the effects of mS-11, a chemically optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphological abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Additionally, we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA-exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine density in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding.

CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells.

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44-expressing population from a Dex-sensitive MM cell line, RPMI8226, in which the CD44-high population had a significantly higher potential to resist Dex than did the CD44-low population. Furthermore, we demonstrate that CD44 engagement by an anti-CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex-induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti-CD44 mAb led to phosphorylation and degradation of IkappaB-alpha, thus preventing its Dex-induced up-regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.

Racemization of the amyloidal beta Asp1 residue blocks the acceleration of fibril formation caused by racemization of the Asp23 residue.

Amyloid beta proteins extracted from the amyloid cores of neuritic plaques are considerably racemized at their Asp residues. To assess the impact of D-Asp on amyloid beta(1-42) conformation and on initiation of amyloid fibril formation, we used wild-type amyloid beta(1-42) and analogs in which D-Asp was substituted for L-Asp at residues 1, 7, 23, and all combinations of these residues. Amyloid fibril formation was enhanced by D-Asp23; modulation of Asp chirality at N-terminal position 1 blocked this enhancement and modulation at position 7 augmented it. Knowledge of such chirality modifications may help to develop potent inhibitors of amyloid fibril formation.