Diisopropylamine dichloroacetate, a novel pyruvate dehydrogenase kinase 4 inhibitor, as a potential therapeutic agent for metabolic disorders and multiorgan failure in severe influenza.

Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-cytokine cycle, which is closely linked to the influenza virus-cytokine-trypsin cycle, resulting in prevention of multiorgan failure in severe influenza.

Evaluation of the masking of dimethyl sulfide odors by citronellal, limonene and citral through the use of trained odor sensor mice.

Previous studies indicate that the most common result of mixing two odors is the decreased olfactory perception of one or both components in the mixture. An excellent example of this phenomenon is provided by the masking of an unpleasant odor by a pleasant odor. This study hypothesized that dimethyl sulfide (DS; a major chemical component of oral malodor) might be masked by citronellal, a monoterpene aldehyde that produces an intense lemon aroma. To investigate this hypothesis, mice were chosen as odor sensor animals. Mice were trained in a Y maze to discriminate between DS (10 ppm in aqueous solution) and water. A series of generalization tests revealed that these trained "odor sensor" mice could also distinguish between 1 ppm DS and water, but not between 0.1 ppm DS and water. The mice were then confronted with the original choice of 10 ppm DS and water, but now in the presence of various concentrations of citronellal. The mice failed to detect the odor of DS when confronted with 30 ppm citronellal. The mice were similarly confused when confronted with citral (90 ppm) or limonene (3000 ppm). This study is the first to show that citrus odorants can mask the odor of DS, altering the behavioral responses of trained odor sensor mice.

Citronellal ingestion decreases the appeal of male mouse urinary pheromone for female mice.

To determine whether ingestion of citronellal decreases the attractive power of the male mouse urinary odor, female mice were used in preference tests. A series of tests revealed that the female mice preferred voided urine odors from aged mice over those from younger adult mice. However, exogenous citronellal directly inhibited the advantage of the aged males with regard to attraction.

Alteration of mouse urinary odor by ingestion of the xenobiotic monoterpene citronellal.

Body odors provide a rich source of sensory information for other animals. There is considerable evidence to suggest that short-term fluctuations in body odor can be caused by diet; however, few, if any, previous studies have demonstrated that specific compounds can directly mask or alter mouse urinary odor when ingested and thus alter another animal's behavior. To investigate whether the ingestion of citronellal, a monoterpene aldehyde that produces an intense aroma detected by both humans and mice, can alter mouse urinary odor, mice (C57BL6J) were trained in a Y maze to discriminate between the urinary odors of male donor mice that had ingested either citronellal in aqueous solution or a control solution. Trained mice could discriminate between urinary odors from the citronellal ingestion and control groups. A series of generalization tests revealed that citronellal ingestion directly altered mouse urinary odor. Moreover, trained mice that had successfully discriminated between urinary odors from donor mice of different ages failed to detect age-related changes in urine from male mice that had ingested 50 ppm of citronellal. This study is the first to show that ingestion of a xenobiotic can alter mouse urinary odor and confuse the behavioral responses of trained mice to age-related scents.

Effect of nutritive and tonic crude drugs on physical fatigue-induced stress models in mice.

The present study was undertaken to investigate the acute anti-fatigue effect of a liquid nutritive and tonic crude drugs (NTDs) on stress induced in mice. After forced walking for 3 or 6h, the NTDs (applied orally, 10 ml/kg) significantly increased locomotor activity, while the administration of NTDs after rapid eye movement (REM) sleep deprivation stress and after immobilization stress did not show a specific effect, having a similar effect as the vehicle with added vitamins, taurine and caffeine. The administration of NTDs after freezing due to electric shock stress showed a specific effect which was not seen in other control groups, water, vehicle (ethanol) and vehicle including vitamins, taurine and caffeine and so resemble the specific effect of NTDs in the stress of forced walking. The present results indicate that the NTDs produced an anti-fatigue effect on the decreased locomotor activity after forced walking and immobility induced by electric stimulation. However, the crude drugs were not effective in improving immobility after sleep deprivation or immobilization stress.