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Kynurenic acid (KYNA), an unavoidable tryptophan metabolite during fermentation is naturally blended with alcohol in all alcoholic beverages. Thus, alcohol drinking inevitably results in co-intake of KYNA. Effects of alcohol or KYNA on human health have been widely studied. However, the combined effects of both remain unknown. Here we report that alcohol and KYNA have a synergistic impact of on global gene expression, especially the gene sets related to tryptophan metabolism and cell signaling. Adult mice were exposed to alcohol (ethanol) and/or KYNA daily for a week. Transcriptomes of the brain, kidney and liver were profiled via bulk RNA sequencing. Results indicate that while KYNA alone largely promotes, and alcohol alone mostly inhibits gene expression, alcohol and KYNA co-administration has a stronger inhibition of global gene expression. Tryptophan metabolism is severely skewed towards kynurenine pathway by decreasing tryptophan hydroxylase 2 and increasing tryptophan dioxygenase. Quantification of tryptophan metabolic enzymes corroborates the transcriptional changes of these enzymes. Furthermore, the co-administration greatly enhances the GnRH signaling pathway. This research provides critical data to better understand the effects of alcohol and KYNA in mix on human health.

Excessive alcohol (ethanol) use has long been known to affect human health negatively. However, the underlying molecular basis is incompletely understood. Moreover, consumption of alcohol is often mixed with kynurenic acid (KYNA), an abundant tryptophan metabolite produced during fermentation. The combined effect of ethanol and KYNA on host gene expression has not been investigated. The current study used mice as the model to interrogate the impact of ethanol and/or KYNA on global gene transcription. Adult male mice were administered with 2 g/kg ethanol and/or 0.1 mg/kg KYNA by gavage once a day for a week. Three organs: brain, kidney, and liver were collected and their total RNAs extracted for transcriptome sequencing and quantitative real-time PCR. Gene ontology, Kyoto encyclopedia of genes, and genomes pathway analyses revealed that alcohol affects the three organs differentially. Furthermore, the gene expression profile from alcohol and KYNA co-administration was significantly different from that of alcohol or KYNA administration alone. Strikingly, Indolamine 2,3-dioxygenase 1, a rate-limiting enzyme in tryptophan metabolism, was significantly increased in the brain after a combined exposure of alcohol and KYNA, suggesting that Trp metabolism was skewed towards the kynurenine pathway in the brain. Our systemic analysis provides new insights into the mechanism whereby alcohol and KYNA affects organ functions.

Degradation of visual function is a common phenomenon during aging and likely mediated by change in the impaired central visual pathway. Treatment with GABA or its agonist could recover the ability of visual neurons in the primary visual cortex of senescent macaques. However, little is known about how GABAergic system change is related to the aged degradation of visual function in nonhuman primate. With the use of quantitative PCR method, we measured the expression change of 24 GABA related genes in the primary visual cortex (Brodmann's 17) of different age groups. In this study, both of mRNA and protein of glutamic acid decarboxylase (GAD65) were measured by real-time RT-PCR and Western blot, respectively. Results revealed that the level of GAD65 message was not significantly altered, but the proteins were significantly decreased in the aged monkey. As GAD65 plays an important role in GABA synthesis, the down-regulation of GAD65 protein was likely the key factor leading to the observed GABA reduction in the primary visual cortex of the aged macaques. In addition, 7 of 14 GABA receptor genes were up-regulated and one GABA receptor gene was significantly reduced during aging process even after Banjamini correction for multiple comparisons (P0.05). These results suggested that the dysregulation of GAD65 protein might contribute to some age-related neural visual dysfunctions and most of GABA receptor genes induce a clear indication of compensatory effect for the reduced GABA release in the healthy aged monkey cortex.