Assessment of the drug-drug interaction potential for therapeutic proteins with pro-inflammatory activities.

It is well-recognized that therapeutic proteins (TPs) with pro-inflammatory activities elevate the pro-inflammatory cytokines and result in cytokine-drug interactions. In the current review, several pro-inflammatory cytokines, including IL-2, IL-6, IFN-γ, and TNF-α, as well as an anti-inflammatory cytokine IL-10, were summarized for their respective effect on major cytochrome P450 enzymes and efflux transporter PgP. Pro-inflammatory cytokines are generally associated with suppression of CYP enzymes across assay systems but have varied effect on Pgp expression levels and activities depending on the individual cytokines and assay systems, whereas IL-10 had no significant impact on CYP enzymes and P-gp. A cocktail drug-drug interaction (DDI) study design could be an ideal approach for simultaneously assess the impact of TPs with pro-inflammatory activities on multiple CYP enzymes. Clinical DDI studies using the cocktail approach have been conducted for several TPs with pro-inflammatory activities and for those TPs with pro-inflammatory activities which had no clinical DDI study conducted, languages for potential DDI risk due to cytokine-drug interaction were included in the label. Up to date drug cocktails, including clinically validated and unvalidated for DDI assessment, were summarized in this review. Most clinically validated cocktails focused either on CYP enzymes or transporters. Additional effort was needed to validate a cocktail to include both the major CYP enzymes and key transporters. In silico methods for assessment of the DDI for TPs with pro-inflammatory activities were also discussed.

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.