OBJECTIVE: The multidrug resistance 1 (ABCB1, MDR1) gene, encoding P-glycoprotein, is extensively distributed and expressed in various tissues, such as a blood-brain barrier transporter. P-glycoprotein plays an important role in controlling the passage of substances between the blood and brain. The current study aimed to investigate possible associations of functional ABCB1 polymorphisms (C3435T, G2677T and C1236T) with response to antidepressant treatment and serum cortisol levels in Taiwanese patients with major depressive disorder (MDD). METHODS: We recruited 112 MDD patients who were randomized to fluoxetine (n=58, mean dose: 21.4+/-4.5 mg/day) or venlafaxine (n=54, 80.2+/-34.7 mg/day) treatment for 6 weeks. The 21-item Hamilton Depression Rating Scale (HDRS) was administered initially and biweekly after treatment, and cortisol levels were assessed initially and after 6-week antidepressant treatment. RESULTS: The initial HDRS scores and the HDRS scores after six weeks of antidepressant treatment were not significantly different among the different genotypes in each polymorphism of ABCB1. The percentage changes of HDRS scores over time were significantly different in the polymorphisms of ABCB1 G2677T (p=0.002). MDD patients with the G/G genotype of ABCB1 G2677T had a worse antidepressant treatment response. However, the polymorphisms of ABCB1 genotypes were not significantly associated with cortisol levels before and after antidepressant treatment in MDD patients. CONCLUSION: The results suggested that the variants of ABCB1 may influence the short-term antidepressant response in MDD patients. Further details of the underlying mechanisms of ABCB1 in antidepressant treatment remain to be clarified.
Antidepressive Agents ; Blood-Brain Barrier ; Brain ; Depression ; Depressive Disorder, Major ; Drug Resistance, Multiple ; Fluoxetine ; Genotype ; Humans ; Hydrocortisone ; P-Glycoprotein ; P-Glycoproteins ; Venlafaxine Hydrochloride

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications.
Embryonic Stem Cells ; Female ; Fibroblasts ; Foreskin ; Granulosa Cells ; Humans* ; Induced Pluripotent Stem Cells ; Lymphocyte Culture Test, Mixed ; Lymphocytes* ; Major Histocompatibility Complex ; Phenotype ; Pluripotent Stem Cells* ; RNA ; Signal Transduction ; Sirolimus ; Stem Cells ; Transcriptome