Organized Resting-state Functional Dysconnectivity of the Prefrontal Cortex in Patients with Schizophrenia.

Schizophrenia has prominent functional dysconnectivity, especially in the prefrontal cortex (PFC). However, it is unclear whether in the same group of patients with schizophrenia, PFC functional dysconnectivity appears in an organized manner or is stochastically located in different subregions. By investigating the resting-state functional connectivity (rsFC) of each PFC subregion from the Brainnetome atlas in 40 schizophrenia patients and 40 healthy subjects, we found 24 altered connections in schizophrenia, and the connections were divided into four categories by a clustering analysis: increased connections within the PFC, increased connections between the inferior PFC and the thalamus/striatum, reduced connections between the PFC and the motor control areas, and reduced connections between the orbital PFC and the emotional perception regions. In addition, the four categories of rsFC showed distinct cognitive engagement patterns. Our findings suggest that PFC subregions have specific functional dysconnectivity patterns in schizophrenia and may reflect heterogeneous symptoms and cognitive deficits in schizophrenia.

Impact of the haplotypes of the human pregnane X receptor gene on the basal and St John's wort-induced activity of cytochrome P450 3A4 enzyme.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Human pregnane X receptor (PXR/NR1I2) is a key regulator of cytochrome P450 3A4. To date, there are 198 reported SNPs for the human PXR/NR1I2 gene. Some of these SNPs are found to affect the inducing ability of PXR to CYP3A4. WHAT THIS STUDY ADDS: This study, for the first time, has investigated the effect of PXR haplotype on basal and St John's wort-induced CYP3A4 activity in humans. H1/H1 of the PXR gene had weaker basal transcriptional activity but greater inducible transcriptional activity to CYP3A4 than H1/H2 and H2/H2. AIMS: Human pregnane X receptor (PXR/NR1I2) is the master regulator of CYP3A4, which metabolizes >50% of drugs on the market. This study investigated the relationship between the two most frequent haplotypes [H1 (TCAGGGGCCACC) and H2 (CCGAAAACTAAT)] of PXR and basal and St John's wort (SJW)-induced CYP3A4 activity. METHODS: Ten healthy subjects carrying H1 and H2 haplotypes (three subjects with H1/H1, four with H1/H2 and three with H2/H2) entered this study. The 10 subjects did not carry CYP3A4*4, *5 and *6. All subjects were administrated a 300-mg SJW tablet three times daily for 14 days, and CYP3A4 activity was measured using nifedipine (NIF) as a probe. The plasma concentrations of NIF and dehydronifedipine (DNIF) were determined by a validated liquid chromatography/mass spectrometry/mass spectrometry method. RESULTS: After administration of SJW, the AUC(0-infinity) of NIF decreased significantly, and the AUC(0-infinity) of DNIF increased significantly (P < 0.05). For H1/H2, the AUC(0-infinity) of NIF decreased by 42.4%, and the AUC(0-infinity) of DNIF increased by 20.2%; for H2/H2, the AUC(0-infinity) of NIF decreased by 47.9%, and the AUC(0-infinity) of DNIF increased by 33.0%; for H1/H1, the AUC(0-infinity) of NIF decreased by 29.0%, yet the AUC(0-infinity) of DNIF increased by 106.7%. The increase of the AUC(0-infinity) of DNIF in H1/H1 was significantly different from the other two haplotype pairs (P < 0.05). Meanwhile, before administration of SJW, the ratio of AUC(0-infinity(DNIF))/AUC(0-infinity(NIF)) was the lowest for H1/H1 (22.1%), compared with H1/H2 (58.7%) and H2/H2 (30.0%). CONCLUSIONS: H1/H1 of the human PXR gene had weaker basal transcriptional activity but greater inducible transcriptional activity to CYP3A4 than H1/H2 and H2/H2.