Search

Aim Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. Materials and methods Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. Key findings Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. Significance AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.

Estradiol (E2) is locally synthesized within the hippocampus in addition to the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. Molecular mechanisms of modulation through synaptic estrogen receptor (ER) and its downstream signaling, however, have been still unknown. We investigated induction of LTP by the presence of E2 upon weak theta burst stimulation (weak-TBS) in CA1 region of adult male hippocampus. Since only weak-TBS did not induce full-LTP, weak-TBS was sub-threshold stimulation. We observed LTP induction by the presence of E2, after incubation of hippocampal slices with 10 nM E2 for 30 min, upon weak-TBS. This E2-induced LTP was blocked by ICI, an ER antagonist. This E2-LTP induction was inhibited by blocking Erk MAPK, PKA, PKC, PI3K, NR2B and CaMKII, individually, suggesting that Erk MAPK, PKA, PKC, PI3K and CaMKII may be involved in downstream signaling for activation of NMDA receptors. Interestingly, dihydrotestosterone suppressed the E2-LTP. We also investigated rapid changes of dendritic spines (=postsynapses) in response to E2, using hippocampal slices from adult male rats. We found 1 nM E2 increased the density of spines by approximately 1.3-fold within 2 h by imaging Lucifer Yellow-injected CA1 pyramidal neurons. The E2-induced spine increase was blocked by ICI. The increase in spines was suppressed by blocking PI3K, Erk MAPK, p38 MAPK, PKA, PKC, LIMK, CaMKII or calcineurin, individually. On the other hand, blocking JNK did not inhibit the E2-induced spine increase. Taken together, these results suggest that E2 rapidly induced LTP and also increased the spine density through kinase networks that are driven by synaptic ER. This article is part of a Special Issue entitled SI: Brain and Memory.

This article is part of a Special Issue “Estradiol and cognition”. Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2 h. Spine head diameter analysis showed that the density of middle-head spines (0.4–0.5 μm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3β antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER.

Objective To investigate if mandibular condylar cartilage is derived from the periosteum of the ossifying mandible or from a separate, programmed blastema. Materials and methods Fetal mice at E14.0–16.0, fetal rats at E16.0–18.0, and human embryos at 9 and 10wks of gestation were used. The initial formation of rat condylar cartilage was investigated by using serial sections and enzyme-histochemistry to detect alkaline phosphatase activity. Histological observations of serial sections of human fetuses as well as 3D-reconstruction models were also analyzed. The expression of collagen type mRNA in developing rat condylar cartilage was directly compared with that in mice by performing in situ hybridization. Results An anlage of the rat condylar process (condylar anlage) was clearly identified in the posterior position of the ossifying mandible and was continuous with it at E16.0. Newly formed rat condylar cartilage was observed at E16.5 and was continuous with the ossifying mandible. Mesenchymal cells in the condylar anlage at E16.0 showed alkaline phosphatase activity and chondrocytes in the newly formed condylar cartilage also showed enzymatic activity. Thus, rat mandibular condylar cartilage that derives from alkaline phosphatase-positive periosteum-like cells is continuous with the ossifying mandible, as previously demonstrated in mice, but rapid differentiation into hypertrophic chondrocytes in rats is not remarkable compared to that in mice. The condylar anlage and the newly formed cartilage were also continuous with the ossifying mandible in human embryos. Conclusions Mammalian mandibular condylar cartilage derives from the periosteum of the ossifying mandible in mice, rats, and humans.

The reaction section of the naphtha hydro-desulfurization (HDS) process is a heating and cooling thermal process consisting of a feed/effluent heat exchanger and a fired heater. Energy savings are fundamentally made as a result of the maximized heat recovery in the heat exchanger and the reduced heat duty of the fired heater. To achieve further energy saving in the process, “self-heat recuperation technology” (SHRT) was adopted. In this technology, a compressor was introduced. The suction side of the compressor needed a lower pressure and the feed stream evaporated much easily. The discharged side of the compressor satisfied the operating conditions of both pressure and temperature at the inlet of the reactor. And the reactor effluent stream was able to be used completely to preheat and vaporize the feed stream. All the heat in the process stream was re-circulated without using a fired heater. SHRT was applied to the naphtha HDS process of 18,000 barrel per stream day (BPSD) in the refinery and the mass and energy balance of the process was calculated using commercially available simulation software, Invensys PROII version 8.1. This process-simulation case study confirmed that despite there being no more energy saving potential in the conventional process that makes use of a fired heater, the advanced process with SHRT can reduce the energy consumption significantly by using the recuperated heat of the feed stream.

Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10 nM DHT or T induced rapid increase in the density of thorns within 2 h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.