Histone acetylation has been linked to depression, the etiology of which involves many factors such as genetics, environments, and epigenetics. The aim of the present study was to investigate whether it was associated with epigenetic histone modification and gene expression of enzymes responsible for the biosynthesis of norepinephrine and serotonin in rat depression model induced by chronic unpredictable stress (CUS). Eight-week-old male Sprague-Dawley rats were exposed to CUS over 28 days. It was shown that the CUS-induced rats displayed remarked anxiety- and depression-like behavior with weakened locomotor activity in open field test and prolonged immobility in forced swimming test. Western blot revealed that CUS led to significant decrease in acetylation of H3 at Lysine 9 (K9) and H4 at Lysine 12 (K12) with obviously increasing histone deacetylases 5 (HDAC5) expression in hippocampus of CUS-induced rats. Meanwhile, there was an obviously decreased expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) both at protein and mRNA levels. Administration of sodium valproate (VPA), a histone deacetylase 5 (HDAC5) inhibitor, not only significantly relieved the anxiety- and depression-like behaviors of CUS-induced rats but also clearly blunted decrease of H3(K9) and H4(K12) acetylation and expression of TH and TPH, and prevented increase of HDAC5 expression. The results indicate that there exists possible interrelation between TH and TPH gene expression and epigenetic histone acetylation in CUS-induced depressive rats, which at least partly contributes to the etiology of depression.

No abstract

No abstract

No abstract

In human plasma, the total concentration of non-protein binding (NPB) drugs is equal to the free drug concentration because NPB drugs do not or hardly bind to plasma proteins. Thus, centrifuge ultrafiltration (CF-UF) has been used in the determination of the concentration of NPB drugs in human plasma. However, with only a common centrifugation, the recovery and the reproducibility were not as excellent as expected. In addition, we discovered that the values of the volume ratio of ultrafiltrate to sample solution (Vu/Vs) were different and could not be well controlled, which may affect the determination of the drug concentration. The problem also affected the determination of other NBP drugs. In the present work, we used biapenem as a representative drug to study the effect of Vu/Vs on the analysis of NPB drugs concentration in human plasma. The results showed that a Vu/Vs value of less than 0.4 had no effect on the analysis of free drug concentration, while a Vu/Vs value of more than 0.4 was associated with increased recovery rate and overestimation of drug concentration. Therefore, to maintain a Vu/Vs value of less than 0.4 and even at a constant value is the key to accurately determine the concentration of NPB drugs in plasma. Fortunately, with an HFCF-UF device, the Vu/Vs could be well controlled and kept at 0.08 in this study. The recovery rates were almost 100% and the analysis precision was greatly improved. In pharmacokinetics studies, this method was successfully employed to determine the concentration of biapenem with excellent accuracy and reproducibility. HFCF-UF may become a feasible platform for the determination of NPB drugs.