Background Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function. Methods Sepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8–12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence. Results CLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown. Conclusion SOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

No abstract

Background Perioperative neurocognitive disorders (PNDs) occur frequently after surgery and worsen patient outcome. How C-X-C motif chemokine (CXCL) 13 and its sole receptor CXCR5 contribute to PNDs remains poorly understood. Methods A PND model was created in adult male C57BL/6J and CXCR5−/− mice by exploratory laparotomy. Mice were pretreated via intracerebroventricular injection with recombinant CXCL13, short hairpin RNA against CXCL13 or a scrambled control RNA, or ERK inhibitor PD98059. Then surgery was performed to induce PNDs, and animals were assessed in the Barnes maze trial followed by a fear-conditioning test. Expression of CXCL13, CXCR5, and ERK in hippocampus was examined using Western blot, quantitative PCR, and immunohistochemistry. Levels of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in hippocampus were assessed by Western blot. Results Surgery impaired learning and memory, and it increased expression of CXCL13 and CXCR5 in the hippocampus. CXCL13 knockdown partially reversed the effects of surgery on CXCR5 and cognitive dysfunction. CXCR5 knockout led to similar cognitive outcomes as CXCL13 knockdown, and it repressed surgery-induced activation of ERK and production of IL-1β and TNF-α in hippocampus. Recombinant CXCL13 induced cognitive deficits and increased the expression of phospho-ERK as well as IL-1β and TNF-α in hippocampus of wild-type mice, but not CXCR5−/− mice. PD98059 partially blocked CXCL13-induced cognitive dysfunction as well as production of IL-1β and TNF-α. Conclusions CXCL13-induced activation of CXCR5 may contribute to PNDs by triggering ERK-mediated production of pro-inflammatory cytokines in hippocampus.

To elucidate the neuroprotective function of metformin in suppressing propofolinduced apoptosis of HT-22 cells. Methods: HT-22 cells were treated with 0, 10 or 100 μmol/L propofol, followed by determination of their proliferative ability. Subsequently, changes in proliferation and apoptosis of propofol-treated HT-22 cells induced with metformin were assessed. Apoptosisassociated genes in HT-22 cells were detected by Western blot. At last, regulatory effects of Cav-1 on propofol and metformin-treated HT-22 cells were examined. Results: Propofol treatment dose-dependently decreased proliferative ability and increased apoptosis ability in HT-22 cells, which were partially blocked by metformin administration. Upregulated Bcl-2 and downregulated Bax were observed in propofol-treated HT-22 cells following metformin administration. In addition, Cav-1 level in HT-22 cells was regulated by metformin treatment. Notably, metformin reversed propofol-induced apoptosis stimulation and proliferation decline in HT-22 cells via downregulating Cav-1. Conclusion: In our study, we found that propofol could induce apoptosis of HT-22 cells and metformin could rescue the apoptosis effect regulated by propofol. Then, we found that metformin protects propofol-induced neuronal apoptosis via downregulating Cav-1.

Aims To determine role of CYP2D6 activity in the pharmacokinetics of propafenone (PPF) enantiomers in native Chinese subjects. Methods Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabolic phenotyping, were enrolled. Blood samples (0~15 h) were taken after oral administration of a single dose (400 mg ) of racemic-propafenone hydrochloride. A reverse-phase h.p.l.c. method with pre-column derivatization was employed to quantitate enantiomeric concentrations of propafenone in plasma. Results For the EM subjects, S-PPF was less rapidly metabolized and had higher peak plasma concentrations than R-PPF (413±143 vs 291±109 ng ml −1 , P<0.001).The AUC was markedly higher for S-PPF than for R-PPF (2214±776 vs 1639±630 mg h l −1 , P<0.001), whereas the clearance of S-PPF was significantly lower than that of R-PPF (96.0±39.0 vs 138±78 l h −1 , P<0.01). There were no differences in t 1/2 , and C max between the two isomers ( P >0.05). In the one PM subject, not only did S-PPF appear to undergo less rapid metabolism than R-PPF, but the subject also showed 2~3 fold differences in C max , CL and AUC compared with EMs. The correlation coefficients (r s ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (C max , CL and AUC) were 0.63, −0.87, 0.87 for S-PPF and 0.57, −0.73, 0.86 for R-PPF, respectively. Conclusions Our results suggest that CYP2D6 activity contributes to the pharmacokinetic variability of propafenone enantiomers in Chinese subjects.Keywords: propafenone, enantiomer, pharmacokinetics, CYP2D6, phenotype, Chinese metabolic phenotyping in a Chinese population has Introduction shown that Chinese extensive metabolizers (EMs) consisted of about 99% (119/120) of the Chinese population Propafenone (PPF), a commonly used antiarrhythmic agent, is given clinically as a racemic mixture of S-PPF and that only one subject could be classified as a PM with respect to CYP2D6 [4]. The purpose of this study and R-PPF [1]. The two enantiomers are metabolized at different rates in Caucasians, with the R-PPF being was to examine the dispositon of propafenone enantiomers in 16 EMs and one PM to determine if stereoselective eliminated faster than the S-PPF [2]. Propafenone is biotransformed mainly through cytochrome P450 2D6 pharmacokinetics of propafenone occurs and whether the kinetics of propafenone enantiomers depends on CYP2D6 (CYP2D6) to the active metabolite 5-hydroxypropafenone (5-OH PPF) and less importantly through activity in Chinese subjects. CYP3A4 to N-desalkylpropafenone ( N-desalkyl PPF). Previous work has shown that the metabolism of PPF is Methods polymorphic and genetically determined, resulting in higher plasma drug concentrations in the 7% of Caucasians Subjects who are poor metabolizers (PMs) with respect to Seventeen (eleven men and six women) healthy native CYP2D6 [3]. Our recent research on dextromethorphan Chinese subjects (age range, 23 to 45 years; weight range, 50 to 75 kg) were recruited fr...