Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

Expressional and Prognostic Value of S100A16 in Pancreatic Cancer Via Integrated Bioinformatics Analyses.

Studies have shown that the calcium-binding protein family S100 may play a role in the development of pancreatic cancer (PC), but the role of S100A16 in PC is still unknown. In this study, Oncomine was first used to detect the expression level and prognosis of S100A16 in PC and other tumors. The results showed that S100A16 was highly expressed in PC tissues compared with a normal pancreas, and the increased expression level may be related to poor prognosis in PC patients. The TCGA and ICGC RNA-seq data of PC patients were downloaded, and the S100A16-related differentially expressed genome (DEGs) was defined by taking the intersection of two gene sets. The GO and KEGG pathways were then analyzed. For clinical analysis, boxplots were depicted for the correlation between clinical characteristics and S100A16 expression. Then Cox regression was applied for exploring the prognostic value of S100A16 for PDAC patients. Based on the Cox regression model, we further estabished a S100A16-related risk score system to strengthen the ability to predict patients' prognosis. After integrating the risk score model and multiple clinicopathological factors, we finally established a nomogram that could predict the survival time of patients. Moreover, Gene set enrichment the effect of S100A16 expression differences on downstream biological processes. At last, using TIMER, ImmuneCellAI and GSEA we analyzed the correlation between S100A16 and pancreatic cancer immune infiltration and predicted the response of patients to checkpoint Blocker (ICB). In summary, S100A16 is involved in the occurrence and development of PC, affecting the prognosis of patients, and may have potential reference values for the immunotherapy of PC.

Small RNA and Transcriptome Sequencing Reveal a Potential miRNA-Mediated Interaction Network That Functions during Somatic Embryogenesis in Lilium pumilum DC. Fisch.

Plant somatic embryos are widely used in the fields of germplasm conservation, breeding for genetic engineering and artificial seed production. MicroRNAs (miRNAs) play pivotal roles in somatic embryogenesis (SE) regulation. However, their regulatory roles during various stages of SE remain unclear. In this study, six types of embryogenic samples of Lilium pumilum DC. Fisch., including organogenic callus, embryogenic callus induced for 4 weeks, embryogenic callus induced for 6 weeks, globular embryos, torpedo embryos and cotyledon embryos, were prepared for small RNA sequencing. The results revealed a total of 2,378,760 small RNA reads, among which the most common size was 24 nt. Four hundred and fifty-two known miRNAs, belonging to more than 86 families, 57 novel miRNAs and 40 miRNA*s were identified. The 86 known miRNA families were sorted according to an alignment with their homologs across 24 land plants into the following four categories: 23 highly conserved, 4 moderately conserved, 15 less conserved and 44 species-specific miRNAs. Differentially expressed known miRNAs were identified during various stages of SE. Subsequently, the expression levels of 12 differentially expressed miRNAs and 4 targets were validated using qRT-PCR. In addition, six samples were mixed in equal amounts for transcript sequencing, and the sequencing data were used as transcripts for miRNA target prediction. A total of 66,422 unigenes with an average length of 800 bp were assembled from 56,258,974 raw reads. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that 38,004 and 15,497 unigenes were successfully assigned to GO terms and KEGG pathways, respectively. Among the unigenes, 2,182 transcripts were predicted to be targets for 396 known miRNAs. The potential targets of the identified miRNAs were mostly classified into the following GO terms: cell, binding and metabolic process. Enriched KEGG analysis demonstrated that carbohydrate metabolism was the predominant pathway in Lilium SE. Thus, we performed systemic characterization, homology comparisons and profiling of miRNA expression, and we constructed an miRNA-target network during Lilium SE for the first time. Our findings establish a foundation for the further exploration of critical genes and elucidation of SE in Lilium.

Pharmacokinetics and tissue distribution of Aucubin, Ajugol and Catalpol in rats using a validated simultaneous LC-ESI-MS/MS assay.

To enable an investigation of pharmacokinetics and tissue distribution of Aucubin, Ajugol and Catalpol in rats, a high-performance liquid chromatography-electro spray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of the three compounds. Biological samples were prepared by a simple protein precipitation with methanol (containing 0.05% formic acid). The analytes were separated by a C18 reversed phase column and detected with a triple quadrupole tandem mass spectrometer in the multiple-reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 364.3→149.0 for Aucubin, m/z 366.5→151.1 for Ajugol, m/z 380.0→183.3 for Catalpol and m/z 530.3→183.1 for Picroside-II (IS) in positive ionization. Good linearity of each calibration curve was produced over the concentration range of 1-1000ng/mL. The lower limit of quantification (LLOQ) was 1ng/mL for the three analytes. This method was successfully applied to the pharmacokinetic and tissue distribution studies of Aucubin, Ajugol and Catalpol in rat. The current results revealed pharmacokinetic behaviors of the herb compound and provided novel evidence of the presence of Aucubin and Catalpol in rat brain. The acquired data would be helpful for the clinical application and further studies of Traditional Chinese Medicines (TCM) with active ingredients of Iridoid Glycosides.

A pre-clinical pharmacokinetic study in rats of three naturally occurring iridoid glycosides, Picroside-I, II and III, using a validated simultaneous HPLC-MS/MS assay.

A selective and sensitive high-performance liquid chromatography-electro-spray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of Picroside-I, II, and III in rat plasma and tissue homogenate to aid the pre-clinical studies. The chromatographic separation was performed on a Hypersil GOLD AQ C18 column using a gradient elution program with a mobile phase consisting of 2mM ammonium acetate and acetonitrile. The detection was achieved using a triple quadrupole tandem MS in negative ionization multiple reaction monitoring (MRM) mode. One-step protein precipitation was selected for plasma and tissue sample preparation while liquid-liquid extraction failed to achieve satisfactory recoveries. The calibration curves of all three analytes in either plasma or tissue homogenate showed good linearity over the concentration range of 0.5-500ng/mL with a limit of quantitation at 0.5ng/mL. Both the intra- and inter-day accuracy and precision were within ±10%. The extraction recoveries were >70%, and the relative matrix effect ranged from 80.4% to 107.4% in all the biological samples. All the analytes were stable in matrices for at least 24h at room temperature, or 21 days in frozen. Three freeze/thaw cycles did not cause degradation. The method was successfully applied for quantification of the three iridoid glycosides in the collected plasma and various tissues following intravenous administration in rats. Picroside-I, II, and III were all eliminated rapidly with large volume of distribution. Among the three glycosides, Picroside-II showed the highest liver uptake, and only Picroside-I and II were found to get across the blood brain barrier (BBB). These results were consistent with their hepatoprotective or neuroprotective effects reported clinically. With the aid of the efficient and reliable simultaneous LC-ESI-MS/MS assay this pharmacokinetic study provided insights into their therapeutic targets of these three iridoid glycosides as well as valuable experimental basis for an expansion of their clinical indications.