Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment.

A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer's disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention.

Depressive-like behaviors in a rat model of chronic cerebral hypoperfusion.

The vascular depression hypothesis suggests that there is an association between cerebrovascular pathophysiology and depression in the elderly. We investigated depressive-like behaviors and perturbations in the hypothalamus-pituitary-adrenal (HPA) axis in a rat model of chronic cerebral hypoperfusion. We modeled chronic cerebral hypoperfusion by permanent occlusion of the bilateral common carotid arteries (BCCAo) in Wistar rats. Sucrose preference, forced swim, and social interaction tests were performed to measure depressive-like behaviors. The plasma levels of adrenocorticotropic hormone and corticosterone, and the hippocampal expression of the glucocorticoid receptor (GR) were assessed. Sucrose preference (P = 0.045) and social withdrawal (P = 0.038) were significantly enhanced in BCCAo rats. Increased plasma levels of corticosterone (P = 0.034) and impaired cytosolic-to-nuclear translocation of the GR protein were observed in the hippocampus (P = 0.038) of BCCAo rats. Our experimental results support the clinical hypothesis that vascular depression can be induced by chronic cerebral hypoperfusion. Increased HPA axis activity and perturbation of the GR signaling pathway in the hippocampus may be associated with depressive-like behaviors in rats with chronic cerebral hypoperfusion.

Multiple biological properties of macelignan and its pharmacological implications.

Macelignan found in the nutmeg mace of Myristica fragrans obtains increasing attention as a new avenue in treating various diseases. Macelignan has been shown to possess a spectrum of pharmacological activities, including anti-bacterial, anti-inflammatory, anti-cancer, anti-diabetes, and hepatoprotective activities; recently, it has also been shown to have neuroprotective activities. This review summarizes the current research on the biological effects of macelignan derived from M. fragrans, with emphasis on the importance in understanding and treating complex diseases such as cancer and Alzheimer's disease.

Induced pluripotent stem cell research: a revolutionary approach to face the challenges in drug screening.

Discovery of induced pluripotent stem (iPS) cells in 2006 provided a new path for cell transplantation and drug screening. The iPS cells are stem cells derived from somatic cells that have been genetically reprogrammed into a pluripotent state. Similar to embryonic stem (ES) cells, iPS cells are capable of differentiating into three germ layers, eliminating some of the hurdles in ES cell technology. Further progress and advances in iPS cell technology, from viral to non-viral systems and from integrating to non-integrating approaches of foreign genes into the host genome, have enhanced the existing technology, making it more feasible for clinical applications. In particular, advances in iPS cell technology should enable autologous transplantation and more efficient drug discovery. Cell transplantation may lead to improved treatments for various diseases, including neurological, endocrine, and hepatic diseases. In studies on drug discovery, iPS cells generated from patient-derived somatic cells could be differentiated into specific cells expressing specific phenotypes, which could then be used as disease models. Thus, iPS cells can be helpful in understanding the mechanisms of disease progression and in cell-based efficient drug screening. Here, we summarize the history and progress of iPS cell technology, provide support for the growing interest in iPS cell applications with emphasis on practical uses in cell-based drug screening, and discuss some challenges faced in the use of this technology.

Porcine aortic endothelial cell genes responsive to selected inflammatory stimulators.

Use of porcine tissues has been suggested as a promising solution for severe shortage of transplantable human organs. The immediate hurdle for xenotransplantation is acute immune/inflammatory vascular rejection of the transplant. Because endothelial cells play a key role in the initiation and the amplification of inflammation, alteration of gene expression in human endothelial cells, by various inflammatory stimulators has been studied extensively. However, transcriptional changes induced by human and other inflammatory stimulators in porcine endothelial cells have thus far not been studied. In this study, we treated porcine endothelial cells with human tumor necrosis factor (TNF)-alpha, porcine interferon (IFN)-gamma, H(2)O(2) and lypopolysaccharide (LPS) and profiled transcriptional change at 1 hr, 6 hr and 24 hr, using pig oligonucleotide 13K microarray. We found that mRNA species such as chemokine (C-X-C motif) ligand 6 (CXCL6) and Cathepsin S were significantly induced in porcine endothelial cells, as was previously reported with human endothelial cell. We also found that mRNA species including secreted frizzled-related protein 2 (SFRP2), radical S-adenosyl methionine domain containing 2 (RSAD2), structure specific recognition protein 1 (SSRP1) also were highly overexpressed in porcine endothelial cells. This result shows clues to understand underlying mechanisms of xenotransplantation rejection and the highly responsive porcine genes may serve as novel targets to be regulated for improving the function of grafted porcine donor organs.

Expression analysis of early response-related genes in rat liver epithelial cells exposed to thioacetamide in vitro.

Thioacetamide (TA) is a potent hepatotoxicant known to affect liver metabolism, inhibit mRNA transport and induce immune suppression. The genetic mechanism underlining this biological toxic compound is well understood using microarray technology. Thus, we used high-throughput rat genome oligonucleotide microarrays containing approximately 22,000 genes to investigate the genetic components of TA-related cytotoxicity in WB-F344 rat liver epithelial (WB-F344) cells. We treated cells with TA (two concentrations over five time periods, ranging from 1 to 24 hr), isolated total RNA at 1, 3, 6, 12 and 24 hr following TA treatment and hybridized the RNA to microarrays. Clustering analysis distinguished two groups of genes, early (1 and 3 hr) and late (6, 12 and 24 hr) phase genes. In total, 2,129 and 2,348 differentially-expressed genes were identified following treatment with low and high concentrations of TA, respectively. A common set of 1,229 genes that were differentially expressed following treatment with both low (1,000 muM) and high (10,000 muM) concentrations of TA had similar expression patterns. Interestingly, 1,410 genes at the low concentration and 1,858 genes at the high concentration were differentially expressed in the early phases, suggesting that these genes associated with the early response to TA may be useful as early markers of hepatotoxicity.

Application of multiplex bead array assay for Yq microdeletion analysis in infertile males.

The purpose of this study was to apply the multiplex bead array as a diagnostic tool for male infertility. The multiplex bead array offers a new platform in high-throughput nucleic acid detection. Six loci, including sex-determining regions on the Y (SRY) chromosome as a control and five sequence-tagged sites (STS) in azoospermia-factor regions, were used in this system. Extracted genomic DNA from infertile male blood was used for multiplex polymerase chain reaction (PCR). After multiplex PCR using specific Cy3-labeled primer sets, the PCR product was hybridized with capture probes. A multiplexed PCR-liquid bead was arrayed for simultaneous detection using the Luminex system. This assay system correctly identified the presence or deletion of the Y chromosome. Therefore, this method provides a sensitive and high-throughput method for probing the deletion of the Y chromosome, and offers a completely new approach to male infertility screening.