Lubloch2688

These effects are time- and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression. Alzheimer's disease (AD) is characterized by two pathologic species, extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. Astrocytes that maintain normal homeostasis in the brain undergo a set of molecular, cellular and functional changes called reactive astrogliosis in various neurological diseases including AD. It is hypothesized that reactive astrocytes initially tend to protect neurons by reducing Aβ load and by secreting a plethora of cytokines, however, their functions have only been poorly investigated. Our studies on the kinetics of activation of cortical astrocytes following Aβ-exposure revealed significant level of activation as early as in 6 h. The astrocyte conditioned medium (ACM) from 6 h Aβ-treated astrocytes (Aβ-ACM) provided significant neuroprotection of cultured cortical neurons against Aβ insults. Analysis of the secreted proteins in Aβ-ACM revealed a marked increase of Tissue inhibitor of Metalloproteinase-1 (TIMP-1) within 6 h. Interestingly, we found that neutralization of TIMP-1 with antibody or knockdown with siRNA in astrocytes abolished most of the neuroprotective ability of the 6 h Aβ-ACM on Aβ-treated cultured neurons. Furthermore addition of exogenous rat recombinant TIMP-1 protein protects primary neurons from Aβ mediated toxicity. In a well characterized Aβ-infused rodent model of AD, intra-cerebroventricular administration of TIMP-1 revealed a reduction in Aβ load and apoptosis in hippocampal and cortical regions. Finally, we found that TIMP-1 can ameliorate Aβ-induced cognitive dysfunctions through restoration of Akt and its downstream pathway and maintenance of synaptic integrity. Thus, our results not only provide a functional clarity for TIMP-1, secreted by activated astrocytes, but also support it as a major candidate in cytokine-mediated therapy of AD especially at the early phase of disease progression. ETHNOPHARMACOLOGICAL RELEVANCE The bulbs and flowers of plants from the Lilium genus have historically been used in Asian and Greco-Roman medicine to treat burns and promote skin healing. AIM OF THE STUDY To evaluate a steroidal glycoalkaloid isolated from Easter lily bulbs for its potential wound healing promoting properties. MATERIALS AND METHODS A lily-derived steroidal glycoalkaloid (LSGA), (22R, 25R)-spirosol-5-en-3β-yl O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-glucopyranoside, was isolated from Easter lily bulbs, and its structure was confirmed by LC-MS and NMR spectrometry. LSGA effects on wound scratch closure were evaluated in a primary human dermal fibroblast cell culture, and the changes in gene expression profiles were quantitated using an 84 wound-related gene qPCR microarray. RESULTS LSGA promoted migration of dermal fibroblasts into the wounded area. The treatment was associated with a rapid upregulation of early inflammatory (CD40LG, CXCL11, IFNG, IL10, IL2 and IL4), cell growth (CSF3 and TNF) and remodeling (CTSG, F13A1, FGA, MMP and PLG) genes both in the wounded and unwounded cells treated with LSGA. A selective decrease in gene expression profiles associated with inflammatory (CXCL2 and CCL7) and remodeling (MMP7 and PLAT) phases was observed in wounded cells treated with LSGA, in contrast to the wounded cells. CONCLUSION This study demonstrates that a glycoalkaloid present in lilies promoted fibroblast migration in vitro and affected inflammatory, remodeling and growth factor gene expression. The decreases in expression of key genes may impact the wound healing process, possibly contributing to an earlier end of the inflammatory response and shortening the early phases of model tissue reconstitution. The results of this preliminary investigation may provide a basis for the historical use of lily bulbs to promote dermal healing after injury. V.ETHNOPHARMACOLOGICAL RELEVANCE Qing Dai, a famous traditional Chinese medicine (TCM), is prepared by a traditional fermentation process with the aerial part of Strobilanthes cusia. Currently, this TCM could treat various clinical inflammatory diseases, such as ulcerative colitis and psoriasis, however, the bioactive components of Qing Dai are unknown clearly. AIM OF THE STUDY To isolate and identify the anti-IL-17A components of Qing Dai. MATERIALS AND METHODS Silica, RP-18 gels, and size exclusion resin were used for column chromatography to isolate the pure compounds. BlasticidinS The structures of isolates were elucidated by NMR, MS, UV, IR spectra, and optical rotation. IL-17A protein and gene expressions were also evaluated in the Th17 cell model and luciferase reporter assay, respectively. RESULTS Two indole alkaloids, including one new indigodole D and cephalandole B, were isolated from Qing Dai. Indigodole D could inhibit IL-17A protein production during the Th17 polarization (EC50 2.16 μg/mL) or after the polarization (EC50 5.99 μg/mL) without cytotoxicity toward Th17 cells. Cephalandole B did not inhibit the IL-17A protein secretion. Nevertheless, both isolates notably inhibited IL-17A gene expression, especially cephalandole B, in a dose-dependent manner in Jukat cells with IL-17A luciferase reporter. CONCLUSIONS Indole alkaloids, indigodoles A, C, D, tryptanthrin, and indirubin could contribute to anti-IL 17A properties of Qing Dai. The possible biogenetic mechanisms of above-mentioned indoles were also speculated in this investigation for further promising anti-IL-17 lead drugs development. The human right inferior frontal cortex (IFC) plays a critical role in response inhibition. It has also been demonstrated that the IFC is heterogeneous and that the ventral part of the IFC (vIFC) is more critical to inhibition of prepotent response tendency. Recent areal parcellation analyses based on resting-state functional connectivity have revealed that the right vIFC consists of multiple functional areas. In the present study, we characterized the parcellated areas (parcels) in the right vIFC using graph theory analysis, which characterizes local connectivity properties of a brain network by referring to its global structure of functional connectivity. Functional magnetic resonance imaging (MRI) scans were obtained during performance of a stop-signal task and during resting state. The cerebral cortex was parcellated into areas using resting-state functional connectivity. The parcels were then subjected to graph theory analysis to reveal central areas. Two parcels, ventral and dorsal, in the posterior part of the vIFC, exhibited significant brain activity during response inhibition. The ventral parcel exhibited a positive correlation between betweenness centrality and brain activity while the dorsal parcel did not. Correlations were significantly stronger in the ventral parcel. Moreover, the ventral parcel exhibited a negative correlation between brain activity during response inhibition and stop-signal reaction time (SSRT), a behavioral measure used to evaluate stopping performance. These dissociation results suggest that the ventral region in the vIFC plays a more central role in the brain network by increasing brain activity, which may further predict better performance of response inhibition. Synaptic plasticity, such as long term potentiation (LTP) and long term depression (LTD), underlies the cellular mechanism of learning and memory. Chemical-induced LTP (cLTP), which facilitates biochemical analysis of molecular changes in brain slices or neuronal cultures, has been accepted as an in vitro model to explore synaptic plasticity. cLTP, by either forskolin and rolipram (F&R) or glycine, is thought to be dependent on NMDA receptor. However, subunit-specific dependence and regulation of the NMDA receptor in cLTP remain poorly understood. In the present study, we found that phosphorylation level of GluN2B at tyrosine 1472 was modulated by F&R-induced LTP but not by glycine-induced LTP in hippocampal slices. Furthermore, an increased phosphorylation level of GluA1 at serine 845 by F&R-induced LTP rather than glycine-induced LTP was dependent on the activation of GluN2B, which is supported by the results from GluN2B antagonists, small interfering peptide and CRISPR-Cas9-mediated knock out of GluN2B. Taken together, we reveal the significant role of GluN2B in F&R-induced LTP, uncovering the role of GluN2B subunit of NMDA receptor in a specified cLTP. In this study, we investigated the potential role of C-X-C chemokine receptor type (CXCR) 5 in neurocognitive function in a mouse model of sepsis-associated encephalopathy (SAE). Adult male C57BL/6J mice received intracerebroventricular injections of small interfering RNAs (siRNAs) against CXCR5 or scrambled control siRNA. After 3 days, SAE was induced by cecal ligation and puncture (CLP, n = 16 per group). Memory and learning ability were tested using the Morris water maze (MWM) on days 5-9 after CLP. Hippocampal expression of CXCR5, interleukin (IL)-1β and IL-6 were measured by western blot. Cell proliferation and the numbers of immature and mature neurons in the dentate gyrus were assessed by immunohistochemistry. CLP mice had deficits in memory and learning, as shown by increased latency in the MWM training sessions and decreased time spent in and crossing the target quadrant on day 9. CLP also increased the number of proliferating and immature neurons and decreased the number of mature neurons. This was accompanied by increased expression of CXCR5, IL-1β and IL-6 in the hippocampus. CXCR5 knockdown attenuated the memory and learning deficits induced by CLP and partially reversed the effects of CLP on numbers of proliferating, immature and mature neurons, and on expression of IL-1β and IL-6 in the hippocampus. These results suggest that CXCR5 knockdown can attenuate sepsis-induced deficits in hippocampal neurogenesis and cognitive function in mice with SAE. Myasthenia gravis (MG) is a relatively rare neurological disease that is usually associated with antibodies to the acetylcholine receptor (AChR). These antibodies (Abs) cause loss of the AChRs from the neuromuscular junction (NMJ), resulting in muscle weakness, that can be life-threatening. Another form of the disease is caused by antibodies to muscle specific kinase (MuSK) that result in impaired AChR clustering and numbers at the NMJ, and may also interfere with presynaptic adaptive mechanisms. Other autoimmune disorders, Lambert Eaton myasthenic syndrome and acquired neuromyotonia, are associated with antibodies to presynaptic voltage-gated calcium and potassium channels respectively. All four conditions can be diagnosed by specific clinical features, electromyography and serum antibody tests, and can be treated effectively by a combination of pharmacological approaches and procedures that reduce the levels of the IgG antibodies. They form the first of a spectrum of diseases in which serum autoantibodies bind to extracellular domains of neuronal proteins throughout the nervous system and lead to constellations of clinical features including paralysis, sensory disturbance and pain, memory loss, seizures, psychiatric disturbance and movement disorders.