scholarly journals The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Shen-Qing Zhang ◽  
Long-Long Cao ◽  
Yun-Yue Liang ◽  
Pu Wang
Keyword(s):  
Preclinical Model ◽  
High Dose ◽  
Term Administration ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Stimulation Of ◽  
Bace 1

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

scholarly journals Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

2020 ◽  
Author(s):  
Guo-Biao Xu ◽  
Pei-Pei Guan ◽  
Pu Wang
Keyword(s):  
Cognitive Decline ◽  
Michael Addition ◽  
Dependent Manner ◽  
Western Blots ◽  
Michael Adduct ◽  
Term Administration ◽  
Prostaglandin A1

Abstract Background: Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2), which potentially involved in regulating the development and progression of Alzheimer’s disease (AD). As a cyclopentenone (cy) PG, PGA1 is characterized by the presence of a chemically reactive α, β-unsaturated carbonyl. Although PGA1 is potentially involved in regulating multiple biological processes via michael addition, its specific roles in AD remained unclear.Methods: The tauP301S transgenic (Tg) mice were employed as in vivo AD models and neuroblastoma (N) 2a cells as in vitro neuronal models. By intracerebroventricular injected (i.c.v) with PGA1, the binding proteins to PGA1 are analyzed by HPLC-MS-MS. In addition, western blots are used to determine the phosphorylation of tau in PGA1 treated Tg mice in the absence or presence of okadaic acid (OA), an inhibitor of protein phosphotase (PP) 2A. Combining a synthesis of pull down assay, immunoprecipitation, western blots and HPLC-MS-MS, PP2A scaffold subunit A alpha (PPP2R1A) was identified to be activated by directly binding on PGA1 in cysteine 377-dependent manner. Via inhibiting the hyperphosphorylation of tau, morris maze test was employed to determine the inhibitory effects of PGA1 on cognitive decline of tauP301S Tg mice.Results: By incubation with neuroblastoma (n)2a cells and pull down assay, mass spectra (MS) analysis revealed that PGA1 binds with more than 1000 proteins, among which contains the proteins of AD, especially tau protein. Moreover, short-term administration of PGA1 to tauP301S Tg mice significantly decreased the phosphorylation of tau at the sites of Thr181, Ser202 and Ser404 in a dose-dependent manner. To the reason, it’s caused by activating PPP2R1A in tauP301S Tg mice. More importantly, PGA1 has the ability to form michael adduct with PPP2R1A via its cysteine 377 motif, which is critical for the enzymatic activity of PP2A. By activating PP2A, long-term application of PGA1 to tauP301S Tg mice significantly reduced the phosphorylation of tau, which results in improving the cognitive decline of tauP301S Tg mice.Conclusion: Our data provided the first insights needed to decipher the mechanisms underlying the ameliorating effects of PGA1 on cognitive decline of tauP301S Tg mice via activating PP2A in a PPP2R1AC377-dependent Michael adducting mechanisms.

scholarly journals Riligustilide Attenuated Renal Injury by the Blockade of Renin

2018 ◽  
Vol 50 (2) ◽  
pp. 654-667 ◽  
Author(s):  
Juan Kong ◽  
Li Han ◽  
Han Su ◽  
Yihan Hu ◽  
Xueshi Huang ◽  
...  
Keyword(s):  
Renal Injury ◽  
Chinese Herb ◽  
Underlying Mechanism ◽  
Vehicle Group ◽  
Mice Model ◽  
Kidney Fibrosis ◽  
Term Administration

Background/Aims: Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases. Methods: The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model. Results: The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro. Conclusion: C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.

scholarly journals Cocoa: antioxidant and immunomodulator

2009 ◽  
Vol 101 (7) ◽  
pp. 931-940 ◽  
Author(s):  
Emma Ramiro-Puig ◽  
Margarida Castell
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Cell Signalling ◽  
Antioxidant Properties ◽  
High Dose ◽  
T Helper ◽  
T Helper 1

Cocoa, a product consumed since 600 BC, is now a subject of increasing interest because of its antioxidant properties, which are mainly attributed to the content of flavonoids such as ( − )-epicatechin, catechin and procyanidins. Moreover, recent findings suggest a regulatory effect of cocoa on the immune cells implicated in innate and acquired immunity. Cocoa exerts regulatory activity on the secretion of inflammatory mediators from macrophages and other leucocytesin vitro. In addition, emerging data fromin vivostudies support an immunomodulating effect. Long-term cocoa intake in rats affects both intestinal and systemic immune function. Studies in this line suggest that high-dose cocoa intake in young rats favours the T helper 1 (Th1) response and increases intestinal γδ T lymphocyte count, whereas the antibody-secreting response decreases. The mechanisms involved in this activity are uncertain; nonetheless, because redox-sensitive pathways control immune cell function, the action of cocoa flavonoids on modulating cell signalling and gene expression deserves investigation.

scholarly journals Long-Term Azithromycin Therapy in Cystic Fibrosis Patients: A Study on Drug Levels and Sputum Properties

2004 ◽  
Vol 11 (2) ◽  
pp. 151-155 ◽  
Author(s):  
Ulrich Baumann ◽  
Malcolm King ◽  
Ernst M App ◽  
Shusheng Tai ◽  
Armin König ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Low Dose ◽  
Term Therapy ◽  
High Dose ◽  
Drug Levels ◽  
Diffuse Panbronchiolitis ◽  
Underlying Mechanisms

BACKGROUND:Following reports on the treatment of diffuse panbronchiolitis (DPB), recent studies demonstrate that long term therapy with azithromycin (AZM) is effective in cystic fibrosis (CF) patients. However, the underlying mechanisms remain uncertain. Some macrolides, including AZM, display inhibition of virulence factors and other antipseudomonal effects at subinhibitory levels in vitro.OBJECTIVES:Drug doses used for CF and DPB therapy were investigated to determine whether they achieve corresponding sputum drug levels in CF patients in vivo.METHODS:In an open, prospective study, 14 CF patients with chronic Pseudomonas aeruginosa airway infection received 250 mg AZM either daily ('high dose') or twice weekly ('low dose') for 12 weeks. Viscoelasticity of sputum was assessed by magnetic microrheology.RESULTS:AZM accumulated in sputum by two orders of magnitude over a period of four weeks. In the following steady state, median AZM concentrations in sputum were 9.5 µg/mL (0.6 to 79.3 µg/mL, interquartiles 1.4 to 33.4 µg/mL) and 0.5 µg/mL (range less than 0.1 [below detection level] to 5.2 µg/mL, interquartiles 0.2 to 1.4 µg/mL) in the high and low dose groups, respectively. Viscoelasticity improved in all patients but one.CONCLUSIONS:The findings suggest that antipseudomonal activity has to be considered among the potential mechanisms of macrolide therapy. Further, viscoelasticity may be a valuable parameter in future clinical trials.

scholarly journals High serum colony-stimulating activity of leukocytopenic patients after intravenous infusions of human urinary colony-stimulating factor

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 685-688
Author(s):  
K Motoyoshi ◽  
F Takaku ◽  
Y Miura
Keyword(s):  
Low Dose ◽  
High Serum ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Intravenous Infusions ◽  
Colony Stimulating Activity ◽  
Stimulating Factor ◽  
Stimulation Of

Eight adult patients suffering from leukocytopenia have been injected by droplet intravenous infusions with partially purified human urinary colony-stimulating factor (CSFHU), which stimulated human monocytes to produce colony-stimulating activity (CSA) in vitro. Three of eight patients were injected with low-dose CSFHU and five with high-dose CSFHU. The infusion of high-dose CSFHU led to a slightly earlier rise in absolute neutrophil counts and a higher CSA level in the serum, as compared to noninjected leukocytopenic patients. There was little toxicity associated with it. Human urinary colony-stimulating factor used in the clinical studies did not have any CSA in vitro in the presence or absence of the patients' sera. These data may suggest that the intravenous infusion of CSFHU increased the serum CSA level, probably through the stimulation of CSA-producing cells in vivo.

Comparison of In Vitro Cardiovascular Function with In Vivo Echocardiographic Assessment After Long-Term Administration of Cyclosporine to Rats

1998 ◽  
Vol 31 (6) ◽  
pp. 828-832 ◽  
Author(s):  
Ruediger C. Braun-Dullaeus ◽  
Markus Feussner ◽  
Gerhard Walker ◽  
Harald Tillmanns ◽  
Werner Haberbosch
Keyword(s):  
Cardiovascular Function ◽  
Term Administration ◽  
Echocardiographic Assessment

A Model System for Proliferation and Characterisation of Stem Cells in Childhood T-ALL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1370-1370
Author(s):  
Charlotte V. Cox ◽  
Roger S. Evely ◽  
Allison Blair
Keyword(s):  
Myeloid Cell ◽  
Scid Mice ◽  
Model Systems ◽  
Preclinical Model ◽  
Post Inoculation ◽  
Number Of Children ◽  
Cell Engraftment

Abstract T cell acute lymphoblastic leukaemias (T-ALL) are highly aggressive malignancies representing 10–15% of paediatric and 25% adult ALLs. T-ALL was considered to arise as a consequence of clonal expansion of early thymocytes. However, progress towards increasing our understanding of the biology of this disease has been hampered by lack of appropriate culture systems to study primary cells and use of murine model systems that often do not accurately reflect human disease. Traditional xenograft models of leukaemia have involved implantation of malignant cells or immortalised leukaemic cell lines with either intraperitoneal or subcutaneous localisation of leukaemia. These models do not mimic the normal pathophysiology of the disease and may therefore provide misleading data. Since evaluation of new agents in paediatric malignancies is limited by the small number of children eligible for clinical trails, there is a need for a predictive preclinical model of paediatric ALL. We have previously used a long-term suspension culture system to evaluate proliferation of T-ALL cells in vitro and demonstrated these cells had a CD34+/CD4−, CD7− phenotype. T-ALL cells with this phenotype were also capable of engrafting NOD/SCID mice, suggesting the disease may arise in a more primitive cell. In this study we have attempted to further characterise T-ALL cells with long-term proliferative ability in vivo and to investigate the kinetics of engraftment. Unsorted cells and cells sorted for the expression of CD133 and CD7 from 5 T-ALL patients were inoculated into sublethally irradiated NOD/SCID mice. Peripheral blood samples were taken at weekly intervals from the lateral tail vein from two weeks post inoculation onwards. BM samples were analysed from 4 weeks post inoculation and all animals were sacrificed no later than 10 weeks post inoculation. Human CD45+ cells were first detected at day 17-post inoculation (1.54–3.8% CD45+). By week 4, this had increased to 4.4–21% CD45+ in PB samples, while levels in BM aspirates were significantly higher at this stage (24–47% CD45+). This pattern of tissue dissemination closely mimics that observed in the patients. The levels of CD45+ cells continued to rise with time and had exceeded 85% in the BM of animals injected with cells from 3 patients by week 7-post inoculation. FISH and flow cytometric analyses showed the engrafted cells had a similar karyotype and phenotype to the patient at diagnosis and there was no evidence of myeloid cell engraftment. Cells harvested from these animals have been used in secondary, tertiary and quaternary transplants with no loss of NOD/SCID repopulating potential and similar engraftment kinetics. Quinary transplants are currently underway. In the sorted cell populations, only the CD133+/CD7− subfraction was capable of engrafting, 0.5–54% CD45+, with as few as 1.4x103–5x103 cells. There was no engraftment with the other subfractions despite injecting 10 to 1000-fold more cells. These engrafted cells expressed high levels of CD34, CD2, CD4 and CD7 and very low levels of CD133. This phenotype was similar to that of the patients at diagnosis, implying they had differentiated in vivo. These data add to the evidence that T-ALL may arise in a cell with a more primitive phenotype, rather than committed thymocytes. These cells may be the most relevant targets for emerging therapeutic strategies and we describe a robust, reproducible in vivo leukaemia model which could be used to investigate the efficacy of novel agents for the treatment of paediatric T-ALL.

Implications of Kindling And Quenching For the Possible Frequency Dependence Of rTMS

CNS Spectrums ◽  
1997 ◽  
Vol 2 (1) ◽  
pp. 54-60 ◽  
Author(s):  
R. M. Post ◽  
T. Kimbrell ◽  
M. Frye ◽  
M. George ◽  
U. McCann ◽  
...  
Keyword(s):  
Low Frequency ◽  
Repeated Administration ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Seizure Threshold ◽  
Frequency Stimulation ◽  
Stimulation Of

AbstractKindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.

Sign in / Sign up

Export Citation Format

Share Document