Decreased neuronal inhibition in vitro after long-term administration of ethanol

Science ◽  
1984 ◽  
Vol 224 (4655) ◽  
pp. 1359-1361 ◽  
Author(s):  
D Durand ◽  
P. Carlen
Keyword(s):  
Neuronal Inhibition ◽  
Term Administration

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 Human Cytomegalovirus Resistance to Deoxyribosylindole Nucleosides Maps to a Transversion Mutation in the Terminase Subunit-Encoding GeneUL89

2014 ◽  
Vol 59 (1) ◽  
pp. 226-232 ◽  
Author(s):  
Brian G. Gentry ◽  
Quang Phan ◽  
Ellie D. Hall ◽  
Julie M. Breitenbach ◽  
Katherine Z. Borysko ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Structural Similarity ◽  
Open Reading Frames ◽  
Wild Type Virus ◽  
Wild Type ◽  
Term Administration ◽  
Transversion Mutation ◽  
Exon 1

ABSTRACTHuman cytomegalovirus (HCMV) infection can cause severe illnesses, including encephalopathy and mental retardation, in immunocompromised and immunologically immature patients. Current pharmacotherapies for treating systemic HCMV infections include ganciclovir, cidofovir, and foscarnet. However, long-term administration of these agents can result in serious adverse effects (myelosuppression and/or nephrotoxicity) and the development of viral strains with reduced susceptibility to drugs. The deoxyribosylindole (indole) nucleosides demonstrate a 20-fold greater activityin vitro(the drug concentration at which 50% of the number of plaques was reduced with the presence of drug compared to the number in the absence of drug [EC50] = 0.34 μM) than ganciclovir (EC50= 7.4 μM) without any observed increase in cytotoxicity. Based on structural similarity to the benzimidazole nucleosides, we hypothesize that the indole nucleosides target the HCMV terminase, an enzyme responsible for packaging viral DNA into capsids and cleaving the DNA into genome-length units. To test this hypothesis, an indole nucleoside-resistant HCMV strain was isolated, the open reading frames of the genes that encode the viral terminase were sequenced, and a G766C mutation in exon 1 ofUL89was identified; this mutation resulted in an E256Q change in the amino acid sequence of the corresponding protein. An HCMV wild-type strain, engineered with this mutation to confirm resistance, demonstrated an 18-fold decrease in susceptibility to the indole nucleosides (EC50= 3.1 ± 0.7 μM) compared to that of wild-type virus (EC50= 0.17 ± 0.04 μM). Interestingly, this mutation did not confer resistance to the benzimidazole nucleosides (EC50for wild-type HCMV = 0.25 ± 0.04 μM, EC50for HCMV pUL89 E256Q = 0.23 ± 0.04 μM). We conclude, therefore, that the G766C mutation that results in the E256Q substitution is unique for indole nucleoside resistance and distinct from previously discovered substitutions that confer both indole and benzimidazole nucleoside resistance (D344E and A355T).

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 Lansoprazole-Induced Osteoporosis via IP3R and SOCE Mediated Calcium Signaling Pathway

2021 ◽  
Author(s):  
Zi-Ping Cheng ◽  
Jie-Yang Liu ◽  
Meng-Yuan Ma ◽  
Shi-Yu Sun ◽  
Zeng-qing Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Vehicle Group ◽  
Dependent Manner ◽  
Micro Ct ◽  
Mineral Density ◽  
Calcium Release Channel ◽  
Blood Calcium ◽  
Term Administration

Abstract Background: Many clinical studies have shown a correlation between proton pump inhibitors (PPIs) and osteoporosis or fractures. The purposes of this study were to establish a murine model of chronic oral administration of PPIs to verify whether PPIs caused bone metabolic impairment, and to investigate the relevant molecular mechanism underlying the effects of PPIs on MC3T3-E1 mouse osteoblasts.Methods: Lansoprazole-induced bone loss model was employed to investigate the damage effects of PPIs. In vivo, immunohistochemistry and HE staining, micro-CT analysis, blood biochemical tests were used to evaluate the effect of lansoprazole on bone injury in mice. In vitro, the effects and related signaling pathway of lansoprazole on MC3T3-E1 cells were investigated by CCK8, EDU kit, flow cytometry, laser confocal, patch clamp, PCR and Western blotting, etc.Results: After 6 months of lansoprazole gavage in ICR mice, micro-CT results showed that compared with the vehicle group, the bone mineral density (BMD) of high-dose group was significantly decreased (P<0.05), and the bone microarchitecture gradually degraded. Biochemical assay of bone serum found that blood calcium and phosphorus were both decreased (P<0.01). We found that long-term administration of lansoprazole impairs skeletal function in mice. In vitro, we found that lansoprazole (LPZ) could cause calcium overload in MC3T3-E1 cells leading to apoptosis, and 2-APB, an inhibitor of IP3R calcium release channel and SOC pathway, efctively blocked calcium increase caused by LPZ, thus protecting cell viability.Conclusion: Long-term administration of LPZ induced osteoporotic symptoms in mice, and LPZ triggered calcium elevation in osteoblasts in a concentration dependent manner, intracellular calcium ([Ca2+] persisted at a high concentration thereby causing endoplasmic reticulum stress (ERS) and inducing osteoblasts apoptosis.

Effect of exogenous bovine growth hormone and ovariectomy on prepubertal mammary growth, serum hormones and acute in-vitro proliferative response of mammary explants from Holstein heifers

1993 ◽  
Vol 139 (1) ◽  
pp. 19-26 ◽  
Author(s):  
S. Purup ◽  
K. Sejrsen ◽  
J. Foldager ◽  
R. M. Akers
Keyword(s):  
Mammary Gland ◽  
Growth Response ◽  
Mammary Development ◽  
Tissue Growth ◽  
Epithelial Tissue ◽  
Holstein Friesian ◽  
Serum Hormone ◽  
Term Administration

ABSTRACT Sixteen prepubertal Holstein Friesian heifers were used to study the effect of long-term administration of bovine GH (bGH) on mammary development in intact and ovariectomized heifers. Eight heifers were ovariectomized at 2·5 months of age. Four intact and four ovariectomized heifers received subcutaneous injection of bGH (15 mg/day) for 15 weeks starting at 176 ± 3 days of age (147 ± 3 kg body weight), while the remaining eight heifers received an equal volume of excipient. Blood samples were collected weekly from 2 months of age. Heifers were slaughtered on the day after the last injection of bGH or excipient. Mammary gland development was quantified by dissection, chemical analysis and computer tomographic scanning. Mammary growth response at the time of slaughter was examined in cultures with explants prepared from parenchyma. Histological and histoautoradiographic studies with explants were performed. Treatment with bGH resulted in a significantly (P<0·05) smaller mammary gland because of a reduced amount of extraparenchymal tissue. Ovariectomy markedly reduced the amount of parenchymal tissue. Growth response in mammary explants showed no treatment differences, suggesting that the decreased amount of parenchyma in ovariectomized heifers was caused by a decrease in mammary cell proliferation occurring some time prior to slaughter. The histological composition of mammary parenchyma was not changed by bGH treatment. However, ovariectomy resulted in less epithelial tissue (P<0·001) and lumen (P<0·05) and more stroma (P< 0·001), expressed as percentage tissue area. Serum hormone concentrations of bGH and insulin-like growth factor-I (IGF-I) were increased by bGH treatment in both intact and ovariectomized heifers. However, despite the fact that mammary growth in ovariectomized heifers was eradicated, the serum concentration of oestradiol was only decreased by one-third compared with intact heifers. The study therefore confirms the importance of ovarian secretions for mammary growth and development in prepubertal heifers. However, the results give no clear evidence of an interaction between ovarian secretions and GH on the regulation of the development of the mammary parenchyma in heifers. Journal of Endocrinology (1993) 139, 19–26

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.

The influence of doxazosin, an α1-adrenergic receptor antagonist on the urinary bladder contractility in pigs

2014 ◽  
Vol 17 (3) ◽  
pp. 527-529 ◽  
Author(s):  
W. Markiewicz ◽  
A. Jasiecka ◽  
D. Barski ◽  
J. Janiuk ◽  
A. Bossowska ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Adrenergic Receptor ◽  
Treated Group ◽  
Control Group ◽  
Detrusor Smooth Muscle ◽  
Before And After ◽  
Term Administration

Abstract In the present study influence of doxazosin on the porcine urinary bladder contractility has been examined. Immature pigs were treated for 30 days with: a) doxazosin (n = 5) per os at a dose of 0.1 mg/kg b.w. or b) placebo (n = 5; control group). Thereafter, animals were sacrificed and urinary bladder strips from the trigone were suspended in organ baths. The tension of the smooth musce was measured before and after exposition to acetylocholine (ACh; 10-5 - 10-3 M), norepinephrine (NE; 10-9 - 10-7 M) and 5-hydroxytryptamine (5-HT; 10-7 - 10-5 M). Both the ACh and 5-HT at the highest doses significantly increased the contractility in each group, but this response was weaker in doxazosin-treated animals. NE caused relaxation in both groups, but the effect was weaker in doxazosine-treated group. The results of our study have shown that long-term administration of doxazosin caused a desensitization of the detrusor smooth muscle for in vitro applied mediators of the autonomic nervous systems.

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

scholarly journals Curcumin Supplementation (Meriva®) Modulates Inflammation, Lipid Peroxidation and Gut Microbiota Composition in Chronic Kidney Disease

Nutrients ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 231
Author(s):  
Francesca Pivari ◽  
Alessandra Mingione ◽  
Giada Piazzini ◽  
Camilla Ceccarani ◽  
Emerenziana Ottaviano ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Lipid Peroxidation ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Term Administration ◽  
Inflammatory State ◽  
Gut Microbiota Composition

Chronic kidney disease (CKD) subjects suffer from high risk of cardiovascular mortality, and any intervention preventing the progression of CKD may have an enormous impact on public health. In the last decade, there has been growing awareness that the gut microbiota (GM) can play a pivotal role in controlling the pathogenesis of systemic inflammatory state and CKD progression. To ameliorate the quality of life in CKD subjects, the use of dietary supplements has increased over time. Among those, curcumin has demonstrated significant in vitro anti-inflammatory properties. In this pilot study, 24 CKD patients and 20 healthy volunteers were recruited. CKD patients followed nutritional counselling and were supplemented with curcumin (Meriva®) for six months. Different parameters were evaluated at baseline and after 3–6 months: uremic toxins, metagenomic of GM, and nutritional, inflammatory, and oxidative status. Curcumin significantly reduced plasma pro-inflammatory mediators (CCL-2, IFN-γ, and IL-4) and lipid peroxidation. Regarding GM, after 6 months of curcumin supplementation, Escherichia-Shigella was significantly lower, while Lachnoclostridium was significant higher. Notably, at family level, Lactobacillaceae spp. were found significantly higher in the last 3 months of supplementation. No adverse events were observed in the supplemented group, confirming the good safety profile of curcumin phytosome after long-term administration.

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