Grape seed proanthocyanidin extract inhibits glutamate-induced cell death through inhibition of calcium signals and nitric oxide formation in cultured rat hippocampal neurons

<p>Abstract</p> <p>Background</p> <p>Proanthocyanidin is a polyphenolic bioflavonoid with known antioxidant activity. Some flavonoids have a modulatory effect on [Ca²⁺]_i. Although proanthocyanidin extract from blueberries reportedly affects Ca²⁺buffering capacity, there are no reports on the effects of proanthocyanidin on glutamate-induced [Ca²⁺]_ior cell death. In the present study, the effects of grape seed proanthocyanidin extract (GSPE) on glutamate-induced excitotoxicity was investigated through calcium signals and nitric oxide (NO) in cultured rat hippocampal neurons.</p> <p>Results</p> <p>Pretreatment with GSPE (0.3-10 μg/ml) for 5 min inhibited the [Ca²⁺]_iincrease normally induced by treatment with glutamate (100 μM) for 1 min, in a concentration-dependent manner. Pretreatment with GSPE (6 μg/ml) for 5 min significantly decreased the [Ca²⁺]_iincrease normally induced by two ionotropic glutamate receptor agonists, N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). GSPE further decreased AMPA-induced response in the presence of 1 μM nimodipine. However, GSPE did not affect the 50 mM K⁺-induced increase in [Ca²⁺]_i. GSPE significantly decreased the metabotropic glutamate receptor agonist (<it>RS</it>)-3,5-Dihydroxyphenylglycine-induced increase in [Ca²⁺]_i, but it did not affect caffeine-induced response. GSPE (0.3-6 μg/ml) significantly inhibited synaptically induced [Ca²⁺]_ispikes by 0.1 mM [Mg²⁺]_o. In addition, pretreatment with GSPE (6 μg/ml) for 5 min inhibited 0.1 mM [Mg²⁺]_o- and glutamate-induced formation of NO. Treatment with GSPE (6 μg/ml) significantly inhibited 0.1 mM [Mg²⁺]_o- and oxygen glucose deprivation-induced neuronal cell death.</p> <p>Conclusions</p> <p>All these data suggest that GSPE inhibits 0.1 mM [Mg²⁺]_o- and oxygen glucose deprivation-induced neurotoxicity through inhibition of calcium signals and NO formation in cultured rat hippocampal neurons.</p

Purification and proteomic identification of putative upstream regulators of polo-like kinase-1 from mitotic cell extracts

AbstractPolo-like kinase-1 (Plk1) is phosphorylated on Thr210 for activation during mitosis. Here, we investigated the question of which kinase(s) is the specific upstream kinase of mitotic Plk1. Upstream kinases of Plk1 were purified from mitotic cell extracts through column chromatography procedures, and identified by mass spectrometry. Candidates for Plk1 kinase included p21-activated kinase, aurora A, and mammalian Ste20-like kinases. Immunoprecipitates of these proteins from mitotic cell extracts phosphorylated Plk1 on Thr210. Even if the activity of Aurora A was blocked with a specific inhibitor, Plk1 phosphorylation still occurred, suggesting that function of Plk1 could be controlled by these kinases for proper mitotic progression, as well as by Aurora A in very late G2 phase for the beginning of mitosis.Structured abstractMINT-7996332: PAK1(uniprotkb:Q13153)physically interacts(MI:0915) withPLK1(uniprotkb:P53350) bypull down(MI:0096)MINT-7996345: PAK3(uniprotkb:O75914)physically interacts(MI:0915) withPLK1(uniprotkb:P53350) bypull down(MI:0096

Insulin Secretion and Incretin Hormone Concentration in Women with Previous Gestational Diabetes Mellitus

BackgroundWe examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) on insulin secretion in women with previous gestational diabetes (pGDM).MethodsA 75-g oral glucose tolerance test (OGTT) was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured.ResultsAmong 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT) and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT.ConclusionGLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates. METHODS: Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used. RESULTS: A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V(c)) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure. CONCLUSIONS: T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users

Cottonseed Oilcake Extract Mediated Green Synthesis of Silver Nanoparticles and Its Antibacterial and Cytotoxic Activity

Agroindustrial byproduct mediated green synthesis of silver nanoparticles was carried out using cottonseed oilcake (CSOC) extract. The aqueous silver nitrate formed stable silver nanoparticles with CSOC extract as a reducing agent for Ag+ to Ag0. The synthesized nanoparticles were characterized using energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) techniques. The synthesized silver nanoparticles (AgNPs) (4 mM) significantly inhibited the growth of phytopathogens, Pseudomonas syringae pv. actinidiae and Ralstonia solanacearum. Further, cytotoxicity of AgNPs was evaluated using rat splenocyte cells. The splenocyte viability was decreased according to the increasing concentration of AgNPs and 90% of cell death was observed at 100 μg/mL

Hematopoietic stem cell transplantation in children with acute leukemia: similar outcomes in recipients of umbilical cord blood versus marrow or peripheral blood stem cells from related or unrelated donors

PurposeThis study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD).MethodsThis retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41).ResultsNeutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD (P<0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; P=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; P<0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; P<0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; P<0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; P=0.04).ConclusionSurvival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative

Primary Squamous Cell Carcinoma of the Liver Initially Presenting with Pseudoachalasia

Pseudoachalasia secondary to primary squamous cell carcinoma (SCC) of the liver is extremely rare and has not been reported until now. Here, we report a unique case of primary SCC of the liver initially presenting with progressive dysphagia along with short periods of significant weight loss. A 58-year-old man initially presented with progressive dysphagia along with significant weight loss over brief periods of time. The radiographic and manometric findings were consistent with achalasia. Subsequent esophagogastroduodenoscopy revealed a moderately dilated esophagus without evidence of neoplasm or organic obstruction. However, firm resistance was encountered while traversing the esophagogastric junction (EGJ), although no mucosal lesion was identified. Due to the clinical suspicion of the presence of a malignant tumor, endoscopic ultrasonography (EUS) and computed tomography scans of the chest and abdomen were obtained. A huge hepatic mass with irregular margins extending to the EGJ was found. EUS-guided fine-needle aspiration was performed, and the mass was diagnosed as a primary SCC of the liver by immunohistochemical staining