Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2

<p>Abstract</p> <p>Background</p> <p>The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model.</p> <p>Methods</p> <p>For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 × 10⁶LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm³. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm³. The left lobes of the lungs were extracted for the measurement of metastatic nodules.</p> <p>Results</p> <p>Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib.</p> <p>Conclusion</p> <p>Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.</p

Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice

Background: Recent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested. Methods: Two syndromic ASD mouse models—Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice—were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures. Findings: As previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions. Conclusions: Our results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models. © 2020, The Author(s).1

Improved hematopoietic differentiation of human pluripotent stem cells via estrogen receptor signaling pathway

Additional file 2: Table S1. Temporal changes (%) of ER-Îą and hematopoietic phenotypes during hiPSC-derived hematopoietic differentiation

Comparison of infarct-related artery vs multivessel revascularization in ST-segment elevation myocardial infarction with multivessel disease: Analysis from Korea Acute Myocardial Infarction Registry

Background: Many ST-segment elevation myocardial infarction (STEMI) patients have multivessel disease. There is still controversy in treatment strategy in STEMI patients with multivessel disease. We compared clinical outcomes of multivessel revascularization with infarct- related artery (IRA) revascularization in STEMI patients. Methods: The 1,644 STEMI patients with multivessel disease (1,106 in IRA group, 538 in multivessel group) who were received primary percutaneous coronary intervention (PCI) were analyzed from a nationwide Korea Acute Myocardial Infarction Registry. Primary endpoint was 12-month major adverse cardiac events (MACE, defined as death, myocardial infarction, and repeated revascularization). Secondary endpoints were 1-month MACE and each component, stent thrombosis during 12 month follow-up, and each components of the 12-month MACE. Results: There were more patients with unfavorable baseline conditions in IRA group. 12-month MACE occurred in 165 (14.9%) patients in IRA group, 81 (15.1%) patients in multivessel group (p = 0.953). There were no statistical significance in the rate of 1-month MACE, each components of 1-month MACE, and stent thrombosis during 12 month follow-up. Each components of 12-month MACE were occurred similarly in both groups except for target lesion revascularization (2.4% in IRA group vs 5.9% in multivessel group, p < 0.0001). After adjusting for confounding factors, multivessel revascularization was not associated with reduced 12-month MACE (OR 1.096, 95% CI 0.676&#8211;1.775, p = 0.711). Conclusions: There were no significant differences in clinical outcomes between both groups except for high risk of target lesion revascularization in multivessel revascularization group

Effect of intracoronary adenosine on ergonovine-induced vasoconstricted coronary arteries

Background: This study aimed to evaluate the effect of adenosine on epicardial coronary artery diameterduring ergonovine provocation testing.Methods: A total of 158 patients who underwent an ergonovine provocation test with intracoronaryadenosine injection between 2011 and 2014 were selected. Patients were divided into four groups basedon the severity of percent diameter stenosis following intracoronary ergonovine administration: Group 1,induced spasm &lt; 50%; Group 2, 50–89%; Group 3, 90–99%; and Group 4, total occlusion.Results: Spasm positivity was observed in 44 (27.8%) cases in the study population (mean age, 57.4 ±± 10.7 years). Intracoronary adenosine increased the diameter of the ergonovine-induced epicardialartery by 0.51 ± 0.31 mm, 0.73 ± 0.39 mm, 0.44 ± 0.59 mm, and 0.01 ± 0.04 mm in Groups 1, 2, 3,and 4, respectively. Subsequent administration of nitroglycerin further increased vessel diameter by0.49 ± 0.28 mm, 0.93 ± 0.68 mm, 2.11 ± 1.25 mm, and 2.23 ± 0.69 mm in Groups 1, 2, 3, and 4,respectively. The ratios of adenosine-induced diameter to reference diameter were significantly lowerin patients with spasm positive results (0.68 [0.59–0.76] vs. 0.18 [0.00–0.41], p &lt; 0.001 in the studypopulation; 0.60 [0.54–0.67] vs. 0.40 [0.27–0.44], p &lt; 0.001 in Group 2) with the best cut-off value of0.505 (sensitivity 0.955, specificity 0.921).Conclusions: Intracoronary administration of adenosine dilated the ergonovine-induced vasoconstrictedepicardial coronary artery. The ratio of adenosine-induced diameter to reference diameter wassignificantly lower in patients with spasm positive results

Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

SummaryAutophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic β cells and glucose homeostasis has not been described. We produced mice with β cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. β cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of β cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient β cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in β cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic β cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles

Receptor protein tyrosine phosphatase delta is not essential for synapse maintenance or transmission at hippocampal synapses

Abstract Members of the leukocyte common antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family, comprising PTPσ, PTPδ and LAR, are key hubs for presynaptic assembly and differentiation in vertebrate neurons. However, roles of individual LAR-RPTP members have not been investigated using member-specific conditional knockout mice. Here, we show that loss of PTPδ had no overt effect on synapse development in mouse cultured hippocampal neurons. Moreover, loss of PTPδ in presynaptic CA1 hippocampal neurons did not influence neurotransmitter release in subicular pyramidal neurons, suggesting that PTPδ is not critical for presynaptic function in vivo. Our results demonstrate that PTPδ is not essential for synapse maintenance or transmission, at least in the mouse hippocampus, and underscore the importance of using sophisticated genetic approaches to confirm the roles of synaptic proteins

Enhanced cardiac expression of two isoforms of matrix metalloproteinase-2 in experimental diabetes mellitus.

BackgroundDiabetic cardiomyopathy (DM CMP) is defined as cardiomyocyte damage and ventricular dysfunction directly associated with diabetes independent of concomitant coronary artery disease or hypertension. Matrix metalloproteinases (MMPs), especially MMP-2, have been reported to underlie the pathogenesis of DM CMP by increasing extracellular collagen content.PurposeWe hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model.MethodsRat cardiomyoblasts (H9C2 cells) were examined to determine whether high glucose can induce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin-induced DM mouse heart model and age-matched controls. The changes of each MMP-2 isoform expression in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify the location and patterns of MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes.ResultsQuantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography. Quantitative RT-PCR and IHC staining showed this abnormal cardiac function was accompanied with the increases in the mRNA levels of the two isoforms of MMP-2 and related to intracellular localization.ConclusionTwo isoforms of MMP-2 were induced by high glucose stimulation in vitro and in a Type 1 DM mouse heart model. Further study is required to examine the role of these isoforms in DM CMP