Nickel (II) complexes of naphthaquinone thiosemicarbazone and semicarbazone: synthesis, structure, spectroscopy, and biological activity

Ni(II) complexes of ortho-naphthaquinone thiosemicarbazone and semicarbazone were synthesized and spectroscopically characterized. The X-ray crystal structure of both the complexes describe a distorted octahedral coordination with two tridentate mono-deprotonated ligands. In vitro anticancer studies on MCF-7 human breast cancer cells reveal that the semicarbazone derivative along with its nickel complex is more active in the inhibition of cell proliferation than the thiosemicarbazone analogue.     

Engineered beta-cells secreting dipeptidyl peptidase IV-resistant glucagon-like peptide-1 show enhanced glucose-responsiveness

Type 2 diabetes is a polygenic disorder characterized by increased insulin resistance, and impaired insulin secretion leading to abnormalities of glucose and lipid metabolism. Reduced responsiveness of the beta-cells to glucose is a critical feature of this syndrome. Glucagon-like peptide 1, a product of the pro-glucagon gene makes beta-cells competent and has many other anti-diabetic properties. We speculated whether GLP-1-based gene therapy could be an approach for treatment of type 2 diabetes. We started with a clone of rat insulinoma cells (S4 cells), which showed reduced responsiveness to glucose in terms of insulin secretion. We transfected these cells with a plasmid encoding a mutated form of GLP-1 (GLP-1-Gly8), which is resistant to the degrading enzyme dipeptidyl-peptidase IV. Activity of secreted GLP-1-Gly8 was assayed using Chinese hamster lung fibroblasts (CHL) cells that expressed cloned GLP-1 receptor and that were transfected with CRE-Luc. Stable cell lines (Glipsulin cells) obtained by this means produced and stored immunoreactive GLP-1-Gly8. In addition to insulin, the Glipsulin cells secreted the GLP-1-Gly8. The secreted GLP-1-Gly8 was active as evidenced by the ability of the conditioned media to elevate cAMP levels in CHL cells expressing GLP-1 receptors. Glipsulin cells responded to glucose with a 6.8 fold increase in insulin secretion compared to a 2.2 fold increase in the control cells. Our results demonstrate that prolonged exposure to GLP-1-Gly8 secreted by increases glucose-responsiveness of these cells. We speculate that engineering GLP-1-Gly8 secretion by beta-cells is a potential gene therapeutic strategy to treat diabetes.     

Multiple arrhythmogenic substrate for tachycardia in a patient with frequent palpitations

We report a 26-year-old woman with frequent episodes of palpitation and dizziness. Resting electrocardiography showed no evidence of ventricular preexcitation. During electrophysiologic study, a concealed right posteroseptal accessory pathway was detected and orthodromic atrioventricular reentrant tachycardia incorporating this pathway as a retrograde limb was reproducibly induced. After successful ablation of right posteroseptal accessory pathway, another tachycardia was induced using a concealed right posterolateral accessory pathway in tachycardia circuit. After loss of retrograde conduction of second accessory pathway with radiofrequency ablation, dual atrioventricular nodal physiology was detected and typical atrioventricular nodal reentrant tachycardia was repeatedly induced. Slow pathway ablation was done successfully. Finally sustained self-terminating atrial tachycardia was induced under isoproterenol infusion but no attempt was made for ablation. During 8-month follow-up, no recurrence of symptoms attributable to tachycardia was observed.     

Coexistence of atrioventricular nodal reentrant tachycardia and idiopathic left ventricular outflow-tract tachycardia

Double tachycardia is a relatively rare condition. We describe a 21 year old woman with history of frequent palpitations. In one of these episodes, she had wide complex tachycardia with right bundle branch and inferior axis morphology. A typical atrioventricular nodal tachycardia was induced during electrophysiologic study, aimed at induction of clinically documented tachycardia. Initially no ventricular tachycardia was inducible. After successful ablation of slow pathway, a wide complex tachycardia was induced by programmed stimulation from right ventricular outflow tract. Mapping localized the focus of tachycardia in left ventricular outflow tract and successfully ablated via retrograde aortic approach. During 7 month's follow-up, she has been symptom free with no recurrence. This work describes successful ablation of rare combination of typical atrioventricular nodal tachycardia and left ventricular outflow tract tachycardia in the same patient during one session.     

Changes in human immunodeficiency virus type 1 fitness and genetic diversity during disease progression

This study examined the relationship between ex vivo human immunodeficiency virus type 1 (HIV-1) fitness and viral genetic diversity during the course of HIV-1 disease. Primary HIV-1 isolates from 10 patients at different time points were competed against control HIV-1 strains in peripheral blood mononuclear cell (PBMC) cultures to determine relative fitness values. Patient HIV-1 isolates sequentially gained fitness during disease at a significant rate that directly correlated with viral load and HIV-1 env C2V3 diversity. A loss in both fitness and viral diversity was observed upon the initiation of antiretroviral therapy. A possible relationship between genotype and phenotype (virus replication efficiency) is supported by the parallel increases in ex vivo fitness and viral diversity during disease, of which the correlation is largely based on specific V3 sequences. Syncytium-inducing, CXCR4-tropic HIV-1 isolates did have higher relative fitness values than non-syncytium-inducing, CCR5-tropic HIV-1 isolates, as determined by dual virus competitions in PBMC, but increases in fitness during disease were not solely powered by a gradual switch in coreceptor usage. These data provide in vivo evidence that increasing HIV-1 replication efficiency may be related to a concomitant increase in HIV-1 diversity, which in turn may be a determining factor in disease progression.     

Transition metal complexes of phenanthrenequinone thiosemicarbazone as potential anticancer agents: synthesis,structure, spectroscopy,electrochemistry and in vitro anticancer activity against human breast cancer cell-line,T47D

The thiosemicarbazone derivative of 9,10-phenanthrenequinone, 1, and its metal complexes were synthesized. The X-ray crystal structure for 1 confirms the presence of the E tautomeric arrangement in this compound. Its copper complex shows 1:1 stoichiometry while nickel and cobalt compounds show 1:2 stoichiometry. The X-ray crystal structure of the nickel complex indicates two tridentate ligands coordinating in the thiolato form yielding an octahedral geometry for the 'mer' isomer. The copper complex exhibits maximum antiproliferative activity against human breast cancer cell-line, T47D probably due to inhibition of steroid binding to the cognitive receptor or by preventing dimerization of the estrogen receptor.     

Involvement of the Src kinase Lyn in phospholipase C-gamma 2 phosphorylation and phosphatidylinositol 3-kinase activation in Epo signalling

We examined the role of the Src kinase Lyn in phospholipase C-gamma 2 (PLC-gamma 2) and phosphatidylinositol (PI) 3-kinase activation in erythropoietin (Epo)-stimulated FDC-P1 cells transfected with a wild type (WT) Epo-receptor (Epo-R). We showed that two inhibitors of Src kinases, PP1 and PP2, abolish both PLC-gamma 2 tyrosine phosphorylation and PI 3-kinase activity in WT Epo-R FDC-P1 cells. We also demonstrated that Epo-phosphorylated Lyn is associated with tyrosine phosphorylated PLC-gamma 2 and PI 3-kinase in WT Epo-R FDC-P1-stimulated cells. Moreover Epo-activated Lyn phosphorylates in vitro PLC-gamma 2 immunoprecipitated from unstimulated cells. Our results suggest that the Src kinase Lyn is involved in PLC-gamma 2 phosphorylation and PI 3-kinase activation induced by Epo.     

Melatonin and locomotor activity in the fiddler crab Uca pugilator

The influence of melatonin on locomotor activity levels was measured in the fiddler crab Uca pugilator. First, activity in untreated, laboratory-acclimated crabs was measured over 48 hours in a 12L:12D photoperiod; this study showed a nocturnal increase in activity. In eyestalk-ablated crabs, overall activity was significantly reduced, and no significant activity pattern occurred. Next, crabs were injected with melatonin or saline (controls) at various times during the 12L:12D photoperiod (0900h, 1200h, and twice at 2100h; each trial was separated by 3-4 days) and monitored for 3 hr post-injection. Control crabs had low activity during early photophase, high at mid-photophase, increasing activity during the first scotophase trial, and decreasing activity during the second scotophase trial. Melatonin had no significant influence on activity when injected during the early-photophase activity trough or early-scotophase activity decline, but significantly increased activity when injected during the mid-photophase activity peak and early-scotophase activity incline. Next, crabs were injected during an early scotophase activity trough and monitored throughout the twelve-hour scotophase. Melatonin did not increase activity until the mid-scotophase activity increase, approximately 6 hours later, showing that the pharmacological dosage persisted in the crabs' systems and had later effects during the incline and peak of activity but not the trough. Eyestalk-ablated crabs were injected with melatonin or saline during early photo- and scotophase. Melatonin significantly increased activity in the photophase but not the scotophase trial, indicating that the responsiveness to melatonin continues following eyestalk removal, but the timing may not match that of intact crabs. Melatonin may be involved in the transmission of environmental timing information from the eyestalks to locomotor centers in U. pugilator.     

Distinct patterns of apoptosis in the lung during liquid ventilation compared with gas ventilation

To determine whether liquid ventilation (LV) causes less cell injury and improves lung function compared with conventional gas ventilation (GV), we analyzed pulmonary physiological profiles, lung histology, and cell death in 110- and 120-day preterm lambs, which were randomized to receive either ventilation modality on FI(O(2)) = 1. LV lungs were well expanded with adequate pulmonary function, whereas GV animals exhibited marked atelectasis, poor pulmonary function, and increased mortality. Both ventilatory strategies induced marked lung cell apoptosis, but with distinct patterns of distribution. Although GV induced apoptosis of epithelium primarily in the lining and within the lumina of bronchioles, LV induced significant apoptosis much more homogeneously throughout lung parenchyma including alveoli and interstitial spaces. These studies suggest that although both forms of ventilation cause regional apoptosis, LV more effectively delivers oxygen and recruits the lung more homogeneously than GV.     

Increase in serum level of interleukin-1 alpha mediates morphine anti-inflammatory effect in carrageenan-induced paw oedema in mice

In the present studies we examined the effects of an intra-peritoneal injection of morphine (7 mg/kg) on carrageenan-induced paw oedema in mice. Carrageenan-induced paw oedema was measured by mercury plethysmometer and was maximal at hour 3, and pretreatment with morphine could reduce the oedema significantly. At the same time the serum levels of interleukin-1 alpha (IL-1 alpha) were increased. Pretreatment with naloxone and dexamethasone abolished morphine anti-inflammatory while decreasing IL-1 alpha serum levels, significantly. These findings suggest that an increase in serum levels of IL-1 alpha plays an important role in the anti-inflammatory effect of morphine.