Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites.

Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) by N(5),N(10)-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O2 to generate superoxide (O2 (●-)), is a significant source of increased ROS levels in drug-treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of defense against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.

Efficacy of accelerated deep transcranial magnetic stimulation wi̇th double cone coi̇l in obsessive-compulsive disorder: A double-blind, placebo-controlled study.

High-frequency deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) with an H-coil has received approval from the Food and Drug Administration for the treatment of obsessive-compulsive disorder (OCD). Nevertheless, there is limited evidence regarding the efficacy of a similar procedure performed using a double-cone coil or in an accelerated regimen. In this study, patients in the active TMS group (n = 14) underwent stimulation of the mPFC and ACC twice daily at a frequency of 20 Hz for three weeks, using a double-cone coil. The same procedure was applied to the control group (n = 15) using a placebo coil. Throughout the study, the patients continued their antidepressant and/or antipsychotic treatments at the same dose. Following treatment, the active TMS group exhibited a more significant reduction in Yale-Brown Obsessive-Compulsive Scale scores (pre-treatment: 25.36 ± 5.4, post-treatment: 18.43 ± 6.86) and Hamilton Anxiety Rating Scale scores (pre-treatment: 10.6 ± 3.5, post-treatment: 6.7 ± 2.7) compared to the sham TMS group. However, there was no statistically significant reduction in symmetry-related obsessive-compulsive symptoms in the TMS group compared to the sham TMS group. dTMS applied to the mPFC and ACC, using a double-cone coil at a 20-Hz frequency twice daily for three weeks, was found to be effective as an adjunctive treatment for treatment-resistant OCD.

Daily vs every other day administration of G-CSF following autologous peripheral stem cell transplantation: a prospective randomized study.

The purpose of the study was to evaluate whether every other day administration of G-CSF was as safe and efficient as daily administration of G-CSF on neutrophil engraftment following autologous peripheral stem cell transplantation (APSCT). Duration of G-CSF administration, incidence of blood stream infections, duration of febrile neutropenia, duration of non-prophylactic antibiotic therapy, transfusion requirements, duration of hospitalization and G-CSF costs were also studied. Forty-seven patients with diagnosis of lymphoma and multiple myeloma undergoing APSCT were randomized to receive post-transplant daily or every other day G-CSF therapy both beginning on day +1. Both groups were comparable with regard to patient characteristics. There was no significant difference in time to neutrophil engraftment (p=0.31). The duration of G-CSF administration was significantly less in the every other day group (p<0.001). There were no detectable differences seen in the number of febrile days, duration of non-prophylactic antibiotics, the incidence of blood stream infections, transfusion requirements and the duration of hospitalization. There was a trend towards a faster platelet recovery in the every other day group, although the difference was not statistically significant (p=0.059). The number of doses of G-CSF used per transplant is significantly reduced, resulting in a significant reduction in drug costs.

Maras powder usage among Turkish psychiatric outpatients.

A kind of smokeless tobacco known as Maras powder, which is used in the southeastern region of Turkey, causes nicotine dependence. The aim of this study was to determine the usage of Maras powder among psychiatric outpatients and nonpsychiatric controls. The study group consisted of 276 psychiatric patients and 283 nonpsychiatric patients from psychiatry and family medicine outpatient clinics. A socio-demographic form, the Fagerström Test for Nicotine Dependence, and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders?4th Edition were given to the participants. The rates of Maras powder usage in the patient group (10.1%) were significantly higher than those in the control group (5.6%). Men were found to use Maras powder at a higher rate in both groups. The rates of Maras powder usage according to the psychiatric diagnosis were evaluated. This is the first study estimating Maras powder usage rates among psychiatric patients in Turkey. The study's limitations are noted.

Cancer cell-selective killing polymer/copper combination.

Chemotherapy has been adopted for cancer treatment for decades. However, its efficacy and safety are frequently compromised by the multidrug-resistance of cancer cells and the poor cancer cell selectivity of anticancer drugs. Hereby, we report a combination of a pyridine-2-thiol containing polymer and copper which can effectively kill a wide spectrum of cancer cells, including drug resistant cancer cells, while sparing normal cells. The polymer nanoparticle enters cells via an exofacial thiol facilitated route, and releases active pyridine-2-thiol with the help of intracellularly elevated glutathione (GSH). Due to their high GSH level, cancer cells are more vulnerable to the polymer/copper combination. In addition, RNA microarray analysis revealed that the treatment can reverse cancer cells' upregulated oncogenes (CIRBP and STMN1) and downregulated tumor suppressor genes (CDKN1C and GADD45B) to further enhance the selectivity for cancer cells.

Night eating syndrome among patients with depression.

OBJECTIVE: The purpose of this study was to identify the rate of night eating syndrome (NES) in a depressed population. METHOD: The study sample was composed of 162 depressed patients and 172 healthy control participants. RESULTS: The rates of night eating in our sample with depression (35.2%) was higher as compared with healthy control participants (19.2%) (p less than 0.05). In addition, in the depression group, the rate of NES-positive patients did not differ in accordance with body mass index (BMI) classification (p more than 0.05). However, in the control group, the rate of NES-positive patients was significantly different with regard to BMI classification, and NES diagnosis was highest in the obese members of the control group (p less than 0.05). Multiple logistic regression analysis was then used to evaluate the relationships of four variables: depression, gender, education status and BMI with the diagnosis of NES. Results showed that significant independent predictors of NES were depression, gender, and a BMI of 25 or greater. DISCUSSION: This is the first study to find that depressed patients are at a significantly greater risk for NES. Depression, male gender and BMI may account for the high rate of NES found in this population.

Synergistic effect of [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] and antidepressant drugs in the mouse forced swimming test: possible involvement of serotonergic pathway.

To augment the effects of classical antidepressant drugs by combination therapies in drug-resistant patients has been an emerging treatment strategy. In the present study, the potential synergistic effect of [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] (ODQ) and antidepressant drugs in the forced swimming test was evaluated. While 5mg/kg intraperitoneal administration of imipramine, fluoxetine or desipramine caused no effect in the duration of immobility in the forced swimming test (sub-effective doses), higher doses (20, 10 and 10mg/kg, respectively) reduced the immobility period (effective doses). When sub-effective doses of ODQ (15mg/kg) and imipramine (5mg/kg) were applied, there was a significant reduction in the immobility time compared with those of each drug alone. Similarly the reduction seen with the effective dose of imipramine (20mg/kg) was also augmented by the co-administration of ODQ (15mg/kg). By its sub-effective dose, ODQ exerted statistically significant augmentations in the responses to either sub-effective (5mg/kg) or effective dose (10mg/kg) of fluoxetine. By contrast, desipramine was not influenced by the co-administration of ODQ (15mg/kg). None of the drugs used in the present study had any effects on the locomotor activity test over the dose range applied. The results show that co-administration of imipramine/fluoxetine and ODQ exhibits a supra-additive effect and that serotonergic rather than noradrenergic pathway may be involved in the synergistic effect of ODQ.

Production of L-DOPA and dopamine in recombinant bacteria bearing the Vitreoscilla hemoglobin gene.

Given the well-established beneficial effects of Vitreoscilla hemoglobin (VHb) on heterologous organisms, the potential of this protein for the production of L-DOPA and dopamine in two bacteria, Citrobacter freundii and Erwinia herbicola, was investigated. The constructed recombinants bearing the VHb gene (vgb(+)) had substantially higher levels of cytoplasmic L-DOPA (112 mg/L for C. freundii and 97 mg/L for E. herbicola) than their respective hosts (30.4 and 33.8 mg/L) and the vgb(-) control strains (35.6 and 35.8 mg/L). Further, the vgb(+) recombinants of C. freundii and E. herbicola had 20-fold and about two orders of magnitude higher dopamine levels than their hosts, repectively. The activity of tyrosine phenol-lyase, the enzyme converting L-tyrosine to L-DOPA, was well-correlated to cytoplasmic L-DOPA levels. As cultures aged, higher tyrosine phenol-lyase activity of the vgb(+) strains was more apparent.

Effect of Vitreoscilla hemoglobin on production of a chemotherapeutic enzyme, L-asparaginase, by Pseudomonas aeruginosa.

The production of L-asparaginase, an enzyme widely used in cancer chemotherapy, is mainly regulated by carbon catabolite repression and oxygen. This study was carried out to understand how different carbon sources and Vitreoscilla hemoglobin (VHb) affect the production of this enzyme in Pseudomonas aeruginosa and its VHb-expressing recombinant strain (PaJC). Both strains grown with various carbon sources showed a distinct profile of the enzyme activity. Compared to no carbohydrate supplemented medium, glucose caused a slight repression of L-asparaginase in P. aeruginosa, while it stimulated it in the PaJC strain. Glucose, regarded as one of the inhibitory sugars for the production L-asparaginase by other bacteria, was determined to be the favorite carbon source compared to lactose, glycerol and mannitol. Furthermore, contrary to common knowledge of oxygen repression of L-asparaginase in other bacteria, oxygen uptake provided by VHb was determined to even stimulate the L-asparaginase synthesis by P. aeruginosa. This study, for the first time, shows that in P. aeruginosa utilizing a recombinant oxygen uptake system, VHb, L-asparaginase synthesis is stimulated by glucose and other carbohydrate sources compared to the host strain. It is concluded that carbon catabolite and oxygen repression of L-asparaginase in fermentative bacteria is not the case for a respiratory non-fermentative bacterium like P. aeruginosa.