Lower doses of vanadate in combination with trigonella restore altered carbohydrate metabolism and antioxidant status in alloxan-diabetic rats

BACKGROUND: Vanadate treatment to diabetic rats has been reported to correct the altered carbohydrate metabolism and antioxidant status. However, vanadate exerts these effects at relatively high doses and several toxic effects are produced. We used low doses of vanadate in combination with Trigonella foenum graecum seed powder (TSP) and evaluated their effect on the enzyme changes in diabetic rats. METHODS: Alloxan-diabetic rats were treated separately with insulin, vanadate (0.6 mg/ml), TSP and a combined dose of Vanadate (0.2 mg/ml) and TSP for 21 days. At the end of the experimental period, blood glucose levels and activities of pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) were measured in cytosolic fraction in the liver and kidney. RESULTS: Blood glucose levels increased markedly in diabetic rats. Treatment with antidiabetic compounds resulted in the reduction of glucose levels. Rats treated with combined dose of vanadate and trigonella had glucose levels comparable to control ones. Similar results were obtained with the activities of PK, PEPCK, SOD, GPx, GR, and CAT in liver and kidney of diabetic rats. Combined dose of vanadate and Trigonella was found to be most effective in correcting these alterations. CONCLUSIONS: Lower doses of vanadate could be used in combination with TSP to effectively counter diabetic alterations without any toxic side effects.     

Drug development in NZ: can a country be a cluster?

The aims of this research were to assess New Zealand's (NZ) growing drug development industry, and compare it with drug development and biotechnology clusters overseas. This article presents the results of questionnaires administered dutring interviews with 60 senior people representing the industry. It narrates their expertise, knowledge management, and innovative behaviors. NZ's industry comprises highly qualified, very experienced, and motivated people. Their organizations have particular expertise in drug discovery, which has arisen from long‐term government support for biomedical research. There is also significant expertise in early‐stage clinical development and contract clinical research. Knowledge sharing was rated as better within organizations than externally. The participants gave the highest ratings of their organizations' innovative performance to solving problems that had caused others difficulty, teamwork and having new ideas; they prefer informal methods of knowledge acquisition. These factors may reflect the NZ approach of applying ingenuity to solve problems and preference for casual and internal knowledge sharing. NZ has a hub of drug development activity; however, its size, limited resources, and remoteness from major markets may limit the development of a complete pharmaceutical industry. NZ could be promoted as a unique “country cluster” offering niche areas of expertise especially in drug discovery and clinical research. Drug Dev Res 73: 51–58, 2012. © 2011 Wiley Periodicals, Inc.     

A novel pharmacophore model to identify leads for simultaneous inhibition of anti-coagulation and anti-inflammatory activities of snake venom phospholipase A(2)

In addition to catalytic action, snake venom phospholipase A(2) induces several pharmacological effects including neurotoxicity, cardiotoxicity as well as anti-coagulant and anti-platelet aggregation effects. Therefore, strategy to identify dual inhibitor for this enzyme will be of much importance in medical research. In this paper, structure-based pharmacophore mapping, molecular docking, protein-ligand interaction fingerprints, binding energy calculations, and binding affinity predictions were employed in a virtual screening strategy to identify new hits for dual inhibition of anti-coagulation and inflammation of phospholipase A(2) . A structure-based pharmacophore map was modeled which comprised of important interactions as observed in co-crystal of phospholipase A(2) and its dual inhibitor indomethacin. The generated model was used to retrieve molecules from ChemBridge, a free database of commercially available compounds. A total of 381 molecules mapped on the developed pharmacophore model from ChemBridge database. The hits retrieved were further screened by molecular docking, protein-ligand interaction fingerprints, binding energy calculations, and binding affinity predictions using Genetic Optimization for Ligand Docking and moe. Based on these results, 32 chemo-types molecules were predicted as potential lead scaffolds for developing novel, potent and structurally diverse dual inhibitor of phospholipase A(2.).     

Combined pharmacophore and 3D-QSAR study on a series of Staphylococcus aureus Sortase A inhibitors

Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q(2) = 0.562 and r(2) = 0.995, comparative molecular similarity indices analysis: q(2) = 0.549 and r(2) = 0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features.     

Diminished glucocorticoid negative feedback in polydipsic hyponatremic schizophrenic patients

CONTEXT: The mechanism and significance of diminished glucocorticoid negative feedback in schizophrenia is unknown but is more commonly observed in schizophrenic patients with primary polydipsia. Polydipsic patients, especially those who are also hyponatremic, exhibit other neuroendocrine abnormalities that have been linked to hippocampal pathology. OBJECTIVE: The objective of the study was to determine the effect of cortisol on plasma ACTH under conditions thought to be most sensitive to hippocampal influences. DESIGN: The design was repeated measures. SETTING: The study was conducted at an inpatient clinical research center. PARTICIPANTS: Participants included eight polydipsic hyponatremic and eight polydipsic normonatremic as well as six schizophrenic patients without water imbalance. Eight healthy community volunteers matched for age and gender were also studied. INTERVENTION: Metyrapone (750 mg) was administered orally at 1430 and 1900 h. Beginning at 1930 h, hydrocortisone was infused over 150 min at 0.03 mg/kg.h. Blood samples and other measures were obtained at 20-min intervals from 1850 to 2320 h. MAIN OUTCOME MEASURES: Plasma ACTH and cortisol were measured. RESULTS: ACTH levels did not decline significantly during the cortisol infusion in the polydipsic hyponatremic group. For any given level of cortisol, ACTH levels were higher in the hyponatremic group. Although levels declined after cortisol in the other three groups, the decline was greatest in patients without water imbalance. CONCLUSIONS: The marked impairment in glucocorticoid negative feedback in polydipsic hyponatremic schizophrenic patients is consistent with hippocampal mineralocorticoid dysfunction.     

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sj?gren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.     

Bone lesions: Role of sediment cytology

This study was conducted to evaluate the role of sediment cytology of biopsy specimen fixatives, which is usually discarded, in early diagnosis of bone lesions. Cytological smears prepared from sediments of biopsy specimen fixatives (sediment cytology) were used to study 65 bone specimens biopsied with suspicion of malignancy. The cytological diagnosis was then compared with histological diagnosis, taking the latter as gold standard. Smears were adequately cellular and showed good preservation of cellular morphology. Some of the smears showed microfragments of tissue. Cytology labeled 29 lesions as malignant, 26 lesions as benign, 3 as inflammatory, and 7 smears as inconclusive because of low cell yield. Sediment cytology was able to correctly diagnose 58 of 65 lesions. There was no false‐positive or false‐negative case. The sediment cytology could be considered as an easy and effective diagnostic tool that can provide early diagnosis for the lesion of bone. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Excessive use of Massively Multi-Player Online Role-Playing Games: A Pilot Study

Massively multiplayer online role-playing games (MMORPGs) are one of the most interesting innovations in the area of online computer gaming. This pilot study set out to examine the psychological and social effects of online gaming using an online questionnaire with particular reference to excessive and ‘dependent’ online gaming. A self-selecting sample of 119 online gamers ranging from 18 to 69 years (mean = 28.5 years) completed the questionnaire. The results showed that 41% of gamers played online to escape and 7% of gamers were classified as ‘dependent’ individuals who were at risk of developing a psychological and behavioural dependence for online gaming using an adapted ‘addiction’ scale. Further analysis showed that excessive online gaming was significantly correlated with psychological and behavioural ‘dependence’. It was also found that ‘dependent’ gamers appear to possess some core components of addiction to MMORPGs (e.g., mood modification, tolerance and relapse).     

Sinorhizobium meliloti phospholipase C required for lipid remodeling during phosphorus limitation

Rhizobia are Gram-negative soil bacteria able to establish nitrogen-fixing root nodules with their respective legume host plants. Besides phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine, rhizobial membranes contain phosphatidylcholine (PC) as a major membrane lipid. Under phosphate-limiting conditions of growth, some bacteria replace their membrane phospholipids with lipids lacking phosphorus. In Sinorhizobium meliloti, these phosphorus-free lipids are sulfoquinovosyl diacylglycerol, ornithine-containing lipid, and diacylglyceryl trimethylhomoserine (DGTS). Pulse–chase experiments suggest that the zwitterionic phospholipids phosphatidylethanolamine and PC act as biosynthetic precursors of DGTS under phosphorus-limiting conditions. A S. meliloti mutant, deficient in the predicted phosphatase {"type":"entrez-protein","attrs":{"text":"SMc00171","term_id":"1174089800","term_text":"SMC00171"}}SMc00171 was unable to degrade PC or to form DGTS in a similar way as the wild type. Cell-free extracts of Escherichia coli, in which {"type":"entrez-protein","attrs":{"text":"SMc00171","term_id":"1174089800","term_text":"SMC00171"}}SMc00171 had been expressed, convert PC to phosphocholine and diacylglycerol, showing that {"type":"entrez-protein","attrs":{"text":"SMc00171","term_id":"1174089800","term_text":"SMC00171"}}SMc00171 functions as a phospholipase C. Diacylglycerol , in turn, is the lipid anchor from which biosynthesis is initiated during the formation of the phosphorus-free membrane lipid DGTS. Inorganic phosphate can be liberated from phosphocholine. These data suggest that, in S. meliloti under phosphate-limiting conditions, membrane phospholipids provide a pool for metabolizable inorganic phosphate, which can be used for the synthesis of other essential phosphorus-containing biomolecules. This is an example of an intracellular phospholipase C in a bacterial system; however, the ability to degrade endogenous preexisting membrane phospholipids as a source of phosphorus may be a general property of Gram-negative soil bacteria.