Clinical evaluation of Deferasirox for removal of cadmium ions in rat

An investigation was conducted to evaluate the ability of Deferasirox (ICL670 or Exjade) following the distribution of cadmium salt in male Wistar rats. Cadmium was introduced to several groups of weanling male Wistar rats through different means, by act of drinking, feeding. A control group was fed on a diet containing normal level of iron. After a period of 30 days, all the rats administered cadmium were severely anemic and showed toxicity symptoms through loss of hair and increasing in cadmium and reduction in iron levels in blood. Chelation therapy was carried out to remove the toxic element from the body. The ability of Deferasirox chelator in removing cadmium was investigated this chelator for 1 week to the remaining rats of similar groups. The results showed that the cadmium level present in blood was significantly reduced and at the same time, iron concentration returned to the normal level. It was concluded that Deferasirox chelator is able to remove cadmium from the body and could be used for the treatment of complications and eradication of symptoms of cadmium intoxication.     

EVEREST: automatic identification and classification of protein domains in all protein sequences

Background  

Proteins are comprised of one or several building blocks, known as domains. Such domains can be classified into families according to their evolutionary origin. Whereas sequencing technologies have advanced immensely in recent years, there are no matching computational methodologies for large-scale determination of protein domains and their boundaries. We provide and rigorously evaluate a novel set of domain families that is automatically generated from sequence data. Our domain family identification process, called EVEREST (EVolutionary Ensembles of REcurrent SegmenTs), begins by constructing a library of protein segments that emerge in an all vs. all pairwise sequence comparison. It then proceeds to cluster these segments into putative domain families. The selection of the best putative families is done using machine learning techniques. A statistical model is then created for each of the chosen families. This procedure is then iterated: the aforementioned statistical models are used to scan all protein sequences, to recreate a library of segments and to cluster them again.     

A new Bacillus pasteurii urease inhibitor from Euphorbia decipiens

Inhibition of Bacillus pasteurii urease enzyme by 3,7,15-tri-O-acetyl-5-O-nicotinoyl-13,14-dihydroxymyrsinol (1), a diterpene ester with a myrsinol-type skeleton, isolated from Euphorbia decipiens Boiss. and Buhse, was un-competitive consistent with the molecular docking results. The Ki value was 117.40 +/- 0.7 microM.     

Identifying functionally important conformational changes in proteins: activation of the yeast α-factor receptor Ste2p

We have developed a procedure in which disulfide cross-links are used to identify regions of proteins that undergo functionally important intramolecular motion. The approach was applied to the identification of disulfide bonds that stabilize the active state of the yeast α-mating pheromone receptor Ste2p, a member of the superfamily of G protein-coupled receptors. Cysteine residues were introduced at random positions in targeted regions of a starting allele of Ste2p that completely lacks cysteines. Libraries of mutated receptors were then screened for alleles that exhibit constitutive signaling. Two strongly activated alleles were recovered containing cysteine residues in transmembrane (TM) segments 5 and 6. Constitutive activity of these alleles was dependent on the presence of both introduced cysteines and was sensitive to reducing agent. Cross-linked peptides derived from the mutant receptors were detected by immunoblotting. Additional sites of cross-linking between TM segments 5 and 6 that did not lead to constitutive activation were also identified. These results indicate that relative motion of the TM segments 5 and 6 in the extracellular half of the membrane is sufficient to activate the receptor and that TM segment 6, but not TM segment 5, exhibits rotational mobility that is not associated with receptor activation.     

Red blood cell lysate modulates the expression of extracellular matrix proteins in dermal fibroblasts

Trichinella spiralis is a zoonotic nematode and food borne parasite and infection with T. spiralis leads to suppression of the host immune response and other immunopathologies. The excretory/secretory (ES) products of T. spiralis play important roles in the process of immunomodulation. However, the mechanisms and related molecules are unknown. Macrophages, a target for immunomodulation by the helminth parasite, play a critical role in initiating and modulating the host immune response to parasite infection. In this study, we examined the effect of ES products from different stages of T. spiralis on modulating J774A.1 macrophage activities. ES products from different stages of T. spiralis reduced the capacity of macrophages to express pro-inflammatory cytokines (tumor necrosis factor α, interleukin-1β , interleukin-6 , and interleukin-12) in response to lipopolysaccharide (LPS) challenge. However, only ES products from 3-day-old adult worms and 5-day-old adult worms/new-born larvae significantly inhibited inducible nitric oxide synthase gene expression in LPS-induced macrophages. In addition, ES products alone boosted the expression of anti-inflammatory cytokines interleukin-10 and transforming growth factor-β and effector molecule arginase 1 in J774A.1 macrophages. Signal transduction studies showed that ES products significantly inhibited nuclear factor-κB translocation into the nucleus and the phosphorylation of both extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase in LPS-stimulated J774A.1 macrophages. These results suggest that ES products regulate host immune response at the macrophage level through inhibition of pro-inflammatory cytokines production and induction of macrophage toward the alternative phenotype, which maybe important for worm survival and host health.     

Cytokine gene polymorphism and asthma susceptibility, progress and control level

Asthma is a multifactor inflammatory disorder, and its management requires understanding of its various pathogenesis and control mechanisms. Cytokines and other inflammatory mediators are important factors in asthma pathophysiology. In this study, we evaluated the role of cytokine polymorphisms in the asthma susceptibility, progress, control, and lung functions. IL-4-C590T polymorphism by PCR-RFLP method, IFN-γ T+874A, TNF-α-A308G, IL-6 G−174C and TGF-β T+869C variants by ARMS-PCR method and IgE serum level by ELISA technique were determined in 81 asthmatic patients and 124 normal subjects. Asthma diagnosis, treatment and control levels were considered using standard schemes and criteria. TNF-α−308GA genotype was more frequent in asthmatics (P = 0.025, OR 3.352), and polymorphisms between different asthma control levels (P > 0.05) were not different. IFN-γ+874AT genotype had a positive correlation with the familial history of asthma (P = 0.034, OR 2.688). IL-6−174C allele (P = 0.045), TNF-α−308GG genotype (P = 0.002) and TNF-α−308G allele (P = 0.004) showed reduced values, and TNF-α−308GA genotype (P = 0.002) increased FEF25-75 value in asthmatics. IFN-γ+874AA genotype caused a decrease in FVC factor (P = 0.045). This study showed that TNF-α−308GA is a risk factor for asthma, but cytokine gene variants do not affect asthma control and IgE serum levels. Variants producing lower levels of IL-6, TNF-α and IFN-γ are associated with reduced pulmonary capacities. To achieve an appropriate schema for asthma management, further studies with consideration of different aspects in a larger group of patients would be more elucidative.     

Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats

Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.     

Energy-based stochastic control of neural mass models suggests time-varying effective connectivity in the resting state

Several studies posit energy as a constraint on the coding and processing of information in the brain due to the high cost of resting and evoked cortical activity. This suggestion has been addressed theoretically with models of a single neuron and two coupled neurons. Neural mass models (NMMs) address mean-field based modeling of the activity and interactions between populations of neurons rather than a few neurons. NMMs have been widely employed for studying the generation of EEG rhythms, and more recently as frameworks for integrated models of neurophysiology and functional MRI (fMRI) responses. To date, the consequences of energy constraints on the activity and interactions of ensembles of neurons have not been addressed. Here we aim to study the impact of constraining energy consumption during the resting-state on NMM parameters. To this end, we first linearized the model, then used stochastic control theory by introducing a quadratic cost function, which transforms the NMM into a stochastic linear quadratic regulator (LQR). Solving the LQR problem introduces a regime in which the NMM parameters, specifically the effective connectivities between neuronal populations, must vary with time. This is in contrast to current NMMs, which assume a constant parameter set for a given condition or task. We further simulated energy-constrained stochastic control of a specific NMM, the Wilson and Cowan model of two coupled neuronal populations, one of which is excitatory and the other inhibitory. These simulations demonstrate that with varying weights of the energy-cost function, the NMM parameters show different time-varying behavior. We conclude that constraining NMMs according to energy consumption may create more realistic models. We further propose to employ linear NMMs with time-varying parameters as an alternative to traditional nonlinear NMMs with constant parameters.