In vivo effects of curcumin on the paraoxonase,carbonic anhydrase,glucose-6-phosphate dehydrogenase and β-glucosidase enzyme activities in dextran sulphate sodium-induced ulcerative colitis mice

Increases in the risk of infections and malignancy due to immune suppressive therapies of inflammatory bowel diseases (IBDs) have led the researchers to focus on more nontoxic and acceptable natural products like curcumin. Here we investigate whether prophylactic and therapeutic application of the curcumin alters the enzyme activities of paraoxonase (PON), carbonic anhydrase (CA), glucose-6-phosphate dehydrogenase (G6PD) and cytosolic β-glucosidase in dextran sulphate sodium (DSS)-induced ulcerative colitis mice. Prophylactic application of curcumin resulted in higher MPO activity, less body weight loss and longer colon lengths compared to therapeutic group indicating preventive role of curcumin in IBDs. DSS-induced decrease in liver and serum PON activities were completely recovered by prophylactic administration of curcumin. DSS-induced reduction in liver cytosolic β-glucosidase activity was not affected by curcumin neither in the prophylactic group nor in the therapeutic group. Erythrocyte CA activity was significantly increased in curcumin groups, however no remarkable change in G6PD activity was observed.     

Combination treatment optimization using a pan-cancer pathway model

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available.     

Mutation of active site residues Asn67 to Ile, Gln92 to Val and Leu204 to Ser in human carbonic anhydrase II: influences on the catalytic activity and affinity for inhibitors

Site-directed mutagenesis has been used to change three amino acid residues involved in the binding of inhibitors (Asn67Ile; Gln92Val and Leu204Ser) within the active site of human carbonic anhydrase (CA, EC 4.2.1.1) II (hCA II). Residues 67, 92 and 204 were changed from hydrophobic to hydrophilic ones, and vice versa. The Asn67Ile and Leu204Ser mutants showed similar k(cat)/K(M) values compared to the wild type (wt) enzyme, whereas the Gln92Val mutant was around 30% less active as a catalyst for CO(2) hydration to bicarbonate compared to the wt protein. Affinity for sulfonamides/sulfamates was decreased in all three mutants compared to wt hCA II. The effect was stronger for the Asn67Ile mutant (the closest residue to the zinc ion), followed by the Gln92Val mutant (residue situated in the middle of the active site) and weakest for the Leu204Ser mutant, an amino acid situated far away from the catalytic metal ion, at the entrance of the cavity. This study shows that small perturbations within the active site architecture have influences on the catalytic efficiency but dramatically change affinity for inhibitors among the CA enzymes, especially when the mutated amino acid residues are nearby the catalytic metal ion.     

Metabolic effects of estrogen substitution in combination with targeted exercise training on the therapy of obesity in ovariectomized Wistar rats

Postmenopausal women tend to have a higher risk in developing obesity and thus metabolic syndrome. Recently we could demonstrate that physical activity and estrogen replacement are effective strategies to prevent the development of nutritional induced obesity in an animal model. The aim of this study was to determine the combined effects of estrogen treatment and exercise training on already established obesity. Therefore ovariectomized (OVX) and sham-operated (SHAM) female Wistar rats were exposed to a high fat diet for ten months. After this induction period obese SHAM and OVX rats either remained sedentary or performed treadmill training for six weeks. In addition OVX rats were treated with 17β-Estradiol (E(2)) alone, or in combination with training. Before and after intervention effects on lipid and glucose metabolism were investigated. Training resulted in SHAM and OVX rats in a significant decrease of body weight, subcutaneous and visceral body fat, size of adipocytes and the serum levels of leptin, cholesterol, low-density lipoprotein and triglycerides. In OVX animals E(2) treatment resulted in similar effects. Often the combination of E(2) treatment and training was most effective. Analysis of the respiratory quotient indicates that SHAM animals had a better fat burning capacity than OVX rats. There was a tendency that training in SHAM animals and E(2) treatment in OVX animals could improve this capacity. Analysis of glucose metabolism revealed that obese SHAM animals had higher glucose tolerance than OVX animals. Training improved glucose tolerance in SHAM and OVX rats, E(2) treatment in OVX rats. The combination of both was most effective. Our results indicate that even after a short intervention period of six weeks E(2) treatment and exercise training improve parameters related to lipid as well as glucose metabolism and energy expenditure in a model of already established obesity. In conclusion a combination of hormone replacement therapy and exercise training could be a very effective strategy to encourage the therapy of diet-induced obesity and its metabolic consequences in postmenopausal women.     

Serum and parotid saliva testosterone,calcium, magnesium,and zinc levels in males,with and without periodontitis

Fourteen male patients with periodontitis and 10 patients free of periodontitis were included in the study. The concentrations of testosterone (T), calcium (Ca), magnesium (Mg), and zinc (Zn) were measured in serum and parotid saliva. Patients with periodontitis had increased Ca and decreased Zn serum levels, and they had decreased Ca and increased T levels in parotid saliva. Furthermore, there was a low correlation between parotid saliva T and Mg levels in the patients with periodontitis (r = 0.61, n = 14, t = 2.663, p less than 0.005), and there is an inverse relationship between serum and parotid saliva Mg levels (r = - 0.58, n = 14, t = 2.468, p less than 0.05).     

Silane-modified magnetic beads: application to immunoglobulin G separation

The magnetic poly(2-hydroxyethyl methacrylate ethylene glycol dimethacrylate) [m-poly(HEMA-EGDMA)] beads (150-250-microm diameter in spherical form) were prepared by a radical suspension polymerization technique. The pseudo-specific ligand, reactive imidazole containing 3-(2-imidazoline-1-yl)propyl (triethoxysilane) (IMEO) was selected as a silanization agent. IMEO was covalently immobilized onto the magnetic beads. IMEO-immobilized m-poly(HEMA-EGDMA) beads were used for the affinity adsorption of immunoglobulin-G (IgG) from aqueous solutions and human plasma. To evaluate the degree of IMEO attachment, the m-poly(HEMA-EGDMA) beads were subjected to Si analysis by using flame atomizer atomic absorption spectrometer, and it was estimated as 36.6 mg IMEO/g of polymer. The nonspecific IgG adsorption onto the plain m-poly(HEMA-EGDMA) beads was very low (about 0.4 mg/g). Higher adsorption values (up to 55 mg/g) were obtained when the m-poly(HEMA-EGDMA)/IMEO beads were used from both aqueous solutions and human plasma. The maximum IgG adsorption on the m-poly(HEMA-EGDMA)-IMEO beads was observed at pH 7.0. The IgG molecules could be repeatedly adsorbed and desorbed with m-poly(HEMA-EGDMA)-IMEO beads without noticeable loss in the IgG adsorption capacity. The adsorption capacity from human plasma in magnetically stabilized fluidized bed decreased drastically from 78.9 to 19.6 mg/g with the increase of the flow rate from 0.2 to 3.5 mL/min.     

The Effects of Boron on Arsenic‐Induced Lipid Peroxidation and Antioxidant Status in Male and Female Rats

The aim of the present study was to investigate the possible protective effects of boron, an antioxidant agent, against arsenic‐induced oxidative stress in male and female rats. In total, 42 Wistar albino male and female rats were divided into three equal groups: The animals in the control group were given normal drinking water, the second group was given drinking water with 100 mg/L arsenic, and the third group was orally administered drinking water with 100 mg/kg boron together with arsenic. At the end of the 28‐day experiment, arsenic increased lipid peroxidation and damage in the tissues of rats. However, boron treatment reversed this arsenic‐induced lipid peroxidation and activities of antioxidant enzymes in rats. Moreover, boron exhibited a protective action against arsenic‐induced histopathological changes in the tissues of rats. In conclusion, boron was found to be effective in protecting rats against arsenic‐induced lipid peroxidation by enhancing antioxidant defense mechanisms.     

Selective separation of human serum albumin with copper(II) chelated poly(hydroxyethyl methacrylate) based nanoparticles

Poly(hydroxyethyl methacrylate) (PHEMA) nanoparticles with an average size of 300 nm in diameter and with a polydispersity index of 1.156 were produced by surfactant free emulsion polymerization. Specific surface area of the PHEMA nanoparticles was found to be 996 m²/g. Metal-chelating ligand 3-(2-imidazoline-1-yl)propyl(triethoxysilane) (IMEO) was covalently attached to the PHEMA nanoparticles. IMEO content was 0.97 mmol IEMO/g. The morphology and properties of these nanoparticles were characterized with scanning electron microscopy, Fourier transform infrared spectroscopy and atomic force microscopy. The Cu²⁺-chelated PHEMA–IMEO nanoparticles were used in the adsorption-elution studies of human serum albumin (HSA) in a batch system. Maximum HSA adsorption amount of the Cu²⁺ chelated nanoparticles was 680 mg HSA/g. The PHEMA–IMEO–Cu²⁺ nanoparticles exhibited a quite high adsorption capacity and fast adsorption rate due to their high specific surface area and the absence of internal diffusion resistance.