Effects of Choline and Magnesium Concurrent Supplementation on Coagulation and Lipid Profile in Patients with Type 2 Diabetes Mellitus: a Pilot Clinical Trial

Biological Trace Element Research - Metabolic failure is associated with dyslipidemia and coagulation which can result in a higher risk of cardiovascular disease (CVD) in type 2 diabetes mellitus...     

Enhanced lymph node retention of subcutaneously injected IgG1-PEG2000-liposomes through pentameric IgM antibody-mediated vesicular aggregation

An efficient strategy for enhancing the lymph node deposition of rapidly drained liposomes from the interstitial injection site is described. Subcutaneously injected small-sized immuno-poly(ethyleneglycol)-liposomes (immuno-PEG-liposomes), containing 10 mol% mPEG₃₅₀-phospholipid and 1 mol% PEG₂₀₀₀-phospholipid in their bilayer and where IgG1 is coupled to the distal end of PEG₂₀₀₀, not only drain rapidly from the interstitial spaces into the initial lymphatic system, but also accumulate efficiently among the lymph nodes draining the region when compared with non-PEG-bearing immunoliposomes where IgG is directly coupled to the phospholipid. Liposome deposition among the draining lymph nodes, however, was further enhanced dramatically following an adjacent subcutaneous injection of a pentameric IgM against the surface attached IgG molecules (IgM:IgG, 10:1) without compromising vesicle drainage from the interstitium. This is suggested to arise either as a result of formation of large immuno-aggregates within the lymphatic vessels with subsequent transport to and trapping among the regional lymph nodes and/or following IgM binding to Fc receptors of the lymph node sinus macrophages forming a platform for subsequent trapping of drained IgG-coupled liposomes. This lymph node targeting approach may be amenable for the design and surface engineering of any rapidly drained nanoparticulate system bearing peptides and proteins that can be aggregated with a desired monoclonal pentameric IgM.     

Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression

Atovaquone is an anti-malarial drug used in combination with proguanil (e.g. Malarone(TM)) for the curative and prophylactic treatment of malaria. Atovaquone, a 2-hydroxynaphthoquinone, is a competitive inhibitor of the quinol oxidation (Q(o)) site of the mitochondrial cytochrome bc(1) complex. Inhibition of this enzyme results in the collapse of the mitochondrial membrane potential, disruption of pyrimidine biosynthesis, and subsequent parasite death. Resistance to atovaquone in the field is associated with point mutations in the Q(o) pocket of cytochrome b, most notably near the conserved Pro(260)-Glu(261)-Trp(262)-Tyr(263) (PEWY) region in the ef loop). The effect of this mutation has been extensively studied in model organisms but hitherto not in the parasite itself. Here, we have performed a molecular and biochemical characterization of an atovaquone-resistant field isolate, TM902CB. Molecular analysis of this strain reveals the presence of the Y268S mutation in cytochrome b. The Y268S mutation is shown to confer a 270-fold shift of the inhibitory constant (K(i)) for atovaquone with a concomitant reduction in the V(max) of the bc(1) complex of ～40% and a 3-fold increase in the observed K(m) for decylubiquinol. Western blotting analyses reveal a reduced iron-sulfur protein content in Y268S bc(1) suggestive of a weakened interaction between this subunit and cytochrome b. Gene expression analysis of the TM902CB strain reveals higher levels of expression, compared with the 3D7 (atovaquone-sensitive) control strain in bc(1) and cytochrome c oxidase genes. It is hypothesized that the observed differential expression of these and other key genes offsets the fitness cost resulting from reduced bc(1) activity.     

Design of a heterosubtypic epitope-based peptide vaccine fused with hemokinin-1 against influenza viruses

Influenza viruses continue to emerge and re-emerge, posing new threats for public health. Control and treatment of influenza depends mainly on vaccination and chemoprophylaxis with approved antiviral drugs. Identification of specific epitopes derived from influenza viruses has significantly advanced the development of epitope-based vaccines. Here, we explore the idea of using HLA binding data to design an epitope-based vaccine that can elicit heterosubtypic T-cell responses against circulating H7N9, H5N1, and H9N2 subtypes. The hemokinin-1(HK-1) peptide sequence was used to induce immune responses against the influenza viruses. Five conserved high score cytotoxic T lymphocyte(CTL) epitopes restricted to HLA-A*0201-binding peptides within the hemagglutinin(HA) protein of the viruses were chosen, and two HA CTL/HK-1 chimera protein models designed. Using in silico analysis, which involves interferon epitope scanning, protein structure prediction, antigenic epitope determination, and model quality evaluation, chimeric proteins were designed. The applicability of one of these proteins as a heterosubtypic epitopebased vaccine candidate was analyzed.     

Chromium Supplementation Can Alleviate the Negative Effects of Heat Stress on Growth Performance,Carcass Traits,and Meat Lipid Oxidation of Broiler Chicks without Any Adverse Impacts on Blood Constituents

This study was conducted to determine the effects of dietary supplementation with Cr nicotinate and Cr chloride and their optimum inclusion rate on performance, carcass traits, meat oxidative stability, serum metabolites, hematological parameters, and liver chromium concentration in heat-stressed broilers. A total number of 420, 1-day-old male broiler chicks were randomly assigned to seven treatments with four replicates of 15 chicks. The dietary treatments consisted of the basal diet supplemented with 0 (control), 500, 1,000, and 1,500 μg/kg Cr in the form of Cr nicotinate and Cr chloride. Chicks were raised for 6 weeks in heat stress condition (33 ± 2°C). Supplements of organic and inorganic Cr particularly at 1,500 μg/kg incorporation increased feed consumption (P < 0.05) and body mass gain of broilers (P < 0.01). Cr supplementation increased carcass yield and decreased abdominal fat (P < 0.01). Supplementation of 1,500 μg/kg Cr nicotinate (P < 0.05) enhanced liver Cr concentration. Storage time increased lipid oxidation of meat (P < 0.01). Cr decreased lipid oxidation of breast and thigh muscles over 2 (P < 0.01) or 6 (P < 0.05) days of storage time. Birds fed 1,500 μg/kg Cr nicotinate, had lower concentration of serum glucose and triglyceride at 21 days (P < 0.05). Hematological parameters tested at 21 and 42 days, were not influenced. The results suggested that dietary Cr supplementation regardless of its source have a positive effect on productive, and carcass traits, also enhances oxidative stability of refrigerated meat in broilers reared under heat stress conditions.     

Effects of Cadmium,Copper, Lead,and Zinc Contamination on Metal Accumulation by Safflower and Wheat

Accumulation of heavy metals (HMs) in cultivated soils is a continuing environmental problem in many parts of the world. An increase in HM concentration can enhance uptake of toxic metals by crops and enter the human food chain. In this study, the uptake behavior of wheat and safflower was evaluated in a calcareous soil by using 12 undisturbed columns in which half were artificially contaminated. Heavy metals in the form of CdCl₂ (15 mg Cd kg^{? 1}), CuSO₄ (585 mg Cu kg^{? 1}), Pb(NO₃)₂ (117 mg Pb kg^{? 1}), and ZnCl₂ (1094 mg Zn kg^{? 1}) were sprayed on the soil surface and completely mixed in the top 10 cm. The background total concentrations of Cd, Cu, Pb and Zn were 1.6, 29.5, 17.5 and 61.2 mg kg^{? 1}, respectively. After metal application, half of the columns (3 contaminated and 3 uncontaminated) were sown with wheat (Triticum aestivum) and the other half with safflower (Carthamus tinctorious) and grown for 74 days until maturity. After harvesting, soil columns were cut into 10-cm sections and analyzed for HNO₃- and DTPA-extractable metal concentrations. Metal concentrations were also measured in different plant tissues. The results showed that artificial contamination of topsoil decreased the transpiration rate of wheat by 12% and that of safflower by 6%. In contaminated columns, Cd, Cu, Pb, and Zn accumulation in wheat shoot was greater by 8.0-, 1.9-, 3.0-, and 2.1-fold than the control, respectively. Accordingly, these numbers were 46.0-, 1.3-, 1.7-, and 1.6-fold in safflower shoot. Soil contamination with HMs resulted in a 55% decrease in shoot dry matter yield of wheat while it had no significant effect on shoot dry matter of safflower. The normalized water consumption for safflower was therefore not affected by metal contamination (≈ 13 mm H₂O g^{? 1} of dry weight for all safflower and uncontaminated wheat treatments), while contaminated wheat was much less water efficient at about 27 mm H₂O g^{? 1} dry weight. It was concluded that although artificial contamination had a negative effect on wheat growth, it did not affect safflower's normal growth and water efficiency.     

Structure–toxicity relationship of phenolic analogs as anti-melanoma agents: An enzyme directed prodrug approach

The aim of this study was to identify a phenolic prodrug compound that is minimally metabolized by rat liver microsomes, but yet could form quinone reactive intermediates in melanoma cells as a result of its bioactivation by tyrosinase. In current work, we investigated 24 phenolic compounds for their metabolism by tyrosinase, rat liver microsomes and their toxicity towards murine B16-F0 and human SK-MEL-28 melanoma cells. A linear correlation was found between toxicities of phenolic analogs towards SK-MEL-28 and B16-F0 melanoma cells, suggesting similar mechanisms of toxicity in both cell lines. 4-HEB was identified as the lead compound. 4-HEB (IC₅₀ 48 h, 75 μM) showed selective toxicity towards five melanocytic melanoma cell lines SK-MEL-28, SK-MEL-5, MeWo, B16-F0 and B16-F10, which express functional tyrosinase, compared to four non-melanoma cells lines SW-620, Saos-2, PC3 and BJ cells and two amelanotic SK-MEL-24, C32 cells, which do not express functional tyrosinase. 4-HEB caused significant intracellular GSH depletion, ROS formation, and showed significantly less toxicity to tyrosinase specific shRNA transfected SK-MEL-28 cells. Our findings suggest that presence of a phenolic group in 4-HEB is critical for its selective toxicity towards melanoma cells.     

Therapeutic potency of oncolytic virotherapy–induced cancer stem cells targeting in brain tumors,current status,and perspectives

Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease.