Tomato lycopene is a natural antioxidant and can alleviate hypercholesterolemia

Lycopene of tomato wastes was extracted and determination. The level of tomato lycopene was 145.50 ppm. An aliquots of the concentrated tomato lycopene, represent 100, 200, 400 and 800 ppm; grade lycopene (200 ppm) and butylated hydroxyl toluene (BHT, 200 ppm) were investigated by the 1,1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging method. These compounds were administered to rats fed on hypercholestrolemic diet daily form 10 weeks by stomach tube. Serum lipid contents (total lipids, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol), oxidative biomarkers (glutathione peroxidase and malonaldhyde), the liver (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities) and kidney (uric acid, urea and creatinine) function testes were measured to assess the safety limits of the lycopene in tomato wastes. The data of the aforementioned measurements indicated that the administration oftomato lycopene did not cause any changes in liver and kidney functions. On the contrary, rats fed on hyperchoestrolemic diet induced significant increases in the enzyme activities and the serum levels of total lipids, total cholesterol, low and high density lipoprotein and decreased levels of the glutathione peroxidase and malonaldhyde

Effect of Smoking on Pharmacokinetics of Clopidogrel, an Antiplatelet Drug

Purpose: To assess the influence of smoking cigarettes on the pharmacokinetics of the antiplatelet drug, clopidogrel.Methods: Thirty four male patients, mean age and weight of 59.3 years and 81.1 kg, respectively, who underwent percutaneous coronary intervention (PCI), took part in the study. Each subject received an oral loading dose of 600 mg clopidogrel eight tablets, each 75 mg). Clopidogrel carboxylate plasma level was measured and non-compartmental analysis was used to determine peak plasma concentration (Cmax), time to achieve peak plasma concentration (Tmax), elimination half-life (t1/2e), and area under the curve (AUC0-∞). Other parameters measured include gamma-glutamyltransferase enzyme (GGT), low density lipoprotein cholesterol (LDL-cholesterol), blood urea nitrogen (BUN) and platelet count.Results: Nineteen patients were smokers (55.9 %). Smokers had higher levels of GGT compared to non-smokers (31.73 ± 14.42 vs. 21.63 ± 11.41 IU/L, p = 0.08) as well as higher levels of LDL-cholesterol (116.79 ± 42.08 vs. 87.07 ± 27.34 mg/dl, p = 0.041, respectively). Smokers had shorter half-life (smokers: 3.47 ± 1.9 h vs. non-smokers: 5.83 ± 4.09 h, p = 0.012). Smoking behavior had no influence on Cmax (p = 0.16), AUC0-∞ (p = 0.65) or Tmax (p = 0.91). In general, the pharmacokinetic parameters were characterized by considerable inter-individual variation (Cmax = 23.2 ± 8.79 μg/ml, coefficient of variation (CV) = 37.9 %), (Tmax = 1.71 ± 1.15 h, CV = 67.2 %), (AUC0-∞ = 120.97 ± 44.4 μg.h/ml, CV = 36.7 %) and (t1/2e = 4.57 ± 3.15 h, CV = 68.9 %).Conclusion: Smoking behavior may not be a significant determinant of the pharmacokinetics of clopidogrel following oral administration of 600 mg dose in patients undergoing PCI.Keywords: Antiplatelet, Clopidogrel, Pharmacokinetics, Smoking, Cigarett

Survivin a radiogenetic promoter for glioblastoma viral gene therapy independently from CArG motifs

BACKGROUND: Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. AIM: To select a potent radiation inducible promoter in the context of brain tumors and to investigate if CArG radio responsive motifs or other elements in the promoter nucleotide sequences can correlate to its response to radiation. METHODS: To select initial candidates for promoter inducible elements, the levels of mRNA expression of six different promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by five different promoters; CMV, VEGF, FLT-1, DR5 and survivin were constructed. Glioma cell lines were infected with different multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0–12 Gy) at single fraction. Fluorescent microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. Different glioma cell lines and normal astrocytes were infected with Ad survivin and exposed to radiation. The promoters were analyzed for presence of CArG radio-responsive motifs and CCAAT box consensus using NCBI blast bioinformatics software. RESULTS: Radiotherapy increases the expression of gene expression by 1.25–2.5 fold in different promoters other than survivin after 2 h of radiation. RNA analysis was done and has shown an increase in copy number of tenfold for survivin. Most importantly cells treated with RT and Ad Luc driven by survivin promoter showed a fivefold increase in expression after 2 Gy of radiation in comparison to non-irradiated cells. Presence or absence of CArG motifs did not correlate with promoter response to radiation. Survivin with the best response to radiation had the lowest number of CCAAT box. CONCLUSION: Survivin is a selective potent radiation inducible promoter for glioblastoma viral gene therapy and this response to radiation could be independent of CArG motifs

Small Molecule Glycomimetics Inhibit Vascular Calcification via c-Met/Notch3/HES1 Signalling

© Copyright by the Author(s). Published by Cell Physiol Biochem Press. BACKGROUND/AIMS: Vascular calcification represents a huge clinical problem contributing to adverse cardiovascular events, with no effective treatment currently available. Upregulation of hepatocyte growth factor has been linked with vascular calcification, and thus, represent a potential target in the development of a novel therapeutic strategy. Glycomimetics have been shown to interrupt HGF-receptor signalling, therefore this study investigated the effect of novel glycomimetics on osteogenic signalling and vascular calcification in vitro. METHODS: Primary human vascular smooth muscle cells (HVSMCs) were induced by β-glycerophosphate (β-GP) and treated with 4 glycomimetic compounds (C1-C4). The effect of β-GP and C1-C4 on alkaline phosphatase (ALP), osteogenic markers and c-Met/Notch3/HES1 signalling was determined using colorimetric assays, qRT-PCR and western blotting respectively. RESULTS: C1-C4 significantly attenuated β-GP-induced calcification, as shown by Alizarin Red S staining and calcium content by day 14. In addition, C1-C4 reduced ALP activity and prevented upregulation of the osteogenic markers, BMP-2, Runx2, Msx2 and OPN. Furthermore, β-GP increased c-Met phosphorylation at day 21, an effect ameliorated by C2 and C4 and the c-Met inhibitor, crizotinib. We next interrogated the effects of the Notch inhibitor DAPT and confirmed an inhibition of β-GP up-regulated Notch3 protein by C2, DAPT and crizotinib compared to controls. Hes-1 protein upregulation by β-GP, was also significantly downregulated by C2 and DAPT. GOLD docking analysis identified a potential binding interaction of C1-C4 to HGF which will be investigated further. CONCLUSION: These findings demonstrate that glycomimetics have potent anti-calcification properties acting via HGF/c-Met and Notch signalling

Bioadhesive Controlled Metronidazole Release Matrix Based on Chitosan and Xanthan Gum

Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole Cmax and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole

Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases IGF-I bioactivity similarly

Aims/hypothesis The aim of this study was to compare IGFI bioactivity 36 weeks after the addition of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) or NPH insulin to metformin therapy in type 2 diabetic patients who had poor glucose control under metformin monotherapy. Methods In the Lantus plus Metformin (LANMET) study, 110 poorly controlled insulin-naive type 2 diabetic patients were randomised to receive metformin with either insulin glargine (G+MET) or NPH insulin (NPH+MET). In the present study, IGF-I bioactivity was measured, retrospectively, in 104 out of the 110 initially included LANMET participants before and after 36 weeks of insulin therapy. IGF-I bioactivity was measured using an IGF-I kinase receptor activation assay. Results After 36 weeks of insulin therapy, insulin doses were comparable between the G+MET (68±5.7 U/day) and NPH+MET (71±6.2 U/day) groups (p=0.68). Before insulin therapy, circulating IGF-I bioactivity was similar between the G+MET (134±9 pmol/l) and NPH+MET (135 ±10 pmol/l) groups (p=0.83). After 36 weeks, IGF-I bioactivity had decreased significantly (p=0.001) and did not differ between the G+MET (116±9 pmol/l) and NPH+MET (117± 10 pmol/l) groups (p=0.91). At baseline and after insulin therapy, total IGF-I concentrations were comparable in both groups (baseline: G+MET 13.3±1.0 vs NPH+MET 13.3± 1.0 nmol/l, p=0.97; and 36 weeks: 13.4±1.0 vs 13.1± 0.9 nmol/l, p=0.71). Total IGF-I concentration did not change during insulin therapy (13.3±0.7 vs 13.3±0.7 nmol/l, baseline vs 36 weeks, p=0.86). Conclusions/interpretation Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled type 2 diabetic patients decreases serum IGF-I bioactivity in a similar manner

Periodic trends and easy estimation of relative stabilities in 11-vertex nido-p-block-heteroboranes and -borates

Density functional theory computations were carried out for 11-vertex nido-p-block-hetero(carba)boranes and -borates containing silicon, germanium, tin, arsenic, antimony, sulfur, selenium and tellurium heteroatoms. A set of quantitative values called “estimated energy penalties” was derived by comparing the energies of two reference structures that differ with respect to one structural feature only. These energy penalties behave additively, i.e., they allow us to reproduce the DFT-computed relative stabilities of 11-vertex nido-heteroboranes in general with good accuracy and to predict the thermodynamic stabilities of unknown structures easily. Energy penalties for neighboring heteroatoms (HetHet and HetHet′) decrease down the group and increase along the period (indirectly proportional to covalent radii). Energy penalties for a five- rather than four-coordinate heteroatom, [Het5k(1) and Het5k(2)], generally, increase down group 14 but decrease down group 16, while there are mixed trends for group 15 heteroatoms. The sum of HetHet′ energy penalties results in different but easily predictable open-face heteroatom positions in the thermodynamically most stable mixed heterocarbaboranes and -borates with more than two heteroatoms