Cardiovascular risk factor profile on a population basis: Results from the Lipid Study Leipzig (LSL)

Population-based lipid screening studies were initiated in the city of Leipzig, Germany, and included more than 30,000 subjects. The objectives of the Lipid Study Leipzig (LSL) were to evaluate the cardiovascular risk factor profile and its dependence on age, nutrition and social factors. In addition, the study results were compared with those of other population-based studies, and the development of cardiovascular risk factors over a 10-year period was evaluated. LSL data were obtained from subjects recruited at community centres, work sites, schools and the University of Leipzig, Germany. Capillary blood cholesterol and high-density lipoprotein-cholesterol levels were measured using the Reflotron dry-chemistry system (Roche Diagnostics, Germany). Study data also included blood pressure, body mass index, waist-to-hip ratio, and the evaluation of dietary and lifestyle factors. The results of LSL show an age-dependent increase in cardiovascular risk, which may have been partly preventable. Furthermore, LSL showed an improvement in cardiovascular risk, with respect to plasma cholesterol, over the past 10 years in men and women older than 30 and 50 years, respectively. The known age dependence of total cholesterol and non-high-density lipoprotein-cholesterol is less pronounced for those following a healthy lifestyle and for vegetarians. This suggests that the age-dependent rise of these parameters is partly preventable.     

Improved anticancer delivery of paclitaxel by albumin surface modification of PLGA nanoparticles

Background

Nanoparticles (NPs) play an important role in anticancer delivery systems. Surface modified NPs with hydrophilic polymers such as human serum albumin (HSA) have long half-life in the blood circulation system.

Methods

The method of modified nanoprecipitation was utilized for encapsulation of paclitaxel (PTX) in poly (lactic-co-glycolic acid) (PLGA). Para-maleimide benzoic hydrazide was conjugated to PLGA for the surface modifications of PLGA NPs, and then HSA was attached on the surface of prepared NPs by maleimide attachment to thiol groups (cysteines) of albumin. The application of HSA provides for the longer blood circulation of stealth NPs due to their escape from reticuloendothelial system (RES). Then the physicochemical properties of NPs like surface morphology, size, zeta potential, and in-vitro drug release were analyzed.

Results

The particle size of NPs ranged from 170 to 190 nm and increased about 20–30 nm after HSA conjugation. The zeta potential was about -6 mV and it decreased further after HSA conjugation. The HSA conjugation in prepared NPs was proved by Fourier transform infrared (FT-IR) spectroscopy, faster degradation of HSA in Differential scanning calorimetry (DSC) characterization, and other evidences such as the increasing in size and the decreasing in zeta potential. The PTX released in a biphasic mode for all colloidal suspensions. A sustained release profile for approximately 33 days was detected after a burst effect of the loaded drug. The in vitro cytotoxicity evaluation also indicated that the HSA NPs are more cytotoxic than plain NPs.

Conclusions

HSA decoration of PLGA NPs may be a suitable method for longer blood circulation of NPs.     

A system dynamics model for national drug policy

Background

Data modeling techniques can create a virtual world to analyze decision systems. National drug authorities can use such techniques to take care of their deficiencies in decision making processes. This study was designed to build a system dynamics model to simulate the effects of market mix variables (5 P’s) on the national drug policy (NDP) indicators including availability, affordability, quality, and rationality. This was aimed to investigate how to increase the rationality of decision making, evaluate different alternatives, reduce the costs and identify the system obstacles.System dynamics is a computer-based approach for analyzing and designing complex systems over time. In this study the cognitive casualty map was developed to make a concept about the system then the stock-flow model was set up based on the market demand and supply concept.

Results

The model demonstrates the interdependencies between the NDP variables through four cognitive maps. Some issues in availability, willingness to pay, rational use and quality of medicines are pointed in the model. The stock-flow diagram shows how the demand for a medicine is formed and how it is responded through NDP objectives. The effects of changing variables on the other NDP variables can be studied after running the stock-flow model.

Conclusion

The model can initiate a fundamental structure for analyzing NDP. The conceptual model made a cognitive map to show many causes’ and effects’ trees and reveals some relations between NDP variables that are usually forgotten in the medicines affairs. The model also provides an opportunity to be expanded with more details on a specific disease for better policy making about medication.     

Zinc Protoporphyrin Polymeric Nanoparticles: Potent Heme Oxygenase Inhibitor for Cancer Therapy

Purpose

Oxidation therapy is an antitumor strategy in which, apoptosis or necrosis is caused by either excess delivery of reactive oxygen species (ROS) as an oxidant or anti-oxidant inhibition. Heme oxygenase (HO) is an anti-oxidant enzyme that plays an important role in cell growth and proliferation. The purpose of this study was to prepare poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with zinc protoporphyrin (ZnPP) to deliver the HO inhibitor into tumor.

Methods

PLGA NPs were prepared using nanoprecipitation technique and their characteristics were optimized by Box-Behnken experimental design. Scanning electron microscopy and in vitro studies consisting of drug release, HO inhibitory effect, cytotoxicity and cellular uptake followed by in vivo biodistribution and blood cytotoxicity were carried out. Internalization of coumerin-6 loaded NPs by PC3 cells was visualized by confocal laser scanning microscopy beside quantitatively analysis.

Results

NPs average size, entrapment efficiency and drug loading were 100.12?±?5.345 nm, 55.6%?±?2.49 and 7.98%?±?0.341 respectively. Equal HO inhibitory effect of NPs compared to free ZnPP was observed. The IC₅₀ value of ZnPP-NPs for PC3 human prostate cancer cells was found to be 2.14?±?0.083 μM.

Conclusion

In conclusion, ZnPP loaded PLGA NPs could exhibit enough HO inhibitory effect against cancer cells to be considered as a promising candidate for cancer treatment investigation.     

Cationic Albumin‐Conjugated Chelating Agent as a Novel Brain Drug Delivery System in Neurodegeneration

The critical role of metal ions and in particular iron in oxidative stress and protein aggregation offers chelation therapy as a sensible pharmaceutical strategy in oxidative stress‐induced neuronal damages. In this research, we conjugated an iron‐chelating agent, deferasirox, to cationized human serum albumin molecules in order to develop a novel brain delivery system for the management of neurodegenerative disorders due to the significant role of oxidative stress‐induced neuronal injury in such diseases. Cationized albumin is known to be able to transport to brain tissue via adsorptive‐mediated transcytosis. The developed structures were molecularly characterized, and their conjugation ratio was determined. PC12 cell line was utilized to evaluate the neuroprotective features of these newly developed molecules in the presence of hydrogen peroxide neuronal damage and to identify the mechanisms behind the observed neuronal protection including apoptotic and autophagic pathways. Furthermore, a rat model of Alzheimer's disease was utilized to evaluate the impact of conjugated structures in vivo. Data analysis revealed that the conjugated species were able to hinder apoptotic cell death while enhancing autophagic process. The developed conjugated species were also able to attenuate amyloid beta‐induced learning deficits when administered peripherally.     

CD44‐Targeted Docetaxel Conjugate for Cancer Cells and Cancer Stem‐Like Cells: A Novel Hyaluronic Acid‐Based Drug Delivery System

A CD44‐targeted macromolecular conjugate of docetaxel was prepared via a pH‐sensitive linkage to hyaluronic acid and was characterized using NMR, gel permeation chromatography, and differential scanning calorimetry. The conjugated species were further evaluated in terms of drug release, cytotoxicity, cellular uptake, cell cycle inhibition, and subacute toxicity in mice. Cellular microscopic studies revealed that CD44‐expressing cells including MCF‐7 cancer stem cells and MDA‐MB‐231 metastatic breast cancer cells had internalized the conjugates via a selective receptor‐mediated mechanism, leading to cell cycle arrest in the G2/M phase. Hyaluronic acid–docetaxel conjugates showed specific toxicity only in CD44‐expressing cells in vitro, along with a decreased risk of neutropenia and dose‐dependent mortality in vivo. Hyaluronic acid–drug conjugates represent a promising and efficient platform for solubilization of sparingly soluble molecules as well as active and selective targeted delivery to cancer cells and cancer stem cells.     

Age-dependence of lipid parameters in the general population and vegetarians

Age-dependent changes of lipid metabolism may arise both as a result of mechanisms of biological ageing and factors influencing age-dependent changes. To study possible influences of nutrition and life-style of vegetarians on age-dependence of lipid parameters, subjects of general population were compared with vegetarians. In the frame of population-based lipid screening projects in the city of Leipzig/Germany (Lipid Study Leipzig, LSL) 10 550 subjects (3,816 men and 6,734 women, age 18-99 years) of general population were compared with 417 vegetarians (vegans, lacto-vegetarians, lacto-ovo-vegetarians, 148 men and 269 women, age 18-93 years). Most of the vegetarians included in the study were members of the German Society of Vegetarians. The study program included capillary blood cholesterol measurements and the determination of high-density lipoprotein (HDL)-cholesterol, the measurement of other cardiovascular risk factors and the evaluation of dietary and life-style factors. Evaluation of cardiovascular risk profile within LSL was connected with individual consultation.The mean total cholesterol and non-HDL-cholesterol level and the total: HDL-cholesterol ratio showed the expected age-dependence, with maximum values within the decade 60-70 years. Vegetarians showed lower total and non-HDL-cholesterol levels in comparison with the general population. Furthermore, the age-dependent increase of these parameters is less pronounced under the conditions of vegetarian nutrition and life-style. Especially in young adulthood a significant difference is observed. Thus, the results of the present study reveal the role of nutritional and life-style factors that determine the lipid profile on a population basis and suggest that the known age-dependent rise of the level of atherogenic plasma lipoproteins is partly preventable.     

Effect of fatty acids on expression of endothelial leukocyte adhesion molecules

Summary.Background: With respect to linoleic acid both beneficial and proatherogenic effects have been described. However, the effect on expression of cell adhesion molecules on human coronary artery endothelial cells (HCAEC) is not yet established. The aim of the experiments was to evaluate the influence of linoleic acid in comparison with palmitic acid regarding the cytokine-induced expression of endothelial leukocyte adhesion molecules (intercellular cell adhesion molecule-1 ICAM-1, vascular cell adhesion molecule-1 VCAM-1, E-selectin).Methods: HCAEC were cultured in microvascular endothelial cell growth medium. In the experiments, the cells were preincubated with linoleic acid and palmitic acid, respectively (10 µmol/l, 2 days) or under control conditions, after which interleukin- 1 (IL-1, 10 ng/ml in the test medium) was added for 1 day. The monoclonal antibodies used were fluorescein isothiocyanate (FITC)- labeled anti-ICAM-1, FITC-labeled anti-VCAM-1, and FITC-labeled anti-E-selectin. Expression was analyzed by flow cytofluorimetry. Next, to examine the effects of fatty acids on adhesion of monocytes to endothelial cells, adhesion experiments with the monocytic U 937 cell line were performed.Results and conclusions: IL-1 increased ICAM-1,VCAM-1, and E-selectin expression compared to controls. Incubation with IL-1 together with linoleic acid reduced the expression of ICAM-1 and VCAM-1 in contrast to palmitic acid. Furthermore, in the presence of linoleic acid a tendency of diminished adhesion of monocytes is seen.The results indicate that a reduced expression of cell adhesion molecules may be relevant to the antiatherogenic effects of linoleic acid. This is in contrast to the properties of palmitic acid.     

The total and HDL-cholesterol levels in populations of St. Petersburg (Russia) and Leipzig (Germany)

BACKGROUND AND AIM: In the early 90s an increase in coronary heart disease (CHD) mortality in post-communist countries was observed. Based on the lipid theory of the pathogenesis of atherosclerosis, we looked to see whether these changes were accompanied by changes in blood lipid profiles and how lipid levels are related in a post-communist country with a relatively high standard of living (East Germany) and a country still facing economic troubles (Russia). METHODS AND RESULTS: This investigation was conducted in 1995-1997 by a cooperative program between the Department of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Leipzig, Germany and the Department of Biochemistry, Institute for Experimental Medicine, St. Petersburg, Russia. The Russian part of the study included 1646 subjects and the German part 3189 subjects. The blood lipids were measured using a dry-chemistry analyzer (Reflotron). Russian and German males had almost the same level of total cholesterol with a significantly lower level of HDL-C in Russians. A significantly lower level of HDL-C was also observed in Russian females. Differences were in range 2-3 mg/dl for males and 8-13 mg/dl for females. In St. Petersburg, almost 40% of all screened young males (age < 30 yr) had hypoalphacholesterolemia. In the St. Petersburg study carried out in 1986-1988, in age group 40-49 years around 6% of those screened had HDL-C lower than 35 mg/dl. In 1995-1997 this number increased to 36%. The number of subjects with HDL-C less than 30 mg/dl in 1986-1988 was only 2.4% and in 1995-1997, 12.3%. CONCLUSION: There is a dramatic decrease in HDL-C in the Russian population, probably due to the socioeconomic factors which began to develop after the fall of communist.