Lipogenesis, aging and hormonal regulation

Thyroid hormones stimulate hepatic synthesis of fatty acids, as well as the activities of lipogenic enzymes. According to the present study, an age-dependence factor is also partially present. In livers of 3- and 18-month-old rats of the Wistar strain, both the velocity of fatty acid synthesis and the activities of lipogenic enzymes were measured in dependence on thyroid function. An impaired stimulation of malic enzyme activity under the conditions of hyperthyreosis was found in the older animals. The rate of fatty acid synthesis was diminished in the group of 18-month-old rats, but there was no age-dependence in respect of the effect of a variation in thyroid status. In adipose tissue of older animals, the activities of lipogenic enzymes were lowered. In this tissue no effects of thyroid hormones in both young and old rats were observed.     

Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel

Background

Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues.

Methods

PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells.

Results

Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg).

Conclusion

In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.     

Bovine serum albumin-loaded pectinate beads as colonic peptide delivery system: preparation and in vitro characterization

Objective of this study was to prepare a drug delivery system for therapeutic peptides that are degraded in the upper part of the gastrointestinal tract due to degradation activity of the enzymes. Delivering peptide to the colon in which enzymatic activity is low is next hope for absorption of these agents. Pectin, a naturally occurring water soluble polysaccharide, as a matrix for peptide delivery was studied. Degradation of pectin by the colonic enzymes makes it suitable for colon-specific delivery of drugs. Bovine serum albumin (BSA) was used as a model peptide. Calcium pectinate beads were prepared by extruding BSA-loaded pectin solution to an agitating calcium chloride solution, and gelled spheres were formed instantaneously by an ionotropic gelation reaction. The effect of several factors such as concentration of pectin, concentration of calcium chloride, and total drug loading on the pattern of drug release in the dissolution medium was studied. Prepared beads showed good resistance in the release medium. The entrapment efficiency of the beads was high (between 63% and 99%). Entrapment efficiency of BSA was reversely dependent to the amount of the drug loaded in the beads. The amount of BSA loaded on the beads affects pattern of drug release. The concentration of the pectin showed the highest impact on the rate of drug release. Presence of the pectiolytic enzymes facilitated the drug release from the beads.     

Animal experiments and clinical studies on intravascular lipid metabolism in relation to thyroid hormone status

Animal-experimental and clinical investigations concerning the intravasal lipid metabolism in disturbances of the thyroid hormones were performed. The results of these investigations show adverse effects of the thyroid hormones between man and rat with regard to the metabolism of lipoproteins rich in triglycerides. While in the clinical investigations performed an increase of the activity of the post-heparin lipase in hyperthyroidism of the type of Basedow's disease, connected with low triglyceride and VLDL levels in the serum was the result, in the animal experiment an opposite behaviour was established. Inverse relations were made evident also in hypofunction of the thyroid gland.     

Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease

OBJECTIVE: In order to suppress de novo cholesterol and VLDL biosynthesis, a long-term therapy trial with lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was initiated in two patients with cholesteryl ester storage disease (CESD), and concentrations of plasma lipids were monitored over a period of 9 years. METHODS: We studied two male patients with enzymatically confirmed CESD in whom long-term lovastatin therapy (8 and 9 years) was begun at the age of 7 and 19 years. The diagnosis of CESD was confirmed by the measurement of human lysosomal acid lipase (hLAL) activity in cultured skin fibroblasts and leukocytes. Restriction fragment length polymorphism (RFLP) analysis revealed that both subjects are homozygotes for the common CESD splice site mutation. Levels of serum lipids and lipoproteins were measured yearly. RESULTS: During the first year, total serum cholesterol decreased from 317 to 201 mg/dl in Patient A and from 228 to 120 mg/dl in Patient B, due mainly to the reduction of low-density lipoprotein (LDL) cholesterol from 262 to 151 mg/dt in Patient A and from 166 to 66 mg/dl in Patient B. Accordingly, the LDL cholesterol : high density lipoprotein (HDL) cholesterol ratio was markedly reduced in both patients after one year of therapy. The treatment was continued and, after 9 years of further medication, low total cholesterol and LDL cholesterol levels were still maintained. CONCLUSIONS: The study demonstrates that HMG-CoA reductase inhibitors are well tolerated drugs during long-term treatment of CESD patients and may help to prevent the development of premature atherosclerosis.     

Circulating vascular cell adhesion molecules VCAM-1, ICAM-1, and E-selectin in dependence on aging

BACKGROUND: Elevated levels of circulating cell adhesion molecules (cCAMs) such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) are found in subjects with vascular diseases and in subjects with several risk factors for atherosclerosis. However, data evaluating cCAMs and biological age are limited. OBJECTIVE: The purpose of this study was to assess in subjects with different cardiovascular risk profiles the levels of cVCAM-1, cICAM-1, and cE-selectin in dependence on age. METHODS: The following groups of subjects were included in the study: 282 apparently healthy subjects of the average population aged 18-89 years, 77 vegetarians who are characterized by a favourable global cardiovascular risk profile, 94 patients with coronary heart disease, and 181 patients with peripheral arterial occlusive disease. Blood samples were obtained after an overnight fast for measurement of cCAMs, lipoproteins, and other clinical/biochemical parameters. The cCAM levels were determined by the use of monoclonal antibody based enzyme-linked immunosorbent assays. RESULTS: Amongst the cCAMs, cVCAM-1 is uniquely elevated in elderly persons with different risks for atherosclerosis, including subjects of the average population, vegetarians with a favourable risk profile, and patients with both coronary heart disease and peripheral arterial occlusive disease. With respect to cICAM-1, an age-dependent elevation was found in the control subjects included in the study. The cE-selectin levels were not correlated with age. Moreover, no associations of cCAMs with serum lipid and lipoprotein levels were found. CONCLUSION: The results of the present study indicate that cVCAM-1 is an age-dependent parameter independent of cardiovascular risk.     

Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) and coronary artery disease

A high plasma homocysteine concentration is a risk factor for atherosclerotic disease and venous thrombosis. Homocysteine levels are influenced by folic acid, vitamin B 6 and vitamin B 12, as well as by hereditary factors. A common genetic variant of the methylenetetrahydrofolate reductase (MTHFR) gene CC 677 T) is associated with thermolability of the MTHFR enzyme and elevated plasma homocysteine concentration, especially in those with low folic acid concentration. The prevalence of point mutation (nucleotide 677 C T) in MTHFR was measured in patients with coronary artery disease (CAD) who all underwent coronary artery bypass surgery (62 cases; age 64.0 ± 9.5 years), and was compared with, age-matched control subjects. In patients with coronary artery disease (CAD), we investigated the prevalence of point mutation (nucleotide 677 C T) in MTHFR in comparison with control subjects. Heterozygous (C/T) prevalence for the 677 C T mutation in the MTHFR was higher in patients with CAD than in control subjects (P<0.05). The prevalence of homozygosity (C/C) for wild-type MTHFR was lower in patients with CAD in comparison with control subjects (P<0.05).Presented in part at the 41st Annual World Congress, International College of Angiology, Sapporo, Japan, July 1999.     

Design and fabrication of dual‐targeted delivery system based on gemcitabine‐conjugated human serum albumin nanoparticles

Dual‐targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride to fabricate Gem‐HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. To evaluate the structural properties of synthesized products, ¹H NMR and FT‐IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate‐targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake, and apoptosis induction on folate receptor overexpressing MDA‐MB‐231 cells in comparison to non‐targeted nanoparticles. Finally, it is considered that the developed dual‐targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells.     

A new treatment forInterdialytic hyperkalemia - the use of fosinopril sodium.

Fosinopril sodium is the first of the phosphinic acid class of angiotensin-converting enzyme inhibitors (ACEI). It is used as an antihypertensive agent, but differs from other ACEI in its dual routes of excretion (liver and kidney), and less incidence of hyperkalemia and cough. We conducted a study in known chronic hemodialysis patients who developed interdialytic hyperkalemia in spite of other treatments to control hyperkalemia. We used fosinopril in this group of patients to assess the effect of fosinopril on serum potassium (K) levels. Twenty-four patients were given fosinopril 10 mg at 18:00 h daily for 8 weeks. K levels were measured before and after each dialysis treatment. Interdialytic weight gains were recorded. The average pretrial potassium level was 6.57 mmol/l (+/- 0.47), and the posttrial level was 5.34 (+/- 0.76); p 相似文献