ApoA- and apoB-containing lipoproteins and Lp(a) concentration in non-dialyzed patients with chronic renal failure

BACKGROUND: End-Stage renal disease is associated with accelerated atherosclerosis and a high incidence of cardiovascular disease. METHODS: The serum levels of lipids and apolipoproteins and Lp(a) were determined in 51 patients with chronic renal failure (CRF) with various advancement, without interference of factors which might disturb Lp(a) metabolism and with proteinuria less than 0.5 g/24 h. The patients studied were divided into two groups: patients with moderate renal failure (CRF-M) and creatinine levels of 2-6mg/dL n = 27; and predialysis patients with end stage renal disease (ESRD) and creatinine levels higher than 8.5 mg/dL n=24. RESULTS: In both studied groups serum concentrations of triglycerides (TG), total apoCIII, apoCIIInonB, apoB:CIII were statistically increased, (except total cholestrol (TC) and LDL-cholestrol (LDL-C), apoB, total apoE, apoEnonB, apoB:E), while the levels of HDL-cholestrol (HDL-C) and apoAl significantly decreased. Lipid and lipoprotein ratios as risk factors of atherosclerosis were similar in both groups. The TC/HDL-C ratio increased, while that of HDL-C/ apoAI and apoAI/apoCIII decreased. Serum Lp(a) concentrations were significantly increased in both studied groups. The medians and ranges of Lp(a) concentration were similar in both groups. Serum Lp(a) levels correlated with total cholesterol (r=0.295; p < 0.05), LDL-C (r = 0.312; p < 0.05) and apoB (r = 0.215; p < 0.05). In addition, no correlation was found between Lp(a) levels and albumin concentrations (r = 0.126; p = 0.421). CONCLUSION: Our results may indicate that the reduced levels of apoA-containing lipoproteins and increased TG-rich apoB-containing lipoproteins and Lp(a) indicated a clear atherogenic pattern in early renal disease. Increased Lp(a) concentration may result in nonspecific synthesis or catabolism disturbances. Measurement and monitoring of lipoprotein family profiles offers a new means for selecting appropriate therapies targeted for normalizing dyslipidemia in non-dialyzed patients.     

Antagonism of picrotoxin-induced changes in dopamine and serotonin metabolism by allopregnanolone and midazolam

The effects of allopregnanolone and midazolam, given intracerebroventricularly, on the behavioral and biochemical effects of picrotoxin, were examined in a model of neurotoxin-induced seizures, in mice. After acute injections, midazolam (ED(50)=39.8 nmol) and allopregnanolone (ED(50)=11.0 nmol) produced similar and dose-dependent protection against picrotoxin-induced seizures. Picrotoxin given intraperitoneally at the ED(85) dose decreased significantly the concentration of serotonin (5-HT), dopamine (DA), homovanilic acid (HVA) and 3,4-dihydroxyindolacetic acid (DOPAC), in the mouse striatum and the frontal cortex, in the period of time immediately preceding the onset of seizures. A single injection of allopregnanolone more potently, in comparison to midazolam, antagonized the biochemical action of picrotoxin, abolishing its effects on DA, HVA and 5-HT concentration, in the mouse striatum and the frontal cortex. These results for the first time provide a direct argument for an involvement of central dopaminergic and serotonergic systems in the seizure development. The present data add also to the accumulating evidence suggesting a favorable pharmacological profile for some neurosteroids currently considered to have a future role in the management of epilepsy.     

Molecular and clinical consequences of in vivo silicones biodegradation

The object of the publication is the presentation of data referring to in vivo silicones biodegradation and their potential clinical and molecular consequences. Summing up, one needs to state that the products of silicones biodegradation are not biologically indifferent. In particular, different types of silanols are inhibitors of proteolytic enzymes and regulators of many metabolic processes as well as affect the cell growth and division, which distinctly indicates the potentially strong pharmacological action. The main objective of the molecular consequences of the biodegradation of siloxanes was the verification what impact siloxanes of various molecular weights and of various chain lengths exert on the conformational stability of biological molecules.     

Cognitive effects of Colostral-Val nonapeptide in aged rats

Colostrinin, a complex of polypeptides derived from sheep colostrum retards the progress of Alzheimer's disease and facilitates acquisition and retrieval of spatial memory in aged rats. Here we investigated the cognitive effects of colostrinin-derived nonapeptide (Colostral-Val nonapeptide, CVNP) in aged rats that demonstrated learning deficits. Administered for 14 days, CVNP did not affect the acquisition of spatial learning or memory retrieval in the Morris water maze. As a result of reversal learning, placebo treated rats shifted searching behavior and swam less in the area of original platform position and more in the area of recent platform position, suggesting formation of the new spatial map. CVNP treated rats did not change the searching pattern and still investigated the area that contained "original" escape platform, suggesting that CVNP treatment delays the extinction of spatial memory. In another experiment, CVNP administered for 8 days did not influence the acquisition of the active avoidance task, but significantly delayed its extinction. The present findings indicate that colostrinin-derived nonapeptide may delay the extinction of long-term memories.     

Towards an understanding of biological role of colostrinin peptides

The aim of this study was to elucidate the structure and possible function of colostrinin, also known as a proline rich polypeptide (PRP). The molecular weight of colostrinin was originally determined by gel filtration to be 17,200 daltons. In the presence of guanidinum chloride, however, the molecular weight was found to be about 6,000 daltons. Further studies utilizing high-performance liquid chromatography (HPLC) and mass spectroscopy revealed that colostrinin is a complex consisting of many low molecular-weight polypeptides. A total of 32 peptides were isolated from the original colostrinin preparation by HPLC and subjected to the N-terminal sequence analysis. The results of sequence analysis revealed significant homology of the peptides to three protein precursors: annexin, β-casein, and a hypothetical β-casein homolog. In addition, the sequence of several peptides showed no significant homology to any specific protein in the current GenBank database. The synthetic peptides of various lengths representing the N-terminal sequence of the colostrinin peptides were made to study some biological effects. Here we report that colostrinin and some of its component peptides are potent inducers of leukocyte proliferation and of certain cytokines. Also, a series of monospecific antibodies were produced in rabbits against the synthetic peptides. The antibodies were used to study the kinetic of antigen reduction in colostrum and mature milk following lambing. A threefold decrease was common for most antigens studied over the period of 72 h. Based on the results of these studies we postulate that colostrinin represents a diverse group of peptides produced in the mammary gland of mammals for the development of the optimal physiologic responses in offspring. Also, it is hoped that the beneficial use of colostrinin in Alzheimer’s Disease (AD), recently reported elsewhere, will revive interest in its clinical application for treatment and/or prophylaxis of many age-related disorders.     

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test.     

Effect of Proline Rich Polypeptide from Ovine Colostrum on Virus Replication in Human Placenta and Amniotic Membrane at Term; Possible Role of Endogenous Tumour Necrosis Factor α

Freshly prepared organ cultures of human placentae and amniotic membranes at term show different sensitivity to vesicular stomatitis virus (VSV) infection. In six of 16 amniotic membranes and seven of 17 placentae VSV replicated to relatively high titres (10³–10⁶TCID₅₀/ml). The others were partially or completely resistant to virus infection (<10¹–10²TCID₅₀/ml). Addition of the immunomodulating agent, proline-rich-polypeptide (PRP) from ovine colostrum to explants freshly obtained from the organs, influenced VSV replication in a manner dependent on the innate immune state of the organ culture. In cultures resistant to the virus, PRP at a concentration of 10 μg/ml increased 10–10 000 times the VSV titre. In contrast, treatment of highly sensitive cultures by PRP hardly influenced viral replication at all. The effect of virus stimulation by PRP was abolished by specific anti-TNF antibodies. The results indicate that endogenous TNF may be one of the mediators of virus stimulation by PRP. Antibodies against TNFα, added to VSV infected organ cultures sensitive to the virus reduced viral replication. The antibodies caused stimulation of virus replication in VSV-infected resistant organ cultures. The results indicate the double role of endogenous TNF in viral replication in placenta and the amniotic membrane.     

Effect of the Concurrent LHRH Antagonist Administration with a LHRH Superagonist in Rats

Purpose. The purpose of this study was to investigate the effect of anovel LHRH antagonist, Orntide acetate, on the initial testosteroneelevation in rats during treatment with a LHRH superagonist,Leuprolide acetate.Methods. Thirteen groups of a rat animal model were administeredeither liquid Orntide or Orntide PLGA microspheres before or simultaneouslywith Leuprolide injections. Serum levels of testosterone weremonitored during the time course of the study using a radioimmunoas say method.Results. Administration of a single daily dose of liquid Orntide resultedin testosterone suppression within 6 h to levels below 0.5 ng/ml(castration level). However, combined administration of liquid Orntide andliquid Leuprolide did not have a significant effect on the initialtestosterone elevation in studied rats. Similarly, there was no effect when liquidOrntide was co-administered with Leuprolide microspheres. Administrationof Orntide microspheres 48 h before Leuprolide microspheressuppressed testosterone levels below the castration level within 24 h,however, did not prevent a rise in testosterone serum concentration uponadministration of Leuprolide microspheres. Also, a second testosteronepeak was observed between days 3 and 15 in the animals which weresimultaneously treated with Orntide microspheres and Leuprolidemicrospheres.Conclusions. Orntide acetate was found to be an effective LHRHantagonist with a rapid onset of pharmacological action and a shortbiological half-life. Administration of a single dose of liquid Orntideor Orntide microspheres, resulted in rapid testosterone suppressionwithout an initial elevation, as seen with LHRH superagonists. However,combined administration of Orntide and Leuprolide did not havean effect on the initial testosterone elevation in rats.