Antiovulatory antagonists of LHRH related to antide

We report 104 analogues of the potent antiovulatory antagonist of LHRH, N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-Ilys-Pro-D-Ala- NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced the Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8 with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay. Antide gives six rats ovulating out of eight (6/8) at 2 micrograms, 4/8 at 4 micrograms, and in the histamine release assay (HRA). ED50 is > 300 micrograms/ml; [Lys(N-Isobutyl)8]Antide gave 2/8 at 2 micrograms/rat; [Lys (8-Qis)5]Antide gave 1/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50. 22 micrograms/ml; [D-Lys(8-Qis)5]Antide gave 4/8 at 1 microgram and 0/8 at 2 micrograms, and in the HRA, ED50 was 27 micrograms/ml; [Lys(8-Qic)8] gave 5/8 at 1 microgram 1/8 at 2 micrograms/ [Lys(2-Pyc)6]Antide gave 3/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50 was 116 micrograms/ml; [D-Lys (2-Pyc)5]Antide gave 5/8 at 1 microgram and in the HRA, ED50 was 100- > 300 micrograms/ml; [Lys(2-Pyc)5.D-Lys(2-Pyc)6]Antide gave 2/8 at 1 microgram. The substitutions of the Nic groups of Antide at Lys5 or D-Lys6 with 8-Qis or with 2-Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to generate potent antiovulatory compounds endowed with moderate or low histamine release.     

Suppressive effects of sairei-to on monoclonal antibody 1-22-3-induced glomerulonephritis: analysis of effective components

The effects of traditional Chinese medicine (Sairei-to) on experimental glomerulonephritis induced in rats by monoclonal antibody (mAb) 1-22-3 injection was examined. The level of proteinuria in the Sairei-to-treated group was significantly lower than that in the PBS treated group. This suppressive effect was caused by the major component of Sairei-to, Syo-saiko-to but not by another component, Gorel-san. The suppressive effect of Syo-saiko-to was identified in its components (Bupleuri radix, Pinelliae tuber and Zingiberis rhizoma), but not in the other combined components (Ginseng radix and Zizyphi fructus). Further study revealed that the suppressive effects of the combined components were mainly derived from Bupleuri radix. It was demonstrated that the actual active ingredient is probably Saikosaponin-d. Light microscopy revealed that Sairei-to and its effective components suppressed the proliferation of mesangial cells and mesangial matrix expansion. Semiquantitative morphological studies of glomerular lesions on the eighth day showed that Syo-saiko-to and its combined components (Bupleuri radix, Zingiberis rhizoma and Pinelliae tuber) suppressed mesangial matrix expansion significantly compared with phosphate-buffered saline control groups (matrix score: 28.0 +/- 19.1 vs 102.3 +/- 14.1; 30.9 +/- 30.1 vs 102.3 +/- 14.1, P < 0.005, respectively). It was concluded that Saikosaponin-d, as well as Bupleuri radix, Syo-saiko-to and Sairei-to can suppress proteinuria and morphological changes in the rat glomerulonephritis model induced by mAb 1-22-3.     

Influence of neuroleptics on cytotoxic activity of macrophages in rats

The aim of the study was to evaluate the influence of neuroleptics on the in vivo and in vitro activities of rat spleen macrophages. In the in vivo study, three neuroleptics (chlorpromazine, haloperidol, and sulpiride) were given once, for 14 or 28 days. In the in vitro study, we evaluated the effects of two different concentrations of the neuroleptics on 3-day cultures of spleen macrophages. Rat spleen macrophages were isolated by the adherence method, and their cytotoxic activity was determined by measuring 51 Cr release from target cells P-815. In the in vitro study, both concentrations of all neuroleptics did not alter the cytotoxic activity of macrophages. In the in vivo study, neuroleptics (chlorpromazine 2 mg/kg, haloperidol 0.5 mg/kg, sulpiride 50 mg/kg) enhanced the cytotoxicity of macrophages both after a single injection and after 14 days. The results of the study indicate that the immunomodulatory effects of the neuroleptics depend mainly on dosage and experimental conditions.     

Photon Correlation Measurement of Ion Oscillation Frequencies in a Combined Trap

Abstract

We present experimental verification of the oscillation frequencies of magnesium ions in a combined trap for a wide range of a.c. voltages and magnetic fields. We employ a new technique to measure these trap resonances using the distribution of time intervals between consecutively detected fluorescence photons.     

Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension in which cortisol acts as a potent mineralocorticoid. The type I variant results in a severe clinical and biochemical phenotype and arises because of mutations in the gene encoding the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), an enzyme responsible for the peripheral inactivation of cortisol to cortisone. Only mild abnormalities of cortisol metabolism have been found in the type II variant of AME, suggesting that it may be a separate gene defect. In an extensive consanguineous Sardinian pedigree affected with "type II" AME, a novel homozygous point mutation (C945T) was found in the human 11beta-HSD2 gene in four affected individuals. Thirteen family members were heterozygous for the resultant R279C amino acid substitution. The LOD score of linkage of the mutation to the disease was 3.23. Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA. Affected individuals were >30 years of age and had both mineralocorticoid hypertension and evidence of impaired metabolism of cortisol to cortisone. The heterozygote state was phenotypically normal but was associated with subtle defects in cortisol metabolism. AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2 gene; classification into distinct subtypes is inappropriate. Hypertensive populations should be screened to identify the prevalence of milder defects in 11beta-HSD2 in patients currently labeled as having "essential" hypertension.     

The neural activity of thiamine: facts and hypotheses

A review of some experimental results as to identification of the specific role of thiamine in functioning of nerve cells is presented. Failure to attribute high neuroactivity of thiamine considering only its known biochemical function as a coenzyme precursor of some key Enzymes of the carbohydrate metabolism has formed conceptions existence of non-coenzyme functions in this vitamin which are realized in nerve cells. The Investigation of this thiamine function has been developing mainly in two principal directions the study of participation of biologically active thiamine derivatives is functioning of the excited membrane ion channels and the study of their role in the synthesis and metabolism of acetylcholine. Taking into account analysis of their own data and those available in literature, the authors formulate a hypothesis which attributes high neuroactivity of thiamine not to the existence of a certain function in the nerve cells new for this vitamin but only to the peculiarities of the structure-functional organization of the cells the existence of excited membrane, and interdependence between the cellular metabolism and transport of loss via the membrane, which underlies regulation of the synthesis, release, capture and catabolism of neurotransmitters.