Several new 10-formyl and 10-hydroxymethyl derivatives of 5,8,10-trideazapteroic acid have been synthesized by a novel and convenient enamine alkylation procedure. Two of these compounds (10a and 10b) were shown to be very powerful inhibitors of L. casei (10a, IC50 = 8 x 10(-6) M; 10b, IC50 = 7 x 10(-6) M) and recombinant mouse (10a, IC50 = 3.4 x 10(-5) M; 10b, IC50 = 2.8 x 10(-5) M) glycinamide ribonucleotide formyltransferase (GARFT). These IC50 values are comparable to the classical GARFT inhibitor (6R)-DDATHF (IC50, L. casei 2.3 x 10(-6)M; recombinant mouse 2.3 x 10(-5) M) under identical assay conditions. For both compounds, the inhibition of L. casei GARFT increased with time of incubation, but not markedly with the recombinant mouse enzyme. Due to their potential ability to interfere with purine biosynthesis and to penetrate microbial cells the new nonclassical GARFT inhibitors reported here may be useful for the treatment of infections caused by microorganisms that are sensitive and resistant to conventional antimicrobial agents.

Acyltransferases↗

PubMedDate not supplied

Serum testosterone response to desialylated human choriogonadotropin in man.

To assess the in vivo steroidogenic activity of desialylated human choriogonadotropin (hCG) in man, highly purified desialylated hCG was administered as a constant intravenous infusion over 6 hours to four normal men at a rate sufficient to maintain substantial levels of desialylated hCG in the serum. The mean percent change of serum testosterone from baseline during the first 6 hours in men given an infusion of desialylated hCG was compared to that in saline-infused controls and that in men given highly purified intact hCG. The mean change of serum testosterone at 6 hours in the group infused with desialylated hCG (129% of baseline) was significantly greater than that of the controls (69% of baseline). Furthermore, the response to desialylated hCG could not be distinguished from that of hCG (125% of baseline). It was concluded that desialylated hCG, when given as a constant intravenous infusion, can elicit a substantial serum testosterone response comparable to that seen with purified hCG, and thus, that desialylated hCG behaves as an agonist of the LH/CG receptors on human Leydig cells.

Adult↗

PubMedDate not supplied

cDNA cloning of a mandibular organ inhibiting hormone from the spider crab Libinia emarginata.

Mandibular organs (MO) produce a crustacean juvenile hormone, methyl farnesoate (MF). MO activity is negatively regulated by factors, called mandibular organ inhibiting hormones (MOIHs), from the crustacean sinus gland X-organ complex in the eyestalks. Three MOIHs have been isolated previously from the spider crab Libinia emarginata and are characterized as members of the crustacean hyperglycemic hormone (CHH) neuropeptide family. In the research reported here, a full length cDNA sequence of 972 bp of a MOIH was isolated by screening a cDNA library constructed from the eyestalks of Libinia emarginata. This cDNA sequence encodes a preprohormone peptide with 137 amino acid residues, including a 26-amino acid long signal peptide, a 34-amino acid long precursor peptide, a dibasic peptide, the full length of 72-amino acid long MOIH, and a tri-peptide Gly-Lys-Lys which designates the potential amidation site at the C-terminus of the mature peptide.

Amino Acid Sequence↗

PubMedDate not supplied

Complement and clusterin in the injured nervous system.

Peripheral nerve injury and neuronal degeneration resulting from toxic ricin induce activation of the classical pathway of complement close to the injured motorneuron perikarya or sensory terminals. In contrast, degeneration of central myelinated fibers is not accompanied by complement expression. The main source of complement in peripheral nerve injury and toxic ricin degeneration appears to be microglia. Brain contusion is associated with complement activation. Some of the complement in this situation may derive from plasma, because the blood-brain barrier is disrupted. Clusterin expression is increased in astrocytes along with their activation in the vicinity of lesioned neurons. In addition, axotomized motorneurons show a marked clusterin upregulation. A relationship between clusterin and cell death is suggested by the prominent aggregation of clusterin in neuronal perikarya destroyed by the effects of toxic ricin, as well as by the neosynthesis of clusterin in apparently degenerating nonneuronal cells, presumed to be oligodendrocytes. Our findings indicate that the expression of complement and clusterin are prominent features of neural degeneration and regeneration, as it is in Alzheimer's disease brains as well. The nerve injury conditions described, therefore, offer attractive experimental models to elucidate the roles of these molecular components in neurodegenerative disorders, thereby providing useful insights into potentially new therapeutic approaches in these conditions.

Animals↗

PubMedDate not supplied

Intrauterine feeding of the growth retarded fetus: can we help?

Intrauterine feeding of the growth retarded fetus appears an attractive therapeutic possibility. However the factors which determine the reversibility of intrauterine growth retardation are poorly understood. While fetal substrate supply is the final common pathway by which many factors restrict fetal growth, improving fetal substrate supply does not always lead to improved fetal growth. Similarly, fetal substrate supply is an important regulator of fetal endocrine status, such as circulating IGF-1 levels, but again, improving fetal substrate supply does not always alter fetal endocrine status or fetal growth. The relationship between substrate supply, endocrine status and growth is regulated in a complex way by placental function. Understanding the role of the placenta in this regulation is essential if in the future we are to help the growth retarded fetus.

Embryonic and Fetal Development↗

PubMedDate not supplied

Different responses to repeated applications of zingerone in behavioral studies, recordings from intact and cultured TG neurons, and from VR1 receptors.

When applied repetitively to the cornea, capsaicin, the pungent compound in hot pepper, causes an initial eye-wiping response that diminishes upon repeated exposure (tachyphylaxis). This diminution, however, is not observed upon repetitive application of its pungent analogue, zingerone, to the cornea or tongue. In addition, compared with capsaicin, the lingual application of zingerone produces a gustatory response with a shorter latency and duration. Because both the tongue and the cornea are innervated by the trigeminal nerve, and because zingerone and capsaicin are structurally related, it is not evident why the responses to these compounds should give such different behavioral and psychophysical endpoints. We have addressed this issue by measuring the neural responses from rat trigeminal ganglion neurons (TG) to repeated applications of zingerone applied to the cornea, from cultured rat TG neurons, and from cloned capsaicin receptors (VR1) expressed in Xenopus oocytes and then comparing these effects to those evoked by capsaicin. Extracellular recordings from the trigeminal ganglion revealed that the responses to repeated corneal applications of 30 mM zingerone show desensitization. Cultured TG neurons, and oocytes expressing VR1 receptors, were also desensitized by repeated applications of zingerone. Electrophysiological recordings revealed that these two vanilloids could activate the same receptor (VR1), currents in the same neuron, and crossdesensitize. The more rapid onset and shorter duration responses seen with zingerone (compared with capsaicin) provides a rationalization for its more rapid onset and shorter duration gustatory response. We attribute the different behavioral responses to periodic applications of these two agonists to two competing effects: one leading to sensitization, and the other to tachyphylaxis. Which of these dominates depends on the concentration, exposure time, and interstimulus interval. Consequently, whether or not zingerone will exhibit tachyphylaxis depends critically on the experimental conditions.

Animals↗

PubMedDate not supplied

Antigen detection assay to monitor the efficacy of praziquantel for treatment of Paragonimus westermani infections.

Explore the source record for details and available documents.

Antigens, Helminth↗

PubMedDate not supplied

Immunoglobulin gene joints compensate for reduced on-rates imposed by somatic mutations in a V(H) gene.

Affinity maturation in the B lymphocyte response to a protein epitope appears to be largely due to a decrease in the off-rate constant of the antibodies (Ab) resulting from somatic mutation without a significant increase in the on-rate constant. Here, we show by site-directed mutagenesis of a germline encoded single-chain Fv that somatic mutations frequently selected in the Ab response to mouse cytochrome c (CYT) at heavy (H) chain positions 31 and 58 actually cause a two and three-fold decrease, respectively, in the on-rate constant as well as a two and five-fold decrease, respectively, in the off-rate constant and together cause nearly an eight-fold decrease in the off-rate. However, additional selection for a tyrosine residue at position 96 in the V(kappa)-J(kappa) joint compensates for the decreased on-rate imposed by the somatic mutations. This allows for an increase in the affinity of Ab during the secondary response. Certain sequences at the V(H)-D-J(H) joint were also shown to maintain a normal on-rate constant in the context of the common H chain mutations and, in addition, to reduce the off-rate, thus increasing the affinity. The results support the idea that both faster on-rates and slower off-rates for B lymphocyte antigen-specific receptors are favored during the maturation of the Ab response to mouse CYT.

Animals↗