Effects of CB-154 (2-Br-alpha-ergocryptine) on prolactin and growth hormone release in an acromegalic patient with galactorrhea.

An acromegalic patient with galactorrhea was treated with an ergot alkaloid, 2-Br-alpha-ergocryptine (CB-154). Serum prolactin decreased rapidly to normal level by CB-154 and the complete cessation of galactorrhea was noted. The inhibitory effect of CB-154 On growth hormone (GH) release was also noted, but slight. The mechanism of inhibitory action of CB-154 on both prolactin and GH secretion was discussed in connection with the experimental model of pituitary tumors, in which both hormones were produced by a single type of tumor cells. The discontinuation of CB-154 treatment was associated with the return of both prolactin and GH levels to the initial high values with resumption of galactorrhea.     

Syntheses of 14C-Labeled Pyrethrin I,Allethrin, Phthalthrin,and Dimethrin on a Submillimole Scale

Studies on the metabolic fate and degradation chemistry of pyrethroid insecticide chemicals are greatly facilitated by the use of compounds radiolabeled, in separate preparations, in the acid and alcohol moieties. Acid-labeled preparations were made by converting d-trans-chrysanthemic acid-1-¹⁴C (88 mg, 1.3 mCi/mm) into d-trans-d-pyrethrin-1-¹⁴C (68 mg, 1.3 mCi/mm), d-trans-d-allethrin-¹⁴C (43 mg, 1.3 mCi/mm), d-trans-dimethrin-¹⁴C (54 mg, 0.294 mCi/mm), and d-trans-phthalthrin-¹⁴C (47 mg, 0.294 mCi/mm), incorporating approximately 81% of the starting radiocarbon into the four pyrethroid preparations. Alcohol-labeled preparations were made by converting acetone-1,3-¹⁴C into d-trans-dl-ailethrin-¹⁴C (146 mg, 0.162 mCi/mm) and formaldehyde-¹⁴C into d-trans-phthalthrin-¹⁴C (299 mg, 0.276 mCi/mm). Each labeled compound had a high stereochemical purity and a radiochemical purity of greater than 99%. Detailed procedures were worked out for all conversions which took place in high yields except in one case: the synthesis of allethrin labeled in the alcohol moiety.     

Studies on Nicotinoids1) as an Insecticide

Toxicities of some nicotinoids as an insecticide were determined. 5′-methylnornicotine, a new synthetic isomer of nicotine, shows similar toxicity to nicotine. The essential moiety in nicotinoids molecule responsible for high toxicity may be 3-pyridylmethylamine group, the amino nitrogen of which must have high basicity (p^K_a′: 7.4~9.0). All nicotinoids of high toxicity are estimated to be largely as monocation at physiological pH of 7.     

Synthesis and Stereochemical Characterization of Hydroxy- and Epoxy-derivatives of Rotenone

One to four routes of synthesis are described for 8′-hydroxyrotenone, 5′-hydroxyrotenone, two epimers of 6′,7′-dihydro-6′,7′-dihydroxyrotenone, two epimers of 6′,7′-epoxyrotenone and the four rotenolones derived from each of these compounds. The stereochemical relationships are determined, in each case, by chemical interconversion, ORD and monochromatic rotation to assess the absolute configuration of the B/C ring juncture and by IR, MS and NMR for the cis- or trans-nature of this juncture. The new compounds described are useful standards for studies on the metabolites and photodecomposition products of rotenone insecticide chemical.     

Studies on Nicotinoids as Insecticides

Synthesis of two nicotine isomers, 5′-methylnornicotine and 6-methylnornicotine is described. The latter shows slightly insecticidal action. Myosmine type bases are easily reduced to nornicotine type with sodium borohydride.     

Chemical Studies on Pyrethroids

Allethrin-(E)-Ol (IV), allethrin-(E)-al (V) and allethrin-(E)-acid (VI), the metabolites of allethrin (III) in the insect body, were synthesized. Their low toxicities to houseflies seem to support the hypothesis that they are products of the detoxication process of allethrin.     

Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Simvastatin at 10(-7) M markedly increased mRNA expression for bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (OCN) in nontransformed osteoblastic cells (MC3T3-E1), while suppressing gene expression for collagenase-1, and collagenase-3. Extracellular accumulation of proteins such as VEGF, OCN, collagenase-digestive proteins, and noncollagenous proteins was increased in the cells treated with 10(-7) M simvastatin, or 10(-8) M cerivastatin. In the culture of MC3T3-E1 cells, statins stimulated mineralization; pretreating MC3T3-E1 cells with mevalonate, or geranylgeranyl pyrophosphate (a mevalonate metabolite) abolished statin-induced mineralization. Statins stimulate osteoblast differentiation in vitro, and may hold promise drugs for the treatment of osteoporosis in the future.     

Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion

Atherosclerosis is associated with immune activation. Immunoglobulin is used for the treatment of immune-mediated diseases. The mechanisms and importance of the Fc portion of immunoglobulin upon experimental atherosclerosis in apolipoprotein E-deficient mice were examined. Experimental atherosclerosis was induced in mice fed a high-fat diet containing 0.3% cholesterol. Over 8, 12, and 16 wk, on alternate days, mice were treated with an intraperitoneal injection of either 1 g.kg-1.day-1 of human intact immunoglobulin or F(ab')2 fragments of human immunoglobulin. Fatty streak formation and fibrofatty plaques were markedly suppressed in mice that received intact immunoglobulin for 8, 12, and 16 wk. In contrast, atherosclerotic lesions were not ameliorated in mice that received F(ab')2 fragments. Immunohistochemical analysis revealed that macrophage accumulation in the fatty streak lesions was suppressed in mice received intact immunoglobulin but not in those that received F(ab')2 fragments. In addition, the cytotoxic activities of splenocytes from immunoglobulin-treated mice, but not from F(ab')2 fragment-treated mice, were significantly suppressed compared with those from human serum albumin-treated mice. Differences in lesion area did not correlate with any significant alterations in serum lipid levels. Immunoglobulin therapy markedly suppressed atherosclerosis due to Fc receptor-mediated anti-inflammatory and immunomodulating actions. The antiatherosclerotic effects of immunoglobulin may be related to the suppression of cytotoxic activity of atherogenic T cells and the reduction of macrophage accumulation in the lesions.     

Developmental genetic profiles of glutamate receptor system,neuromodulator system,protector of normal tissue and mitochondria,and reelin in marmoset cortex: Potential molecular mechanisms of pruning phase of spines in primate synaptic formation process during the end of infancy and prepuberty (II)

This is the second report of a series paper, which reports molecular mechanisms underlying the occurrence of pruning spine phase after rapid spinogenesis phase in neonates and young infant in the primate brain. We performed microarray analysis between the peak of spine numbers [postnatal 3 months (M)] and spine pruning (postnatal 6 M) in prefrontal, inferior temporal, and primary visual cortices of the common marmoset (Callithrix jacchus). The pruning phase is not clearly defined in rodents but is in primates including the marmoset. The differentially expressed genes between 3 M and 6 M in all three cortical areas were selected by two-way analysis of variance. The list of selected genes was analyzed by canonical pathway analysis using “Ingenuity Pathway Analysis of complex omics data” (IPA; Ingenuity Systems, Qiagen, Hilden, Germany). In this report, we discuss these lists of genes for the glutamate receptor system, G-protein-coupled neuromodulator system, protector of normal tissue and mitochondria, and reelin. (1) Glutamate is a common neurotransmitter. Its receptors AMPA1, GRIK1, and their scaffold protein DLG4 decreased as spine numbers decreased. Instead, GRIN3 (NMDA receptor) increased, suggesting that strong NMDA excitatory currents may be required for a single neuron to receive sufficient net synaptic activity in order to compensate for the decrease in synapse. (2) Most of the G protein-coupled receptor genes (e.g., ADRA1D, HTR2A, HTR4, and DRD1) in the selected list were upregulated at 6 M. The downstream gene ROCK2 in these receptor systems plays a role of decreasing synapses, and ROCK2 decreased at 6 M. (3) Synaptic phagosytosis by microglia with complement and other cytokines could cause damage to normal tissue and mitochondria. SOD1, XIAP, CD46, and CD55, which play protective roles in normal tissue and mitochondria, showed higher expression at 6 M than at 3 M, suggesting that normal brain tissue is more protected at 6 M. (4) Reelin has an important role in cortical layer formation. In addition, RELN and three different pathways of reelin were expressed at 6 M, suggesting that new synapse formation decreased at that age. Moreover, if new synapses were formed, their positions were free and probably dependent on activity.     

Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: Potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I)

The synapse number and the related dendritic spine number in the cerebral cortex of primates shows a rapid increase after birth. Depending on the brain region and species, the number of synapses reaches a peak before adulthood, and pruning takes place after this peak (overshoot-type synaptic formation). Human mental disorders, such as autism and schizophrenia, are hypothesized to be a result of either too weak or excessive pruning after the peak is reached. Thus, it is important to study the molecular mechanisms underlying overshoot-type synaptic formation, particularly the pruning phase.