Gamma-aminobutyric acid effects on pituitary gonadotropin secretion

Gamma-aminobutyric acid (GABA) injected into the third ventricle of male rats promotes the release of pituitary luteinizing hormone (LH) but not follicle-stimulating hormone. When GABA was injected directly into the pituitary it was ineffective in promoting LH release. This evidence suggests that GABA may play a role in controlling the discharge of hypothalamic luteinizing hormone releasing factor.     

A parathyroid hormone inhibitor in vivo: design and biological evaluation of a hormone analog

A synthetic analog of bovine parathyroid hormone (bPTH), [tyrosine-34] bPTH-(7-34)NH2, was found to inhibit parathyroid hormone action in vivo. When the analog and parathyroid hormone were infused simultaneously to rats at a molar ratio of 200 to 1, the analog inhibited the excretion of urinary phosphate and adenosine 3',5'-monophosphate. When infused alone at the same dose rate, the analog was devoid of agonist activity. The compound was prepared by following design principles developed for inhibitors of parathyroid hormone, and is believed to be the first antagonist of parathyroid hormone that is effective in vivo.     

Interference with feedback control; a mechanism of antimetabolite action

The action of an enzyme essential for tryptophan biosynthesis is inhibited by tryptophan and also by an analog of tryptophan. Similarly, histidine and one of its analogs inhibit the action of an enzyme essential for histidine biosynthesis. A mutant resistant to the histidine analog produces an apparently altered enzyme which is insensitive to both the analog and histidine.     

Luteinizing hormone-releasing activity in hypophysial stalk blood and elevation by dopamine

Pituitary halves incubated in pituitary stalk plasma release more luteinizing hormone than their opposite halves incubated in plasma from peripheral blood. Glands incubated in stalk plasma from dopamine-treated rats release more luteinizing hormone than glands incubated in stalk plasma from untreated controls. Luteinizing hormone-releasing activity in stalk plasma may be due to the luteinizing hormone-releasing factor, and the secretion of luteinizing hormone-releasing factor may be controlled by a dopaminergic mechanism.     

Growth factors modulate gonadotropin receptor induction in granulosa cell cultures

Epidermal growth factor and fibroblast growth factor inhibited follicle-stimulating hormone-dependent induction of luteinizing hormone receptor in cultured ovarian granulosa cells of the rat. In contrast, platelet-derived growth factor potentiated the induction of luteinizing hormone receptor by follicle-stimulating hormone. These results indicate that growth factors, well known for their effects on mitosis and DNA synthesis in cultured mammalian cells, are also able to modulate hormone-dependent differentiation in an endocrine target cell.     

Peptides with juvenile hormone activity

Peptide derivatives of juvenile hormone analogs which show substantial hormonal activity for certain insects were prepared. The most active compound, L-isoleucyl-L-alanyl-p-aminobenzoic acid ethyl ester, was up to twice as active as juvabione. Like juvabione, the peptide analog showed selective action on pyrrhocorid bugs.     

Systemic activity of a juvenile hormone analog

The peptidic analog of insect juvenile hormone, ethyl pivaloyl-L-alanyl-p-aminobenzoate with enormous biological activity on the red cotton bug, Dysdercus cingulatus, has pronounced systemic effect in sunflower plants. The compound is absorbed by the plant tissues and appears to be translocated throughout the plant system in active form. There is some evidence that juvenile hormone analogs of other types also have similar systemic effects. The discovery of systemic action should aid in the possible utilization of juvenile hormone analogs in insect control programs.     

铬对产蛋鸡生殖激素分泌的影响

为探讨铬元素对产蛋鸡生殖激素分泌的影响及其机制，在基础日粮（含Cr5.09mg/kg)中分别添加铬0，5和50mg/kg饲养4个月，观察其产蛋性能，检测血浆雌二醇（F2），孕酮（P），促黄体生成素（LH）水平，并于试验结束时进行卵泡细胞的离体培养，结果表明，添加5mg/kg铬有利于产蛋率的提高及产蛋高峰期（＞90％）的持久，不同铬日粮对血浆中上述激素水平无显著影响，但在组间产蛋率出现显著差异时，试验P，LH水平也相应地比对照组高，离体试验表明，铬可以通过直接对卵泡发生作用促进E2的合成与分泌（P＜0．01），对P分泌也有促进趋势。     

Suppression of ovulation in the rat by an orally active antagonist of luteinizing hormone-releasing hormone

A synthetic antagonist of luteinizing hormone-releasing hormone blocked ovulation in rats in a dose-dependent manner when given by gavage on the afternoon of proestrus. Ovulation was delayed for at least 1 day in all animals given 2 milligrams of antogonist and in some of the animals treated with 1 or 0.5 milligram. Oral administration of 2 milligrams also blocked the preovulatory surge of luteinizing hormone. This demonstration that antagonists of luteinizing hormone-releasing hormone can have oral antiovulatory activity clearly enhances their therapeutic potential.     

Stress-induced inhibition of reproductive functions: role of endogenous corticotropin-releasing factor

In the adult castrated male rat, exposure to inescapable, intermittent electroshocks inhibited the pulsatile pattern of luteinizing hormone release and markedly lowered its plasma concentrations. The central administration of the corticotropin-releasing factor (CRF) antagonist alpha-helical ovine CRF residues 9 to 41 reversed the inhibitory action of stress. Neither its peripheral injection, nor the intraventricular injection of the inactive CRF analog des-Glu to Arg ovine CRF was effective. These results suggest that endogenous CRF may mediate some deleterious effects of noxious stimuli on reproduction.     

The mechanism for activation of GTP hydrolysis on the ribosome

Protein synthesis requires several guanosine triphosphatase (GTPase) factors, including elongation factor Tu (EF-Tu), which delivers aminoacyl-transfer RNAs (tRNAs) to the ribosome. To understand how the ribosome triggers GTP hydrolysis in translational GTPases, we have determined the crystal structure of EF-Tu and aminoacyl-tRNA bound to the ribosome with a GTP analog, to 3.2 angstrom resolution. EF-Tu is in its active conformation, the switch I loop is ordered, and the catalytic histidine is coordinating the nucleophilic water in position for inline attack on the γ-phosphate of GTP. This activated conformation is due to a critical and conserved interaction of the histidine with A2662 of the sarcin-ricin loop of the 23S ribosomal RNA. The structure suggests a universal mechanism for GTPase activation and hydrolysis in translational GTPases on the ribosome.     

Ornithine decarboxylase stimulation in rat ovary by luteinizing hormone

In normal albino rats with a 4-day estrous cycle, the activity of ovarian ornithine decarboxylase undergoes a transitory rise on the evening of proestrus and only at that time. The response could be elicited by the administration of either luteinizing hormone or human chorionic gonadotrophin. When antiserum to luteinizing hormone was injected at 2 p.m. on the day of proestrus, the induction of ornithine decarboxylase was blocked, an indication that the enzyme is under luteinizing hormone control. The strategic positioning of the induction of ornithine decarboxylase between the normal release of luteinizing hormone and ovulation impties that putrescine is associated with the ovulatory process, and opens a new avenue of research on the control of ovulation.     

Multiple circadian oscillators regulate the timing of behavioral and endocrine rhythms in female golden hamsters

A single daily "surge" in pituitary luteinizing hormone release was observed in ovariectomized-estrogen-treated hamsters expressing an intact circadian rhythm of locomotor activity. In contrast, two luteinizing hormone surges occurred within a single 24-hour period in hamsters whose activity rhythm had dissociated or "split" into two distinct components. These observations indicate that both behavioral and endocrine circadian rhythms are regulated by the same multioscillator system, which seems to be composed of at least two distinct circadian oscillators.     

High-resolution nuclear magnetic resonance spectra of selectively deuterated staphylococcal nuclease

An analog of staphylococcal nuclease has been prepared in which all amino acids, except the six following, are fully deuterated: tryptophan; methionine; tyrosine, in ring positions 2 and 6; histidine, in ring position 2; aspartic acid and asparagine, beta-methylene; and glutamic acid and glutamine, gamma-methylene. The analog has a much simpler high-resolution nuclear magnetic resonance spectrum than the fully protonated enzyme. The effects of calcium ion and of the inhibitor 3', 5'-thymidine diphosphate on the spectrum of the analog were readily detected.     

Male contraception; synergism of gonadotropin-releasing hormone analog and testosterone in suppressing gonadotropin

Long-term administration of either superactive analog's of gonadotropin-releasing hormone or of testosterone suppresses gonadotropin secretion in male animals and humans. Testosterone administered in combination with gonadotropin-releasing hormone analog further suppresses serum gonadotropin levels in male rats. This observation indicates synergistic activity and suggests that the gonadotropin-releasing hormone analog and testosterone act at independent sites within the hypothalamic-pituitary axis. The primary actions of superactive analog are probably mediated by changes at a postreceptor site in the pituitary gonadotropin-secreting cells.     

Complement factor H polymorphism and age-related macular degeneration

Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we tested single-nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.95 x 10(-10)) was identified within the regulation of complement activation locus and was centered over a tyrosine-402 --> histidine-402 protein polymorphism in the gene encoding complement factor H. Possession of at least one histidine at amino acid position 402 increased the risk of AMD 2.7-fold and may account for 50% of the attributable risk of AMD.     

Designing small-molecule switches for protein-protein interactions

Mutations introduced into human growth hormone (hGH) (Thr175 --> Gly-hGH) and the extracellular domain of the hGH receptor (Trp104 --> Gly-hGHbp) created a cavity at the protein-protein interface that resulted in binding affinity being reduced by a factor of 10(6). A small library of indole analogs was screened for small molecules that bind the cavity created by the mutations and restore binding affinity. The ligand 5-chloro-2-trichloromethylimidazole was found to increase the affinity of the mutant hormone for its receptor more than 1000-fold. Cell proliferation and JAK2 phosphorylation assays showed that the mutant hGH activates growth hormone signaling in the presence of added ligand. This approach may allow other protein-protein and protein-nucleic acid interactions to be switched on or off by the addition or depletion of exogenous small molecules.     

Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat

Polypeptide analogs of the known members of the corticotropin-releasing factor (CRF) family were synthesized and tested in vitro and in vivo for enhanced potency or competitive antagonism. Predictive methods and physicochemical measurements had suggested an internal secondary alpha-helical conformation spanning about 25 residues for at least three members of the CRF family. Maximization of alpha-helix-forming potential by amino acid substitutions from the native known sequences (rat/human and ovine CRF, sauvagine, and carp and sucker urotensin 1) led to the synthesis of an analog that was found to be more than twice as potent as either of the parent peptides in vitro. In contrast, certain amino-terminally shortened fragments, such as alpha-helical CRF or ovine CRF residues 8 to 41, 9 to 41, and 10 to 41, were found to be competitive inhibitors in vitro. Selected antagonists were examined and also found to be active in vivo.     

A new, long-lasting competitive inhibitor of angiotensin

An analog of angiotensin II, [Sar(1), Ile(8)]-angiotensin II, has a potent and long-lasting competitive antagonistic effect against angiotensin II when tested for its myotropic action on the isolated rabbit aorta and for its effect on blood pressure in anesthetized cats and dogs. Compared to [Ile(8)]-angiotensin II, the new analog has equal antagonistic potency on the isolated system but a much greater potency in vivo. It is assumed that sarcosine in position 1 protects the peptide against enzymatic degradation and enhances its half-life. This study demonstrates that the modification in both positions 1 and 8 are important for the in vivo antagonistic potencies of angiotensin analogs.     

Antiviral resistance by the polyinosinic acid-poly (1-vinylcytosine) complex

The antiviral activities of analogs of the double-stranded complex of polyinosinic and polycytidylic acids [poly(I).poly(C)], which is a potent interferon inducer, have been studied. Structural changes that modify the polymer backbone substantially, such as loops or 2' --> 5' phosphodiester bonds, lead to decreased antiviral activity. Unexpectedly, however, the complex of polyinosinic acid and poly(1-vinylcytosine), which is only a much more distantly related analog of poly(I) . poly(C), shows high activity. It is postulated that the high activity is related to the reduction of the charge/mass ratio and to the existence of this complex in an aggregated state; these are two factors that generally enhance the uptake of compo unds by cells.