Synergistic effect of estrogen and androgen on induction of uterine thymidine kinase activities in immature rats

Estrdiol-17β induced a significant increase in the uterine thymidine kinase activity with a characteristic isozyme pattern 30 h after injection into immature rats. Testosterone propionate also revealed a similar increase. Following combined injection of estradiol-17β and testosterone propionate, the overall and separate isozyme activities of thymidine kinase increased to nearly the total amount of those when each hormone was injected separately.     

Review of invertebrate biological control agent regulation in Australia, New Zealand, Canada and the USA: recommendations for a harmonized European system

Europe lags far behind Australia, New Zealand, Canada and the USA in terms of implementing regulatory procedures for the import and release of invertebrate biological control agents (IBCAs). A number of standards, documents and guidelines have been produced over recent years in an attempt to harmonize regulation of IBCA introduction into Europe. Despite these efforts, the number of member countries implementing any form of IBCA regulation remains low, with many industries, biological practitioners and regulators fearing that a regulatory system would render the process of approval for IBCA introduction into a country costly and time consuming. Europe’s priority is therefore to formulate a regulatory system that will be readily approved of and adopted by all member countries. In this paper we review the current regulatory processes operating in Australia, New Zealand, Canada and the USA. There is potential for Europe to benefit from the years of experience that these countries have in IBCA regulation. We therefore propose recommendations based on features of the regulatory processes in each of the four countries that work well and that could be adopted to generate a workable Europe‐wide regulatory system.     

Structure–activity relationship analysis of carbobicyclo and oxabicyclo succinimide analogs as potential androgen receptor antagonists

Prostate cancer (PCa) is a frequently diagnosed male cancer and the second leading cause of cancer-related death in many countries. Due to various amino acid mutations that occurred in the ligand binding domain of androgen receptor (AR), the patients were observed insensitive, even resistant to the marketed antiandrogens such as bicalutamide and enzalutamide, which emphasizes the urgent need for novel antiandrogens to solve drug resistance problem. Recently a series of carbobicyclo and oxabicyclo succinimide analogs were reported to effectively antagonize AR. In this study, to explore the structural requirements for these AR antagonists, we performed quantitative structure–activity relationship analysis on carbobicyclo and oxabicyclo succinimide analogs by using two-dimensional multiple linear regressions (MLR) method and three-dimension comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The obtained models show satisfactory results with proper reliabilities and powerful external predictability. Moreover, the CoMFA and CoMSIA contour maps can intuitively represent key features associated with bioactivities. These models may offer guidance for the rational design and modification of new lead compounds for antiandrogens.     

Melatonin Shifts Human Orcadian Rhythms According to a Phase-Response Curve

A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.     

Pharmacokinetic, metabolic, and antidiarrheal properties of ( and ) heptapeptides of sorbin in rodent

The C-terminal heptapeptide-amide (C7-sorbin) is the minimal biologically active fragment of sorbin inducing an increase in intestinal hydroelectrolytic absorption. An analogue (D7-sorbin), characterized by the replacement of the ultimate C-terminal amino acid -alanine-amide by -alanine-amide, was synthetized. For pharmacokinetic studies, D7-sorbin and C7-sorbin were tritium labeled. After IV injection, clearances were 10.6 and 30.2 ml⁻¹ for D7-sorbin and C7-sorbin, respectively, and MRT were 34 and 18 min. After SC administration, C_max attained 0.41% and 0.12% of the dose/ml, respectively. The IP route showed a 45-min delay before C_max and a 100% bioavailability for both peptides. D7-sorbin was principally excreted in urine, as shown by balance study, and in part in intact form, as controlled by mass spectrometry. D7-sorbin induced a significant decrease of the VIP-induced ileal secretion, previously observed with C7-sorbin. The change of -Ala to -Ala increased the stability of the synthetic C-terminal peptide of sorbin whereas its biological activity, bioavailability, and route of elimination were unchanged.     

Expression of the androgen-dependent MMTV-specific orf gene in Shionogi 115 mouse mammary tumor cells

The Shionogi 115 (S115) mouse mammary tumor cells express the MMTV-specific 1.7 kb mRNA (orf) at a high level in the presence of androgens. In lymphoid cells the orf-gene encodes a superantigen which has an important role in establishing self-tolerance but in mammary and breast cancer cells the function of the orf gene is unclear. In the present work we studied the expression of the S115 mammary tumor cell orf sequence and its role in the androgen regulated growth of S115 cells. The cloning and sequencing of the cDNA specific for the 1.7 kb mRNA from the S115 mouse mammary tumor cells revealed a 990 bp DNA sequence with a 99.8% homology to the Mtv-17 proviral strain. There was a difference of only one amino acid (isoleu-tyr) in the coding region. A peptide was synthesized according to the hypervariable C-terminal part of the predicted protein and used to raise a rabbit antiserum. The anti-S115-orf antiserum immunoprecipitated an approximately 45 kDa protein from the metabolically labeled S115 cell lysates. In order to analyze the putative functions of the protein, the orf-sequence was linked to MoMLV-LTR and to the human ß-actin promoter in the mammalian expression vectors pLTRpoly and pHßAPr-1-neo, respectively, and transfected into NIH3T3 and S115 cells. NIH3T3 transfectants expressing orf mRNA did not show a transformed phenotype in vitro. The S115 orf transfectants proliferated somewhat more slowly than the vector transfected control cells in cell culture, both in the presence or absence of androgen, but there was no obvious change in the phenotype of S115 cells or in expression of the fibroblast growth factor 8 (FGF-8). This factor is activated by Mtv-6 integration and mediates androgen effects in these cells. Unexpectedly, however, the formation of tumors by S115 orf cells in nude mice was considerably prolonged and tumor growth retarded when compared with vector transfected control or parent S115 cells. The results suggest that MMTV-orf can be functional in breast cancer cells but the mechanism of the growth repressive effect in mammary tumor remains to be analyzed.