Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone^® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.     

A comparison of the central effects of different progestins used in hormone replacement therapy

Objective: To evaluate the central effect exerted by different progestins used for hormone replacement therapy. Methods: Randomised, placebo-controlled study. One hundred-twenty postmenopausal women on continuous hormonal replacement therapy with transdermal estradiol (50 μg per day) associated, for 10 days every 28 days, with four different progestins: dydrogesterone (DYD; 10 mg per day; n=20), medroxyprogesterone acetete (MPA; 10 mg per day; n=20), nomegestrol acetate (NMG; 5 mg per day; n=20) or norethisterone acetate (NETA; 10 mg per day; n=20). Other 40 women, 10 for each treatment group, were used as controls and were monitored for a single cycle of 28 days during the administration of transdermal estradiol plus placebo. Morning basal body temperature (BBT) was monitored for 28 days. Anxiety, by the state-trait anxiety inventory, and depression, by the self-evaluation depression scale of Zung, were evaluated just prior to and in the last 2 days of the 10-day progestins adjunct. Results: All progestins except DYD increased (P<0.0001) BBT by 0.3–0.5 °C. Anxiety was decreased by DYD (−2.3+1.1; P<0.01) and MPA (−1.5+0.5; P<0.01), but not by NMG or NETA. Depression did not significantly increase during progestins and actually decreased during MPA (−3.0+0.7; P<0.01). Only the effect of DYD on anxiety and that of MPA on depression were significant versus the control group (P<0.05). Conclusions: Different progestins exert different central effects. DYD has the peculiarity of not increasing BBT and of decreasing anxiety, which is also decreased by MPA. Depression is not negatively affected by the tested progestins and it may be ameliorated by MPA. The present data may help to individualise the progestin choice of hormone replacement therapy.     

白细胞介素-38的生物学功能及其与银屑病的关系

白细胞介素(IL)-38是近年来发现的IL-1家族的一员,由T淋巴细胞、B淋巴细胞、NK细胞、上皮细胞分泌.IL-38的特异性受体IL-1Rrp2-Fc广泛表达于各种免疫细胞表面.IL-38作为IL-1受体拮抗剂可能通过与其受体IL-1 Rrp2-Fc结合来发挥生物学效应.IL-38在Th17细胞相关的自身免疫性疾病中发挥着重要的调节作用.研究发现,IL-38可通过抑制Th17细胞的产生来缓解银屑病的进程,因此,其靶向疗法将为自身免疫病的治疗带来希望.     

纳米骨组织工程支架材料生物学效应研究进展

国内外学者将纳米技术运用于支架材料制备了一系列新型的骨组织工程支架材料,并对纳米生物学效应进行了深入的研究。纳米生物材料的生物学效应研究可以更好地从分子水平上认识材料与生命体的相互作用,为构建具有生理功能的新型生物材料提供研究思路和方向。为了更好地认识纳米材料对蛋白、细胞的影响和纳米材料的生物安全性问题,本文综述了近年来纳米骨组织工程支架材料的生物学效应研究进展。     

Modification of juvenile play and other social behaviour in the rat by neonatal progestins: further studies

The effects of altering neonatal levels of progestins on the later development of social play behaviour was studied. Progestin levels were raised in experiment one by administering injections of either progesterone or medroxyprogesterone acetate. This indicated that exposure to either hormone led to reduced levels of social play in juvenile rats of both sexes, confirming earlier reports of lowered levels of play following medroxyprogesterone obtained via maternal milk. In Experiment 2, endogenous progestin levels were lowered by administration of the antiserum to progesterone. The prediction that this should result in raised levels of juvenile play was supported for males, but not for females. Females in Experiment 2 by contrast showed a decrease in play. Possible reasons for this sex difference in response to progesterone antiserum are discussed.     

心力衰竭大鼠血清抗β1肾上腺素受体自身抗体的产生与生物学效应的研究

目的:建立心力衰竭大鼠模型，探讨心力衰竭发生发展过程与抗β₁肾上腺素受体（β₁AR）自身抗体产生的关系，并观察该抗体的生物学效应及其信号转导通路。 方法:采用缩窄腹主动脉法制备心力衰竭大鼠模型；应用酶联免疫吸附测定(ELISA)技术，检测心力衰竭大鼠血清中的抗β₁AR自身抗体；利用亲和层析法纯化心力衰竭大鼠抗体阳性血清中的IgG，观察该抗体IgG对乳鼠心肌细胞搏动频率和成年大鼠心肌细胞腺苷酸环化酶活性的影响。 结果:(1) 心力衰竭大鼠血清中抗β₁AR自身抗体的阳性率(82.8%)和抗体滴度［1∶(67.3±2.4)］明显高于假手术组5%, ［1∶(17.3±2.0)］(P＜0.01);(2) 纯化的抗体IgG既可增加乳鼠心肌细胞的搏动频率，还可增强成鼠心肌细胞腺苷酸环化酶的活性，使cAMP产生量增加。 结论:心力衰竭可以诱导大鼠血清中抗β1AR自身抗体的产生，该抗体具有激动剂样正性变时效应，可增强腺苷酸环化酶活性。提示该自身抗体可能通过β1AR-Gs-AC-cAMP-PKA信号通路对心脏产生病理损害。     

Identification of common polymorphisms in the coding sequence of the human MSH receptor (MCIR) with possible biological effects

The extension locus has been identified in many mammalian species as a gene that determines the relative amounts of eumelanin and phaeomelanin pigments in hair and skin. In at least three species, this locus has been demonstrated to encode the melanocyte-stimulating hormone receptor (MC1-R), and functionally variant alleles have been demonstrated to cause a broad range of pigmentation phenotypes. To test for MC1-R allelic variation in man, genomic DNA was extracted from skin samples collected from patients with different skin types (I–VI), and eye and hair color. A PCR-based approach was used to amplify the full-length coding sequence of the MC1-R and the resulting products were sequenced. Two polymorphic alleles were identified with single point mutations in the coding sequence: a valine-to-methionine substitution at position 92 (V92M), and an aspartic acid-to-glutamic acid substitution at position 84 (D84E). RFLP analysis demonstrated the presence of the V92M allele in 4 out of 60 (6.6%) of individuals examined, predominantly those with blue eyes and blond hair. This polymorphism was found in both heterozygous and homozygous states in individuals with type I skin. The D84E allele was found in one individual with skin type I; this person also has the V92 M allele and thus is a compound heterozygote. © 1997 Wiley-Liss, Inc.     

Lack of stimulatory effect of dienogest on the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by endothelial cell as compared with other synthetic progestins

Objectives: Monocyte adhesion to endothelial cells is an important initial event at the onset of atherosclerosis. It is partially mediated by the expression of adhesion molecules on the endothelial cell surface. While estrogens inhibit the development of atherosclerosis, the effect of co-administered progestin remains controversial. We examined the effect of progestins on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules. Methods: In HUVECs, mRNA expression of progesterone receptors (PRs) and androgen receptors (AR) was determined by RT-PCR. HUVECs were stimulated by interleukin-1β (IL-1β) for 24 h with or without various steroids, and then the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was semiquantified by ELISA. Results: In all preparations of HUVECs used in this study, RT-PCR confirmed mRNA expression of both isoforms of PR, PR-A and PR-B, as well as AR. Addition of progesterone (10⁻¹⁰–10⁻⁷ M) or dienogest (DNG) (10⁻¹⁰–10⁻⁸ M) did not affect IL-1β-stimulated ICAM-1 or VCAM-1 expression. In contrast, medroxyprogesterone acetate, norethindrone acetate and levonorgestrel (10⁻¹⁰–10⁻⁸ M) dose-dependently increased cell adhesion molecules. The progestin-induced increase was blocked by the concomitant addition of mifepristone, a PR antagonist, but not by hydroxyflutamide, an AR antagonist, indicating that the progestin stimulation was mediated predominantly via PR. Conclusions: These results suggest that DNG, unlike other synthetic progestins, lacks stimulation of cell adhesion molecules. For the prevention of atherosclerosis, estrogen in combination with DNG may be a suitable regimen in hormone replacement therapy in postmenopausal women.     

The significance of Wilms Tumor Gene (WT1) and p53 expression in curettage specimens of patients with endometrial carcinomas

In this retrospective experimental study, we assessed the immunohistochemical expression of Wilms Tumor Gene (WT1) and p53 in endometrial biopsies of patients with endometrial cancer, and correlated their expression with the final pathological findings.     

RAS基因多态性与子痫前期肾脏损害的相关性研究

目的探讨肾素-血管紧张素系统基因多态性与子痫前期患者肾脏损害的相关性。方法随机选择子痫前期患者72例,正常妊娠妇女45例,利用PCR和RFLP反应分析其外周血白细胞中ACE基因和AT1R1166基因多态性,比较不同基因型子痫前期患者蛋白尿含量和血清肾功能指标的差异。结果1.ACE基因多态性与尿蛋白含量密切相关,携带D等位基因孕妇的尿蛋白含量显著增加,血清肌酐、尿素氮水平呈上升趋势。2.ACE基因和AT1R1166基因型分布频率在子痫前期患者与正常孕妇间无显著差异。结论ACE基因与子痫前期肾脏损害密切相关,D等位基因是导致肾脏损害的不利因素。     

Analysis of vitamin D receptor gene polymorphisms in women with and without endometriosis

An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Genetic alterations in the vitamin D receptor gene (VDR) may lead to important defects in gene activation that principally affect immune function. We have hypothesized a possible relationship between endometriosis and/or infertility and the VDR polymorphisms (ApaI, TaqI, FokI, and BmsI). The study was a case-control study including 132 women with endometriosis-related infertility, 62 women with idiopathic infertility, and 133 controls. VDR polymorphisms were studied by restriction fragment length polymorphism. We found relatively similar VDR polymorphism genotype frequencies in cases and controls. When patients with minimal/mild and moderate/severe endometriosis were studied separately, no difference was found. When we compared infertile groups with and without endometriosis there was no statistically significant difference. The data suggest that VDR polymorphisms did not play an important role in the pathogenesis of endometriosis and/or infertility in the Brazilian women studied.     

Rapid and inexpensive real-time PCR for genotyping functional polymorphisms within the Toll-like receptor -2, -4, and -9 genes

The discovery of the human Toll-like receptors (TLRs) and the recognition of their pivotal role in sensing microbial pathogens during the last 5 years have resulted in a renewed appreciation of innate immunity. Due to their central role in both, triggering innate immunity as well as linking innate and adaptive immunity, genetic variations within the TLR genes, known to be associated with a variety of infectious diseases, are currently of great interest. Several single nucleotide polymorphisms (SNPs) within TLR genes have been described and seem to be associated with susceptibility to inflammatory diseases. However, methods for genotyping SNPs within the TLR genes, e.g. direct sequencing or polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis, are time-consuming. In this work, we report novel real-time PCR methods for genotyping five TLR SNPs within TLR-2, TLR-4 and TLR-9 that have been associated with various diseases using fluorescence labeled hybridization probes and the LightCycler instrument. In addition, we provide protocols employing a standard Taq polymerase in order to reduce substantially the costs for real-time PCR.     

Evaluation of PvuII and XbaI polymorphisms in the estrogen receptor alpha gene (ESR1) in relation to menstrual cycle timing and reproductive parameters in post-menopausal women

Objective: To evaluate the association of −397T>C and −351A>G single nucleotide polymorphisms (SNPs) – also called PvuII and XbaI, respectively – located on estrogen receptor alpha (ERS1) gene with age at menarche, menopause onset, fertility and miscarriage in a population of post-menopausal women. Study design: Cross-sectional study with 273 healthy, high miscegenated, post-menopausal women (mean age of 63.1 ± 9.7 years old). Subjects were genotyped for PvuII and XbaI SNPs by PCR-RFLP and confirmed by automatic sequencing. Reproduction informations (age at menarche, age at menopause, number of pregnancies, fertility rate and miscarriages) were obtained by retrospective study using a questionnaire. Result(s): Age at menarche, menopause onset, number of pregnancies, total fertility rate, and parity did not seem to be influenced by any of the studied genotypes (chi-square, p > 0.05). However, women carrying the xx genotype showed a 44% higher chance of miscarriage, whereas this value did not trespass 16% for any other genotype analyzed. It has been also observed a higher occurrence of miscarriage in association with combined xxpp genotype of ERS1 gene (chi-square, p < 0.01). Conclusion(s): The present data indicate that the studied SNPs on ERS1 gene do not influence the menstrual cycle timing and parity but there is a strong relationship between the xx ERS1 SNP genotype and the incidence of miscarriage in the post-menopausal population analyzed.     

Variables that may influence the alkaline sedimentation pattern of herpes simplex virus DNA

Summary Herpes simplex virus (HSV) DNA sediments homogeneously on a neutral sucrose gradient but heterogeneously on an alkaline sucrose gradient. Several factors that may influence the alkaline sedimentation pattern of HSV DNA were examined: e.g., the host cell, cell density at time of infection, multiplicity of infection, and the starting material for HSV DNA purification (whether HSV-infected cells or cell-free virus). Based on alkaline sedimentation analysis, these factors appear to play little or no role in the amount of intact single-stranded HSV DNA observed.With 4 Figures     

Family-based analysis of vitamin D receptor gene polymorphisms and type 1 diabetes in the population of South Croatia

Type 1 diabetes mellitus (T1DM) is a disease characterised by the autoimmune destruction of insulin-producing pancreatic β cells. Vitamin D is a known immune system modulator and its effects are exerted via the vitamin D receptor (VDR). Several VDR gene single nucleotide polymorphisms (SNPs) have been commonly studied in relation to T1DM. The aim of this study was to evaluate the role of VDR gene variation in T1DM susceptibility by genotyping four SNPs (FokI-rs10735810, TaqI-rs731236, BsmI-rs1544410, and Tru9I-rs757343) in 160 case–parent trio samples from the population of South Croatia. We observed overtransmission of Tru9I allele G and undertransmission of the Tru9I-BsmI A-A haplotype from parents to affected children (P = 0.032, P = 0.002, respectively). These results indicate a possible role of the VDR gene in T1DM aetiology. In conclusion, this family-based study presents some evidence of association of specific VDR gene variants with T1DM in the population of South Croatia.     

Gender differences in the IL6 -174G>C and ESR2 1730G>A polymorphisms and the risk of Parkinson's disease

The −174G>C (rs1800795) single nucleotide polymorphism (SNP) in the promoter of the interleukin-6 (IL6) gene and the 1730G>A (rs4986938) SNP in the estrogen receptor beta (ESR2) may influence the risk of Parkinson's disease (PD). We investigated these SNPs in 380 unrelated US Caucasian PD cases and 522 controls, including 452 individuals of Ashkenazi Jewish (AJ) origin (260 PD, 192 controls). The G allele of the −174G>C SNP was more common in AJ PD cases (p = 0.033) as well as in Non-Jewish (NJ) men with PD (p = 0.022). The GG genotype increased the risk of PD by over two fold in NJ men (OR = 2.11, 95%CI: 1.14-3.89, p = 0.017), and approached significance in the total AJ group with PD (OR = 1.42, 95%CI: 0.97-2.06, p = 0.067). The A allele of the ESR2 1730G>A SNP was associated with a decreased risk for PD in AJ women, and in this group, having the AA genotype decreased the risk of PD by half (OR = 0.45, 95%CI: 0.22-0.92, p = 0.029). Our data supports a role for the IL6 −174G>C G allele in AJ individuals overall. In NJ Caucasians, this role appears to be gender mediated. In both groups, the effect is independent from ESR2 1730G>A. A separate association for the ESR2 1730G>A SNP was found exclusively in women of AJ descent. Other polymorphisms in tight linkage disequilibrium with the SNP differentially influencing expression, ethnic differences in allele distribution, and gender differences in genetic load related to PD, may underlie our findings. Larger studies in diverse populations, including analysis of surrounding regions are recommended.