PROGINS Mutation of Progesterone Receptors and Its Role in Premature Birth – An Overview

Premature ( or preterm ) birth ( birth prior 37 weeks of gestation ) is big worldwide medical and socioeconomic problem. It percentage is 8-12% of total number of births, and apart from the increased mortality of newborns, it is also cause of increased morbidity in for it. worldwide, as far as some statistical reviewes say, 15 million of babies per year are preterm born. Despite the frequency, consequences and costs of premature delivery, very little has been done for preventing it, especially for preventing early premature deliveries. Etiology of premature labor is multifactorial, and includes pathophysiology, genetics and enviromental factors. Resent scientific researches, particulary in the field of human genomics, show that genetic factors, mostly present in genome of mother, contribute up to 40% variation in delivery time. It is belived that premature birth has same cascade of events like normal birth; just in this case it starts sooner. This process is controlled by series of hormonal effects between fetus, placenta and mother. One of the key signaling pathways in this series is progesterone one. PROGINS allele is progesterone receptor gene modification. It is built of 3 variants : V660L,H770H and alu insertion. Progesterone receptors with PROGINS mutation are less susceptible to progesteron activity, and it looks as the withdrawal of progesterone causes the beggining of birth cascade. +331G/A progesterone receptor mutation is newly discovered mutation. It is belived that this mutation leads to PR-a an PR-B receptor quantity disorder before delivery term. The aim of this review is to resume all recent aknowledgements about PROGINS and +331G/A mutation of progesterone receptor and see if there is the value of these genetic mutations in modulation of risk for preterm birth

Comprehensive data analysis to study parturition

Our limited understanding of the molecular mechanisms driving the onset of normal human parturition makes it difficult to identify ‘what goes wrong’ in conditions such as preterm labour (PTL), preterm prelabour rupture of membranes (PPROM) and postpartum haemorrhage (PPH). This incomplete understanding seriously hampers the development of effective ways to predict, prevent and treat parturition complications, which are a cause of significant neonatal and maternal morbidity. Two principal barriers to improving our understanding are 1) the great complexity of both the molecular interactions initiating parturition and the aetiology of parturition complications, and 2) the difficulty in generating relevant high quality molecular and epidemiological data. To help make sense of this complexity, data should be analysed comprehensively to maximise the amount of useful information gleaned from it. This thesis aimed to explore the use of specialist methods to analyse novel and previously published data to study the molecular mechanisms initiating human parturition and the epidemiology of parturition complications. The molecular mechanisms initiating parturition were explored through a gene expression microarray of labouring and non-labouring myometrial tissue. This is the largest microarray of its kind to date. Functional analysis and a network graph approach were used to reveal genes and molecular pathways associated with labour. The first ever meta-analysis of similar myometrial microarray datasets was also conducted to assess the reliability and generalisability of the results. This work supported the hypothesis that labour is associated with inflammatory events in the myometrium. A computer model of an inflammatory signalling pathway associated with infection-induced PTL was then built to provide proof of concept that such models can be used to study parturition. The model was based on published data and described lipopolysaccharide-induced activation of the transcription factor Nuclear Factor kappa B (NF-κB). This is the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of PTL, and the first model of this pathway to explicitly include molecular interactions upstream of NF-κB activation. The epidemiology of complications at parturition was explored using three methods. Firstly, a novel approach was developed to use network graphs to visualise and analyse a dataset of nearly 50,000 birth records. The approach provided a quick and effective way to preliminarily explore relationships between exposures and pregnancy outcomes in an unbiased data-driven manner. Secondly, a record-linkage study of two datasets of birth records was conducted to determine risk factors for PPH, including intergenerational transmission of risk. This confirmed several known risk factors of PPH and showed that women whose mothers or grandmothers had PPH do not appear to be at increased risk themselves. Finally, a systematic review and meta-analysis of three randomised controlled trials investigated the effectiveness of fetal assessment methods in improving maternal and neonatal outcomes following PPROM. The review concluded that there is currently insufficient evidence on the benefits and harms of any method of fetal assessment, and further randomised controlled trials are required

Digital Infrared Thermal Imaging and its use in Domestic and Non-Domestic Species

Digital infrared thermal imaging (DITI) is a non-invasive diagnostic technique that is used to detect symmetry and asymmetry of surface temperature gradients. DITI can examine many different aspects of thermal physiology and diagnose injury and disease. The objectives of this study were (1) to investigate the use of DITI to determine whether differences in temperature gradients exist between late gestation and non-pregnant mares, (2) to evaluate whether velvet antler (VA) temperature gradients, as measured by DITI would pattern VA growth, and (3) to determine if “normal” temperature gradients of the foot exist among elephants as detected using DITI. To investigate these objectives, three experiments were conducted to determine the value of DITI for research on mammals. Results obtained from the first study indicate DITI was able to detect pregnancy in the horse during late gestation. In the second study DITI successfully patterned the growth and hardening of VA. While in the third study DITI demonstrated its value as a tool to increase overall welfare for captive elephants. In summary these studies suggests that DITI may have value in conducting research with domestic and non-domestic species that are not able to be restrained

Digital Infrared Thermal Imaging and its use in Domestic and Non-Domestic Species

Digital infrared thermal imaging (DITI) is a non-invasive diagnostic technique that is used to detect symmetry and asymmetry of surface temperature gradients. DITI can examine many different aspects of thermal physiology and diagnose injury and disease. The objectives of this study were (1) to investigate the use of DITI to determine whether differences in temperature gradients exist between late gestation and non-pregnant mares, (2) to evaluate whether velvet antler (VA) temperature gradients, as measured by DITI would pattern VA growth, and (3) to determine if “normal” temperature gradients of the foot exist among elephants as detected using DITI. To investigate these objectives, three experiments were conducted to determine the value of DITI for research on mammals. Results obtained from the first study indicate DITI was able to detect pregnancy in the horse during late gestation. In the second study DITI successfully patterned the growth and hardening of VA. While in the third study DITI demonstrated its value as a tool to increase overall welfare for captive elephants. In summary these studies suggests that DITI may have value in conducting research with domestic and non-domestic species that are not able to be restrained

Embryology

Embryology is a branch of science concerned with the morphological aspects of organismal development. The genomic and molecular revolution of the second half of the 20th century, together with the classic descriptive aspects of this science have allowed greater integration in our understanding of many developmental events. Through such integration, modern embryology seeks to provide practical knowledge that can be applied to assisted reproduction, stem cell therapy, birth defects, fetal surgery and other fields. This book focuses on human embryology and aims to provide an up-to-date source of information on a variety of selected topics. The book consists of nine chapters organized into three sections, namely: 1) gametes and infertility, 2) implantation, placentation and early development, and 3) perspectives in embryology. The contents of this book should be of interest to biology and medical students, clinical embryologists, laboratory researchers, obstetricians and urologists, developmental biologists, molecular geneticists and anyone who wishes to know more about recent advances in human development

Function of the Myc-binding protein Miz1 in the mouse mammary gland

The study of the expression and function of proteins important for human health in normal development provides valuable information for the design of therapeutical opportunities in the context of disease. Myc is one of the current most promising targets for a number of cancer types including triple-negative breast cancer and Miz1 has been shown to play an important role in Myc-mediated tumorigenesis. In the present work, the function of the Myc-binding protein Miz1 in the mammary gland is investigated for the first time using two different lines of transgenic mice expressing Cre-recombinase to conditionally knockout the POZ domain of Miz1 in the murine mammary gland. Deletion of this evolutionary-conserved region impedes multimerization and stable association of Miz1 with chromatin. MMTV-Cre mediated deletion was used to investigate Miz1 function in the virgin gland, considering branching morphogenesis and mammary stem/progenitor biology. Ablation under the Wap-Cre promoter provided information about alveologenesis and mammary differentiation. The mammary gland is a very suitable organ for stem cell and developmental studies as rounds of proliferation, differentiation and apoptosis occur after each pregnancy. POZ domain deletion using MMTV-Cre (Line A), already active in the embryo, led to a delayed ductal tree formation, less cellularity in knockout ducts and a Myc-independent accumulation of stem/progenitor cells in virgin mammary glands of Miz1DPOZ animals. No differences in the expression of luminal and myoepithelial markers were observed between control and Miz1DPOZ virgin mice. In addition, the delay in the development of the mammary ductal tree in knockout mice is rescued at around two months of age. Endogenous Miz1 expression in the mammary gland of control animals was found to be highly boosted during lactation by immunohistochemistry and Western blotting. Very low Miz1 levels were detected at the end of pregnancy, which increased after parturition and diminished upon cessation of pup suckling at around 48 hours of forced involution. Miz1 POZ domain ablation in luminal alveolar mammary cells during pregnancy using the WAP-Cre transgenic line resulted in a lactation defect in mutant dams during the first two pregnancies analysed. Mutant lactating glands display a reduced alveologenesis as a result of a diminished mammary cell proliferation and differentiation. These data were also confirmed in vitro using the HC11 murine mammary cell line after retroviral infection for stable knockdown of Miz1. HC11 cells with low levels of Miz1 show a reduced proliferation and a decreased expression of ß-casein after inducing differentiation by addition of a lactogenic hormone cocktail containing prolactin. Apoptosis is unaffected after either Miz1 POZ domain ablation in vivo or stable knockdown of Miz1 in vitro. Mutant glands display lower levels of activated Stat5 which lead to a reduced expression of its transcriptional targets, mainly genes which code for milk proteins like a-casein, b-casein or whey acidic protein (WAP). Gene expression of negative regulators of the Jak2/Stat5 pathway like Socs (Socs1, Socs2 and Socs3) or Caveolin-1 (Cav1) is not upregulated in Miz1DPOZ lactating glands. In contrast, the expression of receptors important for a proper phosphorylation of Stat5, like the prolactin receptor or ErbB4, is decreased in lactating mutant glands. ChIP-Seq experiments revealed that genes encoding the prolactin receptor and ErbB4 are not direct targets of Miz1. Rather, Miz1 binds to genes which regulate vesicular transport and thus alters processes like endocytosis and autophagy in mammary gland cells. A model in which the vesicular transport of these receptors in mutant glands could be disrupted is proposed. In conclusion, this work shows for the first time that Miz1 is important for mammary stem/progenitor cell regulation in the virgin gland and for a proper proliferation and differentiation in the lactating mammary gland

Male Reproductive Anatomy

The male reproductive system, which is made up of the testes, scrotum, epididymis, vas deferens, seminal vesicles, prostate gland, bulbourethral gland, ejaculatory duct, urethra, and penis, functions mainly in the production, nourishment, and temporary storage of spermatozoa. Epigenetic modifications are essential to regulate normal gonadal development and spermatogenesis. The sperm epigenome is highly susceptible influence by a wide spectrum of environmental stimuli. This book focuses on the male reproductive system, discussing topics ranging from aspects of anatomy and risk factors for male infertility to clinical techniques and management of male reproductive health

Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds