A Novel Ecdysone Receptor Mediates Steroid-Regulated Developmental Events during the Mid-Third Instar of Drosophila

The larval salivary gland of Drosophila melanogaster synthesizes and secretes glue glycoproteins that cement developing animals to a solid surface during metamorphosis. The steroid hormone 20-hydroxyecdysone (20E) is an essential signaling molecule that modulates most of the physiological functions of the larval gland. At the end of larval development, it is known that 20E—signaling through a nuclear receptor heterodimer consisting of EcR and USP—induces the early and late puffing cascade of the polytene chromosomes and causes the exocytosis of stored glue granules into the lumen of the gland. It has also been reported that an earlier pulse of hormone induces the temporally and spatially specific transcriptional activation of the glue genes; however, the receptor responsible for triggering this response has not been characterized. Here we show that the coordinated expression of the glue genes midway through the third instar is mediated by 20E acting to induce genes of the Broad Complex (BRC) through a receptor that is not an EcR/USP heterodimer. This result is novel because it demonstrates for the first time that at least some 20E-mediated, mid-larval, developmental responses are controlled by an uncharacterized receptor that does not contain an RXR-like component

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.<br /

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.<br /

Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

<p>Abstract</p> <p>Background</p> <p>Sublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context.</p> <p>Methods</p> <p>Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks.</p> <p>Results</p> <p>Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats.</p> <p>Conclusions</p> <p>Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and suggest that angiotensin II may participate in maintaining the basal rate of granule cell neurogenesis.</p

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Selected metalloproteinases and their inhibitors in prediction of nifedypine tocolysis effectiveness

Wprowadzenie i cel pracy. Za jedną z przyczyn wystąpienia porodu przedwczesnego uważa się zakażenie wewnątrzmaciczne. Metaloproteinazy oraz ich inhibitory pełnią istotną rolę w czasie ciąży, porodu i połogu. Umożliwiają migrację komórek odpowiedzi zapalnej do uszkodzonych tkanek, uwalniają cytokiny i ich receptory z błon komórkowych. Celem pracy była ocena zależności pomiędzy aktywnością: metaloproteinaz MMP-2 i MMP-9, ich inhibitorów TIMP-1 i TIMP-2 (u pacjentek z porodem przedwcześnie zagrażającym) oraz skutecznością tokolizy nifedypiną. Materiał i metoda. Badaniem objęto 21 kobiet z porodem przedwczesnym oraz 35 zdrowych ciężarnych poniżej 37. tygodnia trwania ciąży. Pacjentki podzielono na trzy grupy: pierwszą grupę stanowiły pacjentki z porodem przedwczesnym z nieskuteczną tokolizą, grupę drugą kobiety z objawami porodu przedwczesnego, u których powiodła się tokoliza, grupę trzecią zdrowe ciężarne. Poziom MMP-2, MMP-9 oraz TIMP1 i TIMP2 w surowicy oceniano przy pomocy testu immunoenzymatycznego ELISA. Wyniki. Średnie stężenie MMP-2 w surowicy badanych chorych nie różniło się istotnie w porównaniu z grupą kontrolną. U kobiet z porodem przedwczesnym poziom MMP-9 był wyższy w porównaniu do zdrowych ciężarnych. Stężenie TIMP-1 i TIMP-2 w surowicach ciężarnych z porodem przedwczesnym było wyższe w porównaniu z wynikami uzyskanymi w grupie kontrolnej. Stwierdzono, że u kobiet z porodem przedwczesnym z nieskuteczną tokolizą, poziom TIMP-1 był wyższy, natomiast poziom TIMP-2 był istotnie niższy w porównaniu do ciężarnych z objawami porodu przedwczesnego, u których powiodła się tokoliza. Wnioski. Nieskuteczna tokoliza u kobiet z porodem przedwczesnym może wynikać z zaawansowania procesu zapalnego w momencie rozpoczęcia terapii. Pobudzenie aktywności proteolitycznej składowych układu żelatynazy/inhibitory może świadczyć o aktywnym procesie prowadzącym do skracania i rozwierania się szyjki macicy w przypadku porodu przedwczesnego, a nasilenie aktywności czynników hamujących stanowi mechanizm obronny.Introduction. Matrix metalloproteinases and their inhibitors play an important role in pregnancy, childbirth and postpartum. This system allows inflammatory response cells migration to damaged tissues, release cytokines and cytokine receptors. Preterm cervical ripening is an inflammatory process, with cytokines as important mediators. Objective. The purpose of this study was to evaluate the relationship between metalloproteinases MMP -2 and MMP -9 and their inhibitors TIMP -1 and TIMP -2 in patients with preterm labour in the prediction of nifedypine tocolysis efficacy. Material and Methods. The study included 21 women with preterm labour and 35 healthy pregnant women below 37 weeks of gestation. The patients were divided into three groups: the first group consisted of patients with preterm labour with ineffective tocolysis, the second group of women with preterm labour responded to tocolysis, the third group consisted of healthy pregnant women. The level of serum MMP -2, MMP – 9 and TIMP1 and TIMP2 was assessed using the ELISA kit. Results. The concentration of MMP -2 in preterm labour patients was not significantly different compared to the control group. In women with a preterm labour level of MMP -9 was higher than in healthy pregnant women. The concentration of TIMP -1 and TIMP -2 in sera of pregnant women with preterm delivery was higher compared to the control group. It was found that in women with preterm labour with ineffective tocolysis, the level of TIMP -1 was higher, while the level of TIMP -2 was significantly lower compared to pregnant women with ineffective tocolysis. Conclusions. Ineffective tocolysis may be due to the stage of inflammation at the start of therapy. Activation of the proteolytic activity of gelatinase / inhibitors system may indicate an active process leading to cervix shortening and dilating in preterm labour, and increased activity of metalloproteinase inhibitors is probably a defence mechanism, as noted