scholarly journals Glucocorticoid metabolism and reproduction: a tale of two enzymes

Reproduction ◽  
2003 ◽  
pp. 425-441 ◽  
Author(s):  
AE Michael ◽  
LM Thurston ◽  
MT Rae
Keyword(s):  
Target Cells ◽  
Cellular Mechanisms ◽  
Cortisol Metabolism ◽  
Wide Range ◽  
Uterine Growth ◽  
Enzymatic Inactivation ◽  
Intra Uterine Growth Retardation ◽  
Endogenous Modulators ◽  
Glucocorticoid Metabolism ◽  
Reproductive Processes

Within potential target cells, the actions of physiological glucocorticoids (cortisol and corticosterone) are modulated by isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). To date, two isoforms of 11 beta HSD have been cloned: 11 beta HSD1 acts predominantly as an NADP(H)-dependent reductase to generate active cortisol or corticosterone, and 11 beta HSD2 is a high affinity NAD(+)-dependent enzyme that catalyses the enzymatic inactivation of glucocorticoids. Whereas the regeneration of active glucocorticoids by 11 beta HSD1 has been implicated in the cellular mechanisms of pituitary function, ovulation and parturition, the enzymatic inactivation of cortisol and corticosterone by 11 beta HSD enzymes appears to be central to the protection of gonadal steroidogenesis, prevention of intra-uterine growth retardation, and lactation. Recent evidence indicates that follicular fluid contains endogenous modulators of cortisol metabolism by 11 beta HSD1, the concentrations of which are associated with the clinical outcome of assisted conception cycles and are altered in cystic ovarian disease. In conclusion, the two cloned isoforms of 11 beta HSD fulfil diverse roles in a wide range of reproductive processes from conception to lactation.

scholarly journals Inactivation of glucocorticoids by 11β-hydroxysteroid dehydrogenase enzymes increases during the meiotic maturation of porcine oocytes

Reproduction ◽  
2008 ◽  
Vol 136 (6) ◽  
pp. 725-732 ◽  
Author(s):  
Rachel J Webb ◽  
Neera Sunak ◽  
Lisa Wren ◽  
Anthony E Michael
Keyword(s):  
Oocyte Maturation ◽  
Enzyme Activities ◽  
Germinal Vesicle ◽  
Hydroxysteroid Dehydrogenase ◽  
Target Cells ◽  
Cortisol Metabolism ◽  
Enzymatic Inactivation ◽  
Glucocorticoid Metabolism ◽  
Ovarian Cyst Fluid

Recent reports have shown that glucocorticoids can modulate oocyte maturation in both teleost fish and mammals. Within potential target cells, the actions of physiological glucocorticoids are modulated by 11β-hydroxysteroid dehydrogenase (HSD11B) isoenzymes that catalyse the interconversion of cortisol and cortisone. Hence, the objective of this study was to establish whether HSD11B enzymes mediate cortisol–cortisone metabolism in porcine oocytes and, if so, whether the rate of glucocorticoid metabolism changes during oocyte maturation. Enzyme activities were measured in cumulus–oocyte complexes (COCs) and denuded oocytes (DOs) using radiometric conversion assays. While COCs and DOs oxidised cortisol to inert cortisone, there was no detectable regeneration of cortisol from cortisone. The rate of cortisol oxidation was higher in expanded COCs than in compact COCs containing germinal vesicle (GV) stage oocytes (111±6 vs 2041±115 fmol cortisone/oocyte.24 h; P<0.001). Likewise, HSD11B activities were 17±1 fold higher in DOs from expanded COCs than in those from compact COCs (P<0.001). When GV stage oocytes were subject to a 48 h in vitro maturation protocol, the enzyme activities were significantly increased from 146±18 to 1857±276 fmol cortisone/oocyte.24 h in GV versus MII stage oocytes respectively (P<0.001). Cortisol metabolism was inhibited by established pharmacological inhibitors of HSD11B (glycyrrhetinic acid and carbenoxolone), and by porcine follicular and ovarian cyst fluid. We conclude that an HSD11B enzyme (or enzymes) functions within porcine oocytes to oxidise cortisol, and that this enzymatic inactivation of cortisol increases during oocyte maturation.

Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

2019 ◽  
Vol 19 (15) ◽  
pp. 1835-1845
Author(s):  
Ali Hassanzadeh ◽  
Adel Naimi ◽  
Majid F. Hagh ◽  
Raedeh Saraei ◽  
Faroogh Marofi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Annexin V ◽  
Death Receptors ◽  
Target Cells ◽  
Wide Range ◽  
Apoptotic Proteins ◽  
Necrosis Factor

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL. Material and Methods: First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique. Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells. Conclusion: We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

The role of exploratory mechanisms in evolution

1995 ◽  
Vol 349 (1329) ◽  
pp. 297-297
Keyword(s):  
Dynamic Instability ◽  
Specific Mechanism ◽  
Cellular Mechanisms ◽  
Selection Processes ◽  
Wide Range ◽  
Rapid Changes ◽  
Neuronal Processes ◽  
History Of ◽  
Variation And Selection

Many cellular mechanisms use a process of variation and selection to generate specific patterns. Among these, dynamic instability of microtubules has been shown to employ a specific mechanism to intentionally generate variation. In many systems the growth of neurons or neuronal processes is excessive, the final connections being established by stabilization of functional interactions. When changes in neuronal networks take place, such as in metamorphosis, use is made of the plasticity of neuronal connectivity. In the immune system, specific responses are generated by variation and selection. Processes that explore a wide range of conditions and a wide range of structures can be called exploratory processes. These are very robust and capable of responding to damage, variability in the environment and ontogenic changes in the organisms. Such robustness would be useful for adapting to changes that occur during phylogenetic changes as well. Given the extensive history of extinction and radiation in evolution, it may be supposed that these mechanisms have themselves been selected for their capacity to survive rapid changes in the organism and for their ability to generate cellular variation.

scholarly journals Effects of prenatal glucocorticoid exposure on cardiac calreticulin and calsequestrin protein expression during early development and in adulthood

2003 ◽  
Vol 371 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Maria L. LANGDOWN ◽  
Mark J. HOLNESS ◽  
Mary C. SUGDEN
Keyword(s):  
Cardiac Function ◽  
Protein Expression ◽  
Growth Retardation ◽  
Premature Death ◽  
Fetal Life ◽  
Dexamethasone Treatment ◽  
Increased Risk ◽  
Uterine Growth ◽  
Intra Uterine Growth Retardation ◽  
Glucocorticoid Action

Overexpression of the conserved Ca2+-binding proteins calreticulin and calsequestrin impairs cardiac function, leading to premature death. Calreticulin is vital for embryonic development, but also impairs glucocorticoid action. Glucocorticoid overexposure during late fetal life causes intra-uterine growth retardation and programmed hypertension in adulthood. To determine whether intra-uterine growth retardation or programmed hypertension was associated with altered calreticulin or calsequestrin expression, effects of prenatal glucocorticoid overexposure (maternal dexamethasone treatment on days 15—21 of pregnancy) were examined during fetal life and postnatal development until adulthood (24 weeks). Dexamethasone (100 or 200μg/kg of maternal body weight) was administered via osmotic pump. Calreticulin was detected as a 55kDa band and calsequestrin as 55 and 63kDa bands in 21 day fetal hearts. Only the 55kDa calsequestrin band was detected postnatally. Prenatal glucocorticoid overexposure at the higher dose decreased calreticulin protein expression (26%; P<0.05) but increased calsequestrin protein expression, both 55 and 63kDa bands, by 87% (P<0.01) and 78% (P<0.01); only the 55kDa calsequestrin band was increased at the lower dose (66%; P<0.05). Offspring of dams treated at the lower dexamethasone dose were studied further. In control offspring, cardiac calreticulin protein expression declined between 2 and 3 weeks of age, and remained suppressed until adulthood. Cardiac calsequestrin protein expression increased 2-fold between fetal day 21 and postnatal day 1 and continued to increase until adulthood, at which time it was 3.4-fold higher (P<0.001). Prenatal dexamethasone exposure minimally affected postnatal calsequestrin protein expression, but the postnatal decline in calreticulin protein expression was abrogated and calreticulin protein expression in adulthood was 2.2-fold increased (P<0.001) compared with adult controls. In view of the known associations between cardiac calreticulin overexpression and impaired cardiac function, targeted up-regulation of calreticulin may contribute to the increased risk of adult heart disease introduced as a result of prenatal overexposure to glucocorticoids.

Association of increased maternal ferritin levels with gestational diabetes and intra-uterine growth retardation

2010 ◽  
Vol 36 (1) ◽  
pp. 58-63 ◽  
Author(s):  
V. Soubasi ◽  
S. Petridou ◽  
K. Sarafidis ◽  
Ch. Tsantali ◽  
E. Diamanti ◽  
...  
Keyword(s):  
Gestational Diabetes ◽  
Growth Retardation ◽  
Uterine Growth ◽  
Intra Uterine Growth Retardation

scholarly journals MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 240 ◽  
Author(s):  
Abha Sahni ◽  
Hema Narra ◽  
Jignesh Patel ◽  
Sanjeev Sahni
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Host Cells ◽  
Microvascular Endothelial Cells ◽  
Target Cells ◽  
Fibroblast Growth ◽  
Wide Range ◽  
Microvascular Endothelial

Microvascular endothelial cells (ECs) represent the primary target cells during human rickettsioses and respond to infection via the activation of immediate–early signaling cascades and the resultant induction of gene expression. As small noncoding RNAs dispersed throughout the genome, microRNAs (miRNAs) regulate gene expression post-transcriptionally to govern a wide range of biological processes. Based on our recent findings demonstrating the involvement of fibroblast growth factor receptor 1 (FGFR1) in facilitating rickettsial invasion into host cells and published reports suggesting miR-424 and miR-503 as regulators of FGF2/FGFR1, we measured the expression of miR-424 and miR-503 during R. conorii infection of human dermal microvascular endothelial cells (HMECs). Our results revealed a significant decrease in miR-424 and miR-503 expression in apparent correlation with increased expression of FGF2 and FGFR1. Considering the established phenomenon of endothelial heterogeneity and pulmonary and cerebral edema as the prominent pathogenic features of rickettsial infections, and significant pathogen burden in the lungs and brain in established mouse models of disease, we next quantified miR-424 and miR-503 expression in pulmonary and cerebral microvascular ECs. Again, R. conorii infection dramatically downregulated both miRNAs in these tissue-specific ECs as early as 30 min post-infection in correlation with higher FGF2/FGFR1 expression. Changes in the expression of both miRNAs and FGF2/FGFR1 were next confirmed in a mouse model of R. conorii infection. Furthermore, miR-424 overexpression via transfection of a mimic into host ECs reduced the expression of FGF2/FGFR1 and gave a corresponding decrease in R. conorii invasion, while an inhibitor of miR-424 had the expected opposite effect. Together, these findings implicate the rickettsial manipulation of host gene expression via regulatory miRNAs to ensure efficient cellular entry as the critical requirement to establish intracellular infection.

Tyrosine α ketoglutarate transaminase in the liver of rats with intra-uterine growth retardation

Life Sciences ◽  
1971 ◽  
Vol 10 (19) ◽  
pp. 1115-1123
Author(s):  
C. Degremont ◽  
J.M. Roux ◽  
E. Swierczewski ◽  
C. Tordet-Caridroit
Keyword(s):  
Growth Retardation ◽  
Uterine Growth ◽  
Intra Uterine Growth Retardation

scholarly journals USE OF MICRONUCLEUS EXPERIMENTS FOR THE DETECTION OF HUMAN CANCER RISKS: A BRIEF OVERVIEW

2021 ◽  
Vol 65 (2) ◽  
Author(s):  
Armen Nersesyan ◽  
◽  
Miroslav Mišík ◽  
Andriy Cherkas ◽  
Viktoria Serhiyenko ◽  
...  
Keyword(s):  
Blood Cells ◽  
Environmental Control ◽  
Human Cancer ◽  
Occupational Exposures ◽  
Human Biomonitoring ◽  
Target Cells ◽  
Cancer Risks ◽  
Wide Range

Introduction. Micronuclei (MN) are small extranuclear DNA-containing structures that are formed as a consequence of structural and numerical chromosomal aberrations. The advantage of MN experiments compared to conventional chromosomal analyses in metaphase cells is that the scoring is by far less time consuming and laborious. MN experiments are currently widely used for the routine screening of chemicals in vitro and in vivo but also for environmental control and human biomonitoring Objectives. The purpose of this review was to collect data on the use of MN experiments for the detection of increased cancer risks as a consequence of environmental, lifestyle and occupational exposures and the detection/diagnosis of different forms of cancer. Methods. Analysis of the literature on methods for MN experiments with humans; as well as the use of this technique in different areas of research. Results. To date, a wide range of protocols for human biomonitoring studies has been developed for the measurement of MN formation in peripheral blood cells and in epithelial from different organs (buccal and nasal cavity, cervix and bladder). In addition to MN, other nuclear anomalies can be scored which reflect genetic instability as well as acute toxicity and the division of target cells. Conclusions. The evidence is accumulating that MN can be used as a diagnostic tool for the detection of increased cancer risks as well as for the early diagnosis of cervical and bladder cancer

scholarly journals An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

2021 ◽  
Author(s):  
Darcy S.O. Mora ◽  
Madeline Cox ◽  
Forgivemore Magunda ◽  
Ashley B. Williams ◽  
Lyndsey Linke
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Nucleic Acids ◽  
Endosomal Escape ◽  
Therapeutic Window ◽  
Target Cells ◽  
Full Potential ◽  
Wide Range ◽  
Delivery Platform

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza- targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

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