Steroid Action Research Articles

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs

Fetal growth restriction (FGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

Genistein and Sex Hormone Supplementation Modulated Hepatic PPARα, δ, and γ Subtypes and STAT1 Expressions in a NASH Rat Model with Bilateral Orchidectomy.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic inflammation and steatosis. Currently, limited data exist regarding the risk of NASH in transgender women and the treatment options for this particular population. The use of testosterone supplementation is unfavorable for transgender women, and estrogen supplementation is linked to an increased risk of breast cancer; thus, an isoflavone derivative compound known as "genistein" could serve as a viable substitute for a hormone supplement in this context. The purpose of this study was to investigate the treatment effects and mechanisms of actions of genistein and sex hormones in orchidectomized (ORX) rats with nonalcoholic steatohepatitis induced via a high-fat high-fructose diet (HFHF) model. Male Sprague-Dawley rats (n = 42) were randomly assigned into seven groups; control, ORX + standard diet, HFHF, ORX + HFHF, ORX + HFHF diet + testosterone (50 mg/kg body weight (BW) once weekly), ORX + HFHF diet + estradiol (1.6 mg/kg BW daily), and ORX + HFHF diet + genistein (16 mg/kg BW daily). The duration of the study was 6 weeks. Some parts of liver tissue were used for histological examination by H&E staining. The determination of fat accumulation was performed using Oil Red O staining. SREBP1c and FAS gene expression were quantified using real-time PCR technique. The levels of all types of peroxisome proliferator-activated receptors (PPARs; α, δ, γ), proteins, and signal transducer and activator of transcription 1 (STAT1) signaling pathway were determined by both immunoblotting and immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, and hepatocyte ballooning, and showed higher levels of genes related to de novo lipogenesis, including SREBP1c and FAS. The expression of PPARγ and STAT1 were upregulated, while the expression of PPARα and PPARδ were downregulated in the ORX + HFHF group. Testosterone, estradiol and genistein treatments improved NASH histopathology together with the reversal of all types of PPAR protein expressions. Interestingly, genistein decreased the levels of STAT1 protein expression more than those of testosterone and estradiol treatment. Genistein and sex hormone treatment could ameliorate NASH through the upregulation of PPARα, and PPARδ, and the suppression of PPARγ and STAT1 expression.

Vitamin D3 promotes gastric cancer cell autophagy by mediating p53/AMPK/mTOR signaling.

Objective: Vitamin D3 has the general properties of a lipid-soluble vitamin, but is also an active steroid hormone that can regulate the proliferation, apoptosis and differentiation of many tumor cells, and exerts anticancer activity against numerous malignancies. However, the mechanism underlying the effects of vitamin D3 on tumors is not fully understood. Here, we used network pharmacology and in vitro experimental approaches to explore the mechanism of vitamin D3 activity in the context of gastric cancer. Methods: The Targetnet, SuperPred, SwissTargetPrediction, and PharmMapper databases were screened for potential drug-related targets, while we used data from the PharmGKB, Drugbank, OMIM, DisGeNET, CTD, and GeneCards databases to identify potential targets associated with gastric cancer. Disease-drug crossover genes were obtained by constructing Venn diagrams. Gene ontology and Kyoto Encyclopedia of Genomes (KEGG) enrichment analyses of crossover genes were conducted and STRING was used to generate protein interaction networks and identify core targets. CCK-8 experiments were performed and apoptosis detected to assess the effect of vitamin D3 on gastric cancer cells. Western blotting was applied to detect p53/AMPK/mTOR signaling, as well as autophagy-, cell cycle-, and apoptosis-related proteins. Results: A total of 485 targets of vitamin D3 activity were obtained and 1200 gastric cancer disease-related targets discovered. Further, 60 potential targets for vitamin D3 in gastric cancer treatment were identified. KEGG analysis indicated that potential targets were mainly involved in the cell cycle, HIF-1 signaling, and the AMPK pathway, among other pathways. These findings were validated using cellular experiments, which demonstrated that the viability of AGS and SGC-7901 cells was impeded by vitamin D3. Further, vitamin D3 promoted apoptosis and inhibited the cell cycle in those cell lines, as well as activating the p53/AMPK/mTOR pathway, which promotes autophagy and inhibits tumor development. Conclusion: Our network pharmacological analyses provide preliminarily data supporting a role for vitamin D3 in promoting autophagy and apoptosis in gastric cancer cells, and in activating the p53/AMPK/mTOR pathway, which inhibits gastric cancer cell proliferation. Our findings demonstrate the molecular mechanism underlying the effect of vitamin D3 in cure of gastric cancer.

Steroid hormone signaling: multifaceted support of testicular function.

Embryonic development and adult physiology are dependent on the action of steroid hormones. In particular, the reproductive system is reliant on hormonal signaling to promote gonadal function and to ensure fertility. Here we will describe hormone receptor functions and their impacts on testicular function, focusing on a specific group of essential hormones: androgens, estrogens, progesterone, cortisol, and aldosterone. In addition to focusing on hormone receptor function and localization within the testis, we will highlight the effects of altered receptor signaling, including the consequences of reduced and excess signaling activity. These hormones act through various cellular pathways and receptor types, emphasizing the need for a multifaceted research approach to understand their critical roles in testicular function. Hormones exhibit intricate interactions with each other, as evidenced, for example, by the antagonistic effects of progesterone on mineralocorticoid receptors and cortisol's impact on androgens. In light of research findings in the field demonstrating an intricate interplay between hormones, a systems biology approach is crucial for a nuanced understanding of this complex hormonal network. This review can serve as a resource for further investigation into hormonal support of male reproductive health.

C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors.

C11-oxy C19 and C11-oxy C21 steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C19 steroids was more efficient than C11-oxy C21 steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C21 steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear-C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent-C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as "inactive" C11-oxy steroids, suggesting novel regulatory tiers.

Endocrine Disruptors and Estrogens in Human Prostatic Tissue.

Endocrine disruptors (EDs) are ubiquitous substances both in the environment and everyday products that interfere with the hormonal system. Growing evidence demonstrates their adverse effects on the organism, including the reproductive system and the prostate, owing to their (anti)estrogenic or antiandrogenic effects. Since EDs can interact with steroid hormone actions on-site, understanding the levels of intraprostatic EDs in conjunction with steroids may hold particular significance. The aim of this study was to develop and validate a method for determining estrogens, various groups of EDs (bisphenols, parabens, oxybenzone and nonylphenol) and phytoestrogens in their unconjugated and conjugated forms in prostate tissue by liquid chromatography-tandem mass spectrometry, and subsequently analyze 20 human prostate tissue samples. The method enabled 20 compounds to be analyzed: estrogens (estrone, estradiol, estriol), bisphenols (bisphenol A- BPA, BPS, BPF, BPAF, BPAP, BPZ, BPP), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl- paraben), oxybenzone, nonylphenol and phytoestrogens (daidzein, genistein, equol) with LLOQs between 0.017-2.86 pg/mg of tissue. The most frequently detected EDs in prostate tissues were propylparaben (conjugated and unconjugated forms in 100 % of tissues), methylparaben (unconjugated in 45 % and conjugated in 100 %), ethylparaben (unconjugated in 25 % and conjugated in 100 % BPA (unconjugated in 35 % and conjugated in 60 % and oxybenzone (both forms in 45 % To the best of our knowledge, this is the first study detecting EDs, phytoestrogens and estriol conjugate (E3C) in the prostate. E3C was the most abundant estrogen in prostatic tissue. This highlights the need for further explorations into estrogen metabolism within the prostate.

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells.

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150-3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.

Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species.

Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes. We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone. Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin aminonucleoside-induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria. Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids.

The Role of Adopted Orphan Nuclear Receptors in the Regulation of an Organic Anion Transporting Polypeptide 1B1 (OATP1B1) under the Action of Sex Hormones.

Organic anion transporting polypeptide 1B1 (OATP1B1) is an influx transporter protein of the SLC superfamily, expressed mainly in the liver and some tumor cells. The mechanisms of its regulation are being actively studied. In the present study, the effect of sex hormones (estradiol, progesterone and testosterone) on OATP1B1 expression in HepG2 cells was examined. The role of adopted orphan receptors, farnasoid X receptor (FXR), constitutive androstane receptor (CAR), pregnane X receptor (PXR) and liver X receptor subtype alpha (LXRa), was also evaluated. Hormones were used in concentrations of 1, 10 and 100 μM, with incubation for 24 h. The protein expression of OATP1B1, FXR, CAR, PXR and LXRa was analyzed by Western blot. It was shown that estradiol (10 and 100 μM) increased the expression of OATP1B1, acting through CAR. Testosterone (1, 10 and 100 μM) increased the expression of OATP1B1, acting through FXR, PXR and LXRa. Progesterone (10 and 100 μM) decreased the expression of OATP1B1 (10 and 100 μM) and adopted orphan receptors are not involved in this process. The obtained results have important practical significance and determine ways for targeted regulation of the transporter, in particular in cancer.

Outcomes of initially nonoperative management of diverticulitis with abscess formation in immunosuppressed patients. DIPLICAB study COLLABORATIVE group.

Management of diverticulitis with abscess formation in immunosuppressed patients (IMS) remains unclear. The main objective of the study was to assess short- and long-term outcomes between IMS and immunocompetent patients (IC). The secondary aim was to identify risk factors for emergency surgery. A nationwide retrospective cohort study was performed at 29 Spanish referral centres between 2015-2019 including consecutive patients with first episode of diverticulitis classified as modified Hinchey Ib or II. IMS included immunosuppressive therapy, biologic therapy, malignant neoplasm with active chemotherapy and chronic steroid therapy. A multivariate analysis was performed to identify independent risk factors to emergency surgery in IMS. A total of 1395 patients were included; 118 IMS and 1277 IC. There were no significant differences in emergency surgery between IMS and IC (19.5% and 13.5%, p = 0.075) but IMS was associated with higher mortality (15.1% vs. 0.6%, p < 0.001). Similar recurrent episodes were found between IMS and IC (28% vs. 28.2%, p = 0.963). Following multivariate analysis, immunosuppressive treatment, p = 0.002; OR: 3.35 (1.57-7.15), free gas bubbles, p < 0.001; OR: 2.91 (2.01-4.21), Hinchey II, p = 0.002; OR: 1.88 (1.26-2.83), use of morphine, p < 0.001; OR: 3.08 (1.98-4.80), abscess size ≥5 cm, p = 0.001; OR: 1.97 (1.33-2.93) and leucocytosis at third day, p < 0.001; OR: 1.001 (1.001-1.002) were independently associated with emergency surgery in IMS. Nonoperative management in IMS has been shown to be safe with similar treatment failure than IC. IMS presented higher mortality in emergency surgery and similar rate of recurrent diverticulitis than IC. Identifying risk factors to emergency surgery may anticipate emergency surgery.

Identification of Bioactive Solutions of Corn Silk (Zea mays L.) Extract and Biological Activity Test By Bioinformatics

Corn silk (Zea mays L.) is an agricultural by-product that is discarded as agricultural waste. Corn silk has secondary metabolite compounds that have the potential to become useful bioactive compounds. The purpose of this study is to recognize the bioactive potential of corn hair through compound identification and biological activity. The method used is preparation and extraction by maceration method followed by identification of compounds through LC-MS analysis method and Phytochemical test, bioinformatic PASS test based on data through PubChem, ChemSpider, and way2drug web. The results obtained from corn silk have a group of active compounds, including alkaloids, flavonoids, saponins, steroids and triterpenoids. Analysis of potential bioactivity received Acaciin compounds have high antioxidant bioactivity with a Pa value of 0.815, 2-arachidonoylglycerol has high potential antiinflammatory bioactivity with a Pa value of 0.736 and 1,2-di-O-methyl-4-[(2R)-2,4-dihydro butyramide shows moderate possible antibacterial activity with a Pa value of 0.643. This study concludes that corn silk has high bioactive potential as an antioxidant, anti-inflammatory and antibacterial.

Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface.

The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother and embryo, the endometrium, and its critical processes of decidualization and immune cell recruitment, play a leading role in the establishment of pregnancy, embryonic development, and reproductive capacity. These integral processes are achieved by the concerted actions of steroid hormones and a myriad of growth factor signaling pathways. This review focuses on the roles of the transforming growth factor β (TGFβ) pathway in the endometrium during the earliest stages of pregnancy through the lens of immune cell regulation and function. We discuss how key ligands in the TGFβ family signal through downstream SMAD transcription factors and ultimately remodel the endometrium into a state suitable for embryo implantation and development. We also focus on the key roles of the TGFβ signaling pathway in recruiting uterine natural killer cells and their collective remodeling of the decidua and spiral arteries. By providing key details about immune cell populations and TGFβ signaling within the endometrium, it is our goal to shed light on the intricate remodeling that is required to achieve a successful pregnancy.

Роль менопаузальной гормональной терапии в вопросах профилактики сердечно-сосудистых заболеваний у женщин в пострепродуктивном периоде

Cardiovascular disorders (CVD) in female population are the main cause of mortality, and an increase in the prevalence of myocardial infarction among women is observed in the recent decades, in contrast to the male population showing a decrease in this indicator. Certainly, the mechanisms underlying CVD in people of different sexes have much in common, however, one cannot ignore the differences associated with fundamental genetic determinants of ageing, different characteristics of metabolism and fundamentally different types of hormonal status. It has been found that realization of activity of sex hormones is among major factors ensuring protection against cardiovascular disorders in premenopausal women. The increase in the rate of cardiovascular disorders and the lack of menopausal hormone therapy (MHT) prescription to women in their post-reproductive stage may be partially correlated. Aim. To analyze the data provided by advanced scientific research focused on prescription of menopausal hormone therapy (MHT) aimed at preventing cardiovascular disorders in the post-reproductive period. Methods. Analytical review of domestic and foreign papers on the topic, including using PubMed, Elseviewer, Cochrane library, Elibrary databases. Conclusions. Despite the fact that the issue of prevention and treatment of cardiovascular disorders attracts particular attention of global healthcare, CVDs still rank first in the world as the cause of deaths. In menopausal women, hypoestrogenism is among major pathogenetic links of cardiac abnormalities. To increase adherence of peri- and postmenopausal women to early diagnosis, general practitioners should give due consideration to referral of such women to obstetricians-gynecologists for timely correction of estrogen deficiency. It is also necessary to further study the issue in order to identify early diagnostic predictors of cardiovascular disorders.

Role of sex steroid hormone on hand grip strength and cognitive function in the elderly

The aging process is associated with changes in hormone levels. There is a noticeable change in estrogen levels in women, while in men, there is a change in testosterone levels. In the elderly, as a result of the aging process, changes in these hormone levels affect handgrip strength, and cognitive function. In both women and men, the function of several organs is influenced by sex steroid hormones, namely Oestrogen and androgens. There are two theories of steroid action mechanism on target cells, namely steroid hormone action mechanism genomically and non-genomically. The function and action mechanism of steroid hormone is important because it is the basis of the hormonal aspect for muscle mass, handgrip strength, and cognitive function. Due to the aging process, hormonal changes in the elderly are different compared to the previous period. This has consequences for changes in metabolic processes that affect the body’s condition, including changes in the composition of bones, muscles, and other tissues, such as the brain. In the aging process, it is important to pay attention to nutritional factors because they contribute to hormone levels that help maintain muscle mass, body mass index, hand grip strength, and cognitive function. In the brain, the sex steroid hormone has activating and organizational effects mediated by intracellular or transmembrane G-protein-coupled receptors. Articles published in English in the last 9 years (from 2014 to 2023) were retrieved from Science Direct, PubMed, Springer link, Oxford and Nature using relevant searching terms. The fact that testosterone bioavailability is predominated in the brain in relation to its activity and significant positive association with processing speed, sustained attention, and working memory in older men. To obtain a better quality of life for the elderly, nutritional factors must be considered to maintain optimal sex steroid hormone levels, hand grip strength, and cognitive function.

Bioassay-Guided Fractionation and Biological Activity of Cardenolides from Streptocaulon juventas.

The discovery that Na/K-ATPase acts as a signal transducer led us to investigate the structural diversity of cardiotonic steroids and study their ligand effects. By applying Na/K-ATPase activity assay-guided fractionation, we isolated a total of 20 cardiotonic steroids from Streptocaulon juventas, including an undescribed juventasoside B (10: ) and 19 known cardiotonic steroids. Their structures have been elucidated. Using our platform of purified Na/K-ATPase and an LLC-PK1 cell model, we found that 10: , at a concentration that induces less than 10% Na/K-ATPase inhibition, can stimulate the Na/K-ATPase/Src receptor complex and selectively activate downstream pathways, ultimately altering prostate cancer cell growth. By assessing the ligand effect of the isolated cardiotonic steroids, we found that the regulation of cell viability by the isolated cardiotonic steroids was not associated with their inhibitory potencies against Na/K-ATPase activity but reflected their ligand-binding affinity to the Na/K-ATPase receptor. Based on this discovery, we identified a unique active cardiotonic steroid, digitoxigenin (1: ), and verified that it can protect LLC-PK1 cells from hypoxic injury, implicating its potential use in ischemia/reperfusion injury and inducing collagen synthesis in primary human dermal fibroblast cells, and implicating that compound 2: is the molecular basis of the wound healing activity of S. juventas.

P11.14.B PROGNOSTIC ASSOCIATIONS OF STEROID USE IN GLIOBLASTOMA: A POPULATION-BASED STUDY

Abstract BACKGROUND Steroids are widely used in brain tumor patients to control symptoms related to tumor and cerebral edema. A possible detrimental effect of steroid treatment on prognosis in glioblastoma patients has been proposed. Whether this represents only a negative patient selection due to the potential confounding factor of steroid treatment or whether glucocorticoid use per se causes a worse prognosis remains a matter of debate. MATERIAL AND METHODS We reviewed retrospective data of 225 patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype glioblastoma from 2010 to 2014 in the Canton of Zurich, Switzerland. We assessed clinical data and the use of steroids at different time points. Survival data were analyzed with the Kaplan-Meier method, and corrections for known prognostic or predictive factors were performed with Cox regression analyses. Correlations were determined with Spearman’s correlation coefficient. RESULTS Most patients (N=203, 95%) received steroids at least once in the first year after diagnosis, the majority (N=153, 69%) in the perioperative setting (defined at the time of hospitalisation for the surgery plus/minus seven days), and 94 patients (62%) in the first three months. Steroid use at three months after surgery was associated with with steroid treatment at six months, too (p&amp;lt;0.01). The latter was associated with inferior overall survival after correction for known prognostic factors (p=0.006). CONCLUSION Use of steroids at six months after diagnosis was associated with inferior survival in glioblastoma even when controlling for confounding factors. The precise mode of action of steroids in this setting remains to be identified, but cytoprotective effects of tumor cells versus radiotherapy and chemotherapy as well as decreased immune function of the host are potential mechanisms.

Steroid Hormones Effected in Human Body

Disturbances of the steroidogenesis or altered peripheral metabolism of steroids may result in severe clinical manifestations. Therefore, prompt diagnosis and initiation of medical treatment are desirable. The diagnostics of disorders of steroid hormone production, metabolism, and action have been previously based on immunoassay tests. However, in a modern medical laboratory, due to low accuracy of immunoassays, this technique is continuously replaced by chromatographic separation methods coupled to mass spectrometric detection systems. In this review we present current advances in the diagnostics of adrenal gland disorders, focusing on the role of mass spectrometry in prenatal and newborn screening, and in the diagnostics of sexual maturation disorders.

A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids.

The action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species. To investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR. Almost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR.

E66 Arthropathy as the initial presentation of HIV

Abstract Background Human immunodeficiency virus (HIV) has been associated with musculoskeletal disorders which has been estimated to occur in 11–72% of infected patients. Most of these reports however have been in adults with few published cases of HIV associated arthritis in children. The articular manifestations of HIV, especially overt arthritis, can occur at any stage of the disease but are more prevalent in advanced immunosuppression. With the increased access to early diagnosis and highly active antiretroviral therapy (HAART), such complications have increasingly become rare. However, HIV diagnosis may often be missed or delayed in slow progressors, and in such circumstances, these patients may manifest with arthritis as the initial manifestation of HIV. Therefore, there’s need for consideration of HIV associated arthritis in children presenting with arthropathy of undetermined cause. We hereby present a case of arthritis as the initial manifestation of HIV in a child with missed diagnosis of HIV. Methodology/case presentation A 12-year-old boy was admitted in the Kenyatta National Hospital (KNH) paediatric ward with a history of joint pain and swelling for three months. He had otherwise previously been well. He had no history of fever, trauma, preceding gastroenteritis or urine tract infection. He had no chorea, no erythematous rash and no cardiac complications of rheumatic fever. He was not wasted, and was able to walk with great difficulty. He had bilateral knee and right ankle swelling. The swollen joints were warm to touch with positive ballotment and fluid sweep test. Joint aspiration revealed straw coloured joint effusion. Investigations included a positive HIV rapid test with CD4% of 6, CRP 8.33 mg/l (n = &amp;lt;5), Elevated ESR (111 mm in first h) and negative ANA. Bilateral Knee -rays did not reveal any destructive or erosive changes. A diagnosis of HIV arthropathy was made and the patient was started on HAART, HCQ, prednisone and ibuprofen. He improved, with resolution of the joint swellings, was discharged home after 10 days and follow up in the rheumatology and comprehensive care clinics advised. Conclusion HIV arthropathy should be considered in patients manifesting with arthritis of unknown origin; and the patients evaluated for HIV as a strategy for identifying and including them in care. Highly active antiretroviral therapy, steroids, hydroxychloroquine and NSAIDS may be effective therapy for HIV arthropathy. Disclosure statement: The authors have no conflict of interest to declare.