Steroid Action Research Articles

Coregulators Reside within Drosophila Ecdysone-Inducible Loci before and after Ecdysone Treatment.

Ecdysone signaling in Drosophila remains a popular model for investigating the mechanisms of steroid action in eukaryotes. The ecdysone receptor EcR can effectively bind ecdysone-response elements with or without the presence of a hormone. For years, EcR enhancers were thought to respond to ecdysone via recruiting coactivator complexes, which replace corepressors and stimulate transcription. However, the exact mechanism of transcription activation by ecdysone remains unclear. Here, we present experimental data on 11 various coregulators at ecdysone-responsive loci of Drosophila S2 cells. We describe the regulatory elements where coregulators reside within these loci and assess changes in their binding levels following 20-hydroxyecdysone treatment. In the current study, we detected the presence of some coregulators at the TSSs (active and inactive) and boundaries marked with CP190 rather than enhancers of the ecdysone-responsive loci where EcR binds. We observed minor changes in the coregulators' binding level. Most were present at inducible loci before and after 20-hydroxyecdysone treatment. Our findings suggest that: (1) coregulators can activate a particular TSS operating from some distal region (which could be an enhancer, boundary regulatory region, or inactive TSS); (2) coregulators are not recruited after 20-hydroxyecdysone treatment to the responsive loci; rather, their functional activity changes (shown as an increase in H3K27 acetylation marks generated by CBP/p300/Nejire acetyltransferase). Taken together, our findings imply that the 20-hydroxyecdysone signal enhances the functional activity of coregulators rather than promoting their binding to regulatory regions during the ecdysone response.

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm.

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur.

Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation.

Both the circadian clock and sex hormone signaling can strongly influence brain function, yet little is known about how these 2 powerful modulatory systems might interact during complex neural processes like memory consolidation. Individually, the molecular components and action of each of these systems have been fairly well-characterized, but there is a fundamental lack of information about how these systems cooperate. In the circadian system, clock genes function as timekeeping molecules that convey time-of-day information on a well-stereotyped cycle that is governed by the suprachiasmatic nucleus. Keeping time is particularly important to synchronize various physiological processes across the brain and body, including those that regulate memory consolidation. Similarly, sex hormones are powerful modulators of memory, with androgens, estrogens, and progestins, all influencing memory consolidation within memory-relevant brain regions like the hippocampus. Despite clear evidence that each system can influence memory individually, exactly how the circadian and hormonal systems might interact to impact memory consolidation remains unclear. Research investigating either sex hormone action or circadian gene function within memory-relevant brain regions has unveiled several notable places in which the two systems could interact to control memory. Here, we bring attention to known interactions between the circadian clock and sex hormone signaling. We then review sex hormone-mediated control of memory consolidation, highlighting potential nodes through which the circadian system might interact during memory formation. We suggest that the bidirectional relationship between these two systems is essential for proper control of memory formation based on an animal's hormonal and circadian state.

Abnormal DNA methylation within genes of the steroidogenesis pathway two years after paediatric critical illness and association with stunted growth in height further in time

BackgroundFormer critically ill children show an epigenetic age deceleration 2 years after paediatric intensive care unit (PICU) admission as compared with normally developing healthy children, with stunted growth in height 2 years further in time as physical correlate. This was particularly pronounced in children who were 6 years or older at the time of critical illness. As this age roughly corresponds to the onset of adrenarche and further pubertal development, a relation with altered activation of endocrine pathways is plausible. We hypothesised that children who have been admitted to the PICU, sex- and age-dependently show long-term abnormal DNA methylation within genes involved in steroid hormone synthesis or steroid sulphation/desulphation, possibly aggravated by in-PICU glucocorticoid treatment, which may contribute to stunted growth in height further in time after critical illness.ResultsIn this preplanned secondary analysis of the multicentre PEPaNIC-RCT and its follow-up, we compared the methylation status of genes involved in the biosynthesis of steroid hormones (aldosterone, cortisol and sex hormones) and steroid sulphation/desulphation in buccal mucosa DNA (Infinium HumanMethylation EPIC BeadChip) from former PICU patients at 2-year follow-up (n = 818) and healthy children with comparable sex and age (n = 392). Adjusting for technical variation and baseline risk factors and corrected for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 23 CpG sites (within CYP11A1, POR, CYB5A, HSD17B1, HSD17B2, HSD17B3, HSD17B6, HSD17B10, HSD17B12, CYP19A1, CYP21A2, and CYP11B2) and 4 DNA regions (within HSD17B2, HSD17B8, and HSD17B10) that were mostly hypomethylated. These abnormalities were partially sex- (1 CpG site) or age-dependent (7 CpG sites) and affected by glucocorticoid treatment (3 CpG sites). Finally, multivariable linear models identified robust associations of abnormal methylation of steroidogenic genes with shorter height further in time, at 4-year follow-up.ConclusionsChildren who have been critically ill show abnormal methylation within steroidogenic genes 2 years after PICU admission, which explained part of the stunted growth in height at 4-year follow-up. The abnormalities in DNA methylation may point to a long-term disturbance in the balance between active sex steroids and mineralocorticoids/glucocorticoids after paediatric critical illness, which requires further investigation.

Novel D-modified heterocyclic androstane derivatives as potential anticancer agents: Synthesis, characterization, in vitro and in silico studies

Cancer remains a major health concern worldwide. The most frequently diagnosed types of cancer are caused by abnormal production or action of steroid hormones. In the present study, the synthesis and structural characterization of new heterocyclic androstane derivatives with D-homo lactone, 17α-(pyridine-2′′-ylmethyl) or 17(E)-(pyridine-2′′-ylmethylidene) moiety are presented. All compounds were evaluated for their anti-proliferative activity against HeLa cervical cancer cell line and non-cancerous kidney MDCK cells, where A-homo lactam compound 9A showed the greatest selectivity. Based on in vitro binding assays, N-formyl lactam compound 18 appeared to be the strong and isoform-selective ligand for ERα, while compound 9A displayed binding affinity for the GR-LBD, but also inhibited aldo-keto reductase 1C4 enzyme. Out of four selected compounds, methylpyrazolo derivative 13 showed potential for aromatase binding, while in silico studies provided insight into experimentally confirmed protein-ligand interactions.

IMPACT OF CORTICOSTEROIDS ON PERINATAL OUTCOME

Objective: The study’s main aim was to demonstrate the efficacy of antenatal corticosteroids (betamethasone) to prevent respiratory distress syndrome (RDS) and other related complications in premature babies and to study the outcomes of neonates whose mothers received corticosteroids during the antenatal period. Methods: A total of 50 pregnant women with a risk of preterm delivery admitted to the labor ward of Prathima Institute of Medical Sciences were included in the study. It is a prospective, hospital-based, and longitudinal study. All women coming to the antenatal outpatient department of Prathima Institute of Medical Sciences who are at risk of preterm delivery were selected. The follow-up component of the study involved women identified as at high risk for premature delivery and who had received betamethasone. The neonatologist diagnosed the neonatal complications was taken as an outcome. Results: Of the 50 babies that were enrolled in the study, 27 (54%) were delivered by spontaneous vaginal delivery, 1 by assisted breech (2%), 1 by instrumental delivery (2%), and 18 (36%) were delivered by cesarean section. The occurrence of RDS among babies with low APGAR was 4 (44.44%). Only one intraventricular hemorrhage occurred among the category, with a low APGAR score (11.11%). Out of 19 cases, ten deaths were identified, and nine were alive within 24 h due to the action of steroids. Among 31 cases, two cases were death, and 29 were alive after 24 h of the duration of action of steroid. Even though mothers of all babies in this study admitted to the neonatal unit had received corticosteroids, there was still 24% mortality by 28 days. The results suggest that once admitted to NICU, having only received a single dose of corticosteroids &lt;24 h previously (as opposed to more than 24 h), gestational age &lt;34 weeks, and having any listed neonatal complications were associated with mortality by 28 days. Conclusion: Even though 50% of the neonates suffered complications, over 40% of the subjects were delivered before betamethasone could take effect. Several other factors, apart from betamethasone, influenced the outcome of neonates. The present study showed that the use of ANCS administration is the single most intervention to prevent complications of prematurity which can be done at a public health center or by a private practitioner, even in rural areas.

Management of Acne Vulgaris with Homeopathic Treatment – A Case Series

ABSTRACT Background: Acne Vulgaris is a multi-factorial chronic inflammatory condition, in relation to sebum production of hair follicles under the action of sex hormones. Methods: This is a case series of five patients suffering from acne vulgaris were treated with homoeopathy successfully at the Dermatology OPD of DDPRCRI (H), Noida (UP), India. Global Acne Grading Score (GAGS) was used to assess clinical severity of acne. Majority of study population were in the age group of 18 to 40 years. Results: Face was the commonest site and pustules&amp; cystic were the commonest form of acne at baseline. Three cases were observed to be of moderate and two were severe acne as per GAG Score at baseline. The selection of medicine was done on the basis of homoeopathic individualization, considering location, sensation, modalities (aggravation and amelioration factors) and concomitants of the symptoms in each case. Conclusion: After treatment all cases were observed to be of mild acne as per GAG Score. Homoeopathic medicines Calcarea Carb, Mercurius Sol, and Natrum Mur were found useful.

Mifepristone: effect on PBMC receptivity in healthy women and women with endometrial hyperplastic processes

In our previous study we found that peripheral blood mononuclear cells (PBMC) at women with endometrial proliferative processes increase their sensitivity to the suppressing action of sex steroid hormones. In order to reduce the receptivity of PBMC, it is possible to prescribe hormonal drugs. However, when studying the relative binding activity of the receptors, it was found that the affinity of medroxyprogesterone acetate, norethisterone acetate, in PBMC was 54% and 48% respectively. And research of selective modulators of progesterone receptors is promising.

Toxicity of individual and combined effect of Mefenpyr di-ethyl safener and its co-herbicide, Fenoxaprop-P-ethyl, to zebrafish

Mefenpyr diethyl (MEF), a supposed inert chemical, is a safener used in herbicide formulations with active ingredients such as Fenoxaprop-P-ethyl (FEN), has been found in surface water. Since the hazards of this safener, individually and in combination with its herbicide, toward non-target aquatic organisms, were not known,acute and chronic studies were conducted on various endpoints in embryos of zebrafish (Danio rerio). Endpoints during acute exposures included mortality and hatchability. During chronic exposures, the growth and survival of larvae were determined. Exposure to concentrations of MEF > 3 mg/L alone significantly decreased the rate of hatching, while exposure to FEN alone to > 3 mg/L had no significant effect on the rate of hatching. However, exposure to each of the chemicals individually caused some delay in hatching. When exposed in combination with FEN, adverse effects of MEF on the rate of hatching were mitigated in a dose-dependent manner. During the acute exposure to 3 mg/L, mortality was caused by MEF than FEN. During chronic exposures to 0.1 or 1.0 mg/L, MEF has more toxic potency than FEN. Both compounds caused some abnormalities, including pericardial edema, spinal curvature, tail malformation, and edema of the yoke sac. Based on the activities of SOD and GST, both MEF and FEN caused oxidative stress. FEN reduced the toxic potency of MEF when exposed together, but there were more deformities of greater severity in embryos exposed to MEF than those exposed to FEN. Molecular docking showed that both chemicals could potentially inhibit the activity of sex hormones and hatching enzymes. These results demonstrate that while classified as "inert", the safener, and FEN can cause various effects, including molecular responses and lethality and should be monitored and regulated.

Synergistic action of steroid hormones and hormone-specific autoantibodies in breast cancer progression

Aim. To study the possible synergistic action of steroid hormones and hormone-specific autoantibodies and anti-autoantibodies in conversion of ER+/PR+ tumors into ER-/PR- in breast cancer patients.Materials and Methods. Concentrations of estradiol (E2) and progesterone (Pg) and the levels of hormone-specific idiotypic IgA antibodies (IgA1-E2 and IgA1-Pg) as well as anti-idiotypic IgG antibodies (IgG2-E2 and IgG2-Pg) were studied in the serum of 979 breast cancer patients (432 patients with stage 1 and 547 patients with stages 2-4) by means of enzyme-linked immunosorbent assay. E2 and Pg receptors phenotype (ER/ PR) was determined using immunohistochemistry.Results. Simultaneous increase in IgA1-E2 and IgG2-E2 levels was associated with elevated E2 serum concentration (p = 0.007) in ER+/PR+ breast cancer patients. On the contrary, concurrent increase in IgA1-Pg и IgG2-Pg, was associated with lowered Pg concentration (p = 0.04). The frequency of ER+/PR+ tumors was low and ER-/PR- was high in patients with stages 2-4 breast cancer than in stage 1 in the following cases: 1) IgG2-E2 and IgA1-E2 levels were high regardless of serum E2 (p = 0.004); 2) IgG2-E2 levels were high and IgA1-E2 and E2 levels were low (p = 0.002); 3) IgG2-Pg and Pg levels were high regardless of IgA1-Pg levels (р &lt; 0,001); 4) IgG2-E2 and IgG2-Pg levels were high regardless of E2, Pg, IgA1-E2 and IgA1-Pg levels (р &lt; 0,001). In other combinations of hormones and hormone-specific antibodies and anti-antibodies, there have been no differences in the frequency of ER+/PR+ and ER-/PR- tumors between patients with ascending stages of breast cancer.Conclusion. We for the first time found a synergistic action of hormone-specific idiotypic and anti-idiotypic autoantibodies on the concentration of steroid hormones in the serum of breast cancer patients, and the synergistic action of steroid hormones and hormone-specific idiotypic and anti-idiotypic autoantibodies on tumor steroid receptor conversion.

O-091 The impact of endocrine disruptors on early pregnancy and clinical outcomes in IVF

Abstract The impact of endocrine disruptors on early pregnancy and clinical outcomes in IVF Moncef Benkhalifa (1,2,3), Debbie Montjean (2), Hafida Corsi-Cauet (3), Henri Copin (1,3), Véronique Bach (3), Pierre Miron (2), Rosalie Cabry (1,3) (1) Reproductive Medicine and Reproductive Genetics, University Hospital &amp; School of Medicine. Picardie University Jules Verne. Amiens France (2) ART Centers. Laval and Brossard. Fertilys International Inc. Laval. Québec. Canada (3) PERITOX Laboratory. Picardie University Jules Verne. Amiens. France Since more than 40 years, there are annual increasing of studies, meta-analysis reporting and discussing the potential associations between endocrine disrupting chemicals (EDCs) and human fertility potential declining. Today it’s accepted that a substantial number of environmental and exposition factors affect the fertility and fecundity capacity of couples during the peri and post conception period. It’s accepted that most of EDCs interfere with or mimic steroid hormone action; predominantly by affecting estrogen, androgen and thyroid hormones signaling pathways and disturbing specific molecular process on relation with single or multiple biological functions. Some of EDCs can interact with the male and female reproductive system and lead to endocrine disruption in the testis and ovary. they exert their effects mainly via binding transcription factor receptors, EDCs can alter endocrine function through a variety of mechanisms. At fertility age EDCs may alter the expression and/or activity of enzymes required for synthesis and/or catabolism of testicular and ovarian sex steroids and the expression of hormone receptors and/or their ability to bind their and endogenous ligands. For example, in male, the literature reported a negative correlation between disrupted spermatogenesis and lifestyle factors (environmental-professional expositions) such as alcohol consumption, cigarette smoking, drug use, and obesity caused by high-energy diet. In female infertility diseases, the negative impact of chemicals ED has been studied in animals. Many disorders have been described, such as low ovarian weight, impaired folliculogenesis, a high aneuploidy rate and the acceleration of follicular atresia. Indeed, women exposed to some endocrine-disrupting pesticides (such as atrazine, lindane) have an elevated risk of long menstrual cycles or anovulation but the most serious consequence is POF and endometriosis pathophysiology’s. In our IVF experience in Picardie region (France), we observed that various pesticides with an endocrine-disrupting action are associated with poor oocyte quality (maturation and competency), embryonic defects and poor IVF outcomes, and some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. It was reported that EDCs can reduce embryo implantation chances and increase miscarriage, placenta and post-natal abnormalities. for endometrium receptivity and implantation failure EDCs can play by modifying keys elements of the immune response relevant to pregnancy, and disrupt immune tolerance required for robust placentation, optimal fetal development and be a as contributing risk factors in recurrent miscarriage, preeclampsia, preterm birth and related pathologic gestation Environmental insults, including endocrine disrupting chemicals during critical periods of fetal development, can alter DNA methylation patterns, leading to inappropriate developmental gene expression and disease risks. Similar to environmental factors, endocrine-disrupting chemicals can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations risks also known as “epimutations”. In Conclusion, the negative impact of exposure to various endocrine-disrupting is becoming now a worldwide public health. Indeed, the community should be informed about the fertility decline, low ongoing pregnancy rates, and elevated risk of miscarriage associated with exposure to high doses of pesticides for example. We must keep in mind that humans are exposed to EDCs mixtures composed of hundreds of chemicals every day and not a single chemical in isolation.

Steroids Induced Hyperglycemia: Its Effects and Management

Steroids are medications that have been widely utilized for a number of ailments, both acute and chronic. The action of endogenous steroids, nuclear hormones that penetrate cell membranes to bind to certain glucocorticoid receptors in the cytoplasm of target cells to form glucocorticoid-receptor (GR) complexes, is mimicked by synthetic glucocorticoids. The translocated activated GR complex regulates DNA transcription in the cell nucleus. The main factor for drug-induced hyperglycemia is steroids. They not only worsen hyperglycemia in those who already have diabetes mellitus (DM), but they can also lead to DM in people who've not previously experienced it. Their incidence can reach up to 46% of patients, and their glucose levels can rise by up to 68% over baseline. Steroid effects are often narrow and reversible. Drug-induced diabetes is supposed to go away as steroid doses are decreased because their impact on endocrine metabolism returns to normal; however, this is often not the case. The synthesis of lipolysis, proteolysis, and hepatic glucose is increased by glucocorticoids (GCs) because they act as a substrate for oxidative stress metabolism. A wide range of medical conditions has been treated with GCs. Although steroid-induced hyperglycemia has been proven to be medically effective, it is still a widespread and potentially dangerous issue that must be taken into consideration when administering any GC dose. The most common scenario requires the use of insulin, particularly when the serum glucose level is greater than 200 mg/dL.&#x0D; Keywords: Steroids, Glucocorticoids, Hyperglycemia, Resistance, Insulin

Gut microbiome influences incidence and outcomes of breast cancer by regulating levels and activity of steroid hormones in women.

Breast cancer, the leading cancer type in women worldwide, is affected by reproductive and nonreproductive factors. Estrogen and progesterone influence the incidence and progression of breast cancer. The microbiome of the gut, a complex organ that plays a vital role in digestion and homeostasis, enhances availability of estrogen and progesterone in the host. Thus, an altered gut microbiome may influence the hormone-induced breast cancer incidence. This review describes the current understanding of the roles of gut microbiome in influencing the incidence and progression of breast cancer, with an emphasis on the microbiome-induced metabolism of estrogen and progesterone. Microbiome has been recognized as a promising hallmark of cancer. Next-generation sequencing technologies have aided in rapid identification of components of the gut microbiome that are capable of metabolizing estrogen and progesterone. Moreover, studies have indicated a wider role of the gut microbiome in metabolizing chemotherapeutic and hormonal therapy agents and reducing their efficacy in patients with breast cancer, with a predominant effect in postmenopausal women. The gut microbiome and variations in its composition significantly alter the incidence and therapy outcomes of patients with breast cancer. Thus, a healthy and diverse microbiome is required for better response to anticancer therapies. Finally, the review emphasizes the requirement of studies to elucidate mechanisms that may aid in improving the gut microbiome composition, and hence, survival outcomes of patients with breast cancer.

Serum DHEA and Testosterone Levels Associate Inversely With Coronary Artery Calcification in Elderly Men.

Epidemiological and preclinical data support cardiovascular, mainly protective, effects of sex steroids in men, but the mechanisms underlying the cardiovascular actions of sex steroids are poorly understood. Vascular calcification parallels the development of atherosclerosis, but is increasingly recognized as a diversified, highly regulated process, which itself may have pathophysiological importance for clinical cardiovascular events. To investigate the association between serum sex steroids and coronary artery calcification (CAC) in elderly men. We used gas chromatography tandem mass spectrometry to analyze a comprehensive sex steroid profile, including levels of dehydroepiandrosterone (DHEA), androstenedione, estrone, testosterone, estradiol, and dihydrotestosterone, in men from the population-based AGES-Reykjavik study (n = 1287, mean 76 years). Further, sex hormone-binding globulin (SHBG) was assayed and bioavailable hormone levels calculated. CAC score was determined by computed tomography. The main outcome measures were cross-sectional associations between dehydroepiandrosterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and quintiles of CAC. Serum levels of DHEA, androstenedione, testosterone, dihydrotestosterone, and bioavailable testosterone showed significant inverse associations with CAC, while estrone, estradiol, bioavailable estradiol, and SHBG did not. DHEA, testosterone, and bioavailable testosterone remained associated with CAC after adjustment for traditional cardiovascular risk factors. In addition, our results support partially independent associations between adrenal-derived DHEA and testes-derived testosterone and CAC. Serum levels of DHEA and testosterone are inversely associated with CAC in elderly men, partially independently from each other. These results raise the question whether androgens from both the adrenals and the testes may contribute to male cardiovascular health.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Cancer is a recognized condition of secondary immunosuppression. Lymphoma patients often show a decrease in absolute lymphocyte counts and in peripheral blood gamma-globulin levels. However, less is known about how NK cells are altered in lymphoma patients. The aim of this study was to evaluate the patterns of circulating NK cell dysfunction in lymphoma patients. Methods: We performed a cross-sectional study of patients with a recent diagnosis of nodal lymphoproliferative disorder. Patients with active anticancer treatment or steroid use were excluded. Peripheral blood samples in EDTA were analyzed by multicolor flow cytometry. A custom panel of 30 markers was applied to all samples to test for major subpopulations, maturation, and functional markers. Results were compared to healthy controls. Clinical data were obtained from the electronic database. This study was approved by the institutional IRB and Clinical Ethics Committee. Results: A total of 30 patients were examined between October 2021 and November 2022. The median age was 62 years (range 15–88) and 45.7% were female (16). Patients had the following subtypes: large B-cell lymphoma (LBCL; 9), follicular lymphoma (FL; 9), Hodgkin lymphoma (HL; 5), mantle cell lymphoma (MCL; 4), marginal zone lymphoma (MZL; 2), Waldenström macroglobulinemia (WM; 1). Most patients had advanced stage disease (20). Compared to healthy controls (n = 10), lymphoma patients showed a significant decrease in absolute NK cell counts (ANKC, 319.7 vs. 131.1 cells/mm3; p < 0.0001). MCL patients had the lowest ANKC (68.8) and Hodgkin patients the highest (165.6). Advanced stage disease correlated with lower ANKC compared to localized disease (99.85 vs. 148.9; p = ns). The pattern of maturation was altered in lymphoma patients compared to controls (p = 0.0092). Patients had a higher proportion of immature CD56-bright NK cells (4.97% vs. 2.88%) and lower levels of CD16 expression in the mature CD56-dim subpopulation (68.12% vs. 85.94%). Lymphoma patients also showed dysfunctional expression of receptors and activation markers (Figure). There was a significant increase in the levels of FAS-L, IFNg, CD49b, CD57, CD96, and CD107a, while the levels of TIGIT and NKG2D were significantly decreased. Differences in the expression of immune checkpoints (PD-1, LAG-3, TIM-3), as well as additional activating, inhibitory, and chemokine receptors were not significant. 22 of 30 patients (73.3%) achieved a complete response. All patients with ANKC above 135 cells/mm3 at diagnosis achieved sustained complete remission. The research was funded by: Fondecyt 11200805 Clínica Alemana de Santiago ID1025 Keyword: diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

Role of the Androgen Receptor in Gender-Related Cancers

The androgen receptor (AR) is expressed in many cell types, and its related signaling is widely investigated in hormone-dependent cancers such as prostate and breast. The significance of the AR, however, has been detected even in other cancers, including gastric, bladder, kidney, lung, hepatic, and pancreatic, in which growth and spreading are not strictly or notoriously dependent on sex steroid hormone action. The incidence and mortality of these cancers are, however, somewhat related to gender and, specifically, are higher in men than in women, with the ratio reaching 3–4:1 for bladder cancer. This direct correlation between cancer incidence, mortality, and gender makes sex one of the most important risk factors for these cancers and has incited investigation about the role of sex steroid receptors and their activating hormones in gender-related cancers. In these cancers, the AR is often expressed and seems to play a pivotal role in different processes contributing to cancer onset and progression such as growth, spreading, and epithelial to mesenchymal transition (EMT). This manuscript will offer an overview of the role of the AR in many cancers of the respiratory and gastrointestinal systems wherein its role has been at least partially analyzed. Understanding the role of the AR in these tumors could help us to identify a new biomarker for early diagnostic guidance and to develop better therapeutic approaches by directly targeting the AR or its downstream signaling in individual cells of hormone-related cancers at different stages.

Who is sensitising whom? A participatory interview guide development as an awareness tool within a health care research project

Who is sensitising whom? A participatory interview guide development as an awareness tool within a health care research project

Progesterone interacts with the mutational hot-spot of TRPV4 and acts as a ligand relevant for fast Ca2+-signalling

Steroids are also known to induce immediate physiological and cellular response which occurs within minutes to seconds, or even faster. Such non-genomic actions of steroids are rapid and are proposed to be mediated by different ion channels. Transient receptor potential vanilloid sub-type 4 (TRPV4), is a non-specific polymodal ion channel which is involved in several physiological and cellular processes. In this work, we explored the possibilities of Progesterone (P4) as an endogenous ligand for TRPV4. We demonstrate that P4 docks as well as physically interacts with the TM4-loop-TM5 region of TRPV4, a region which is a mutational hotspot for different diseases. Live cell imaging experiments with a genetically encoded Ca2+-sensor suggests that P4 causes quick influx of Ca2+ specifically in the TRPV4 expressing cells, which can be partially blocked by TRPV4-specific inhibitor, suggesting that P4 can act as a ligand for TRPV4. Such P4-mediated Ca2+-influx is altered in cells expressing disease causing TRPV4 mutants, namely in L596P, R616Q, and also in embryonic lethal mutant L618P. P4 dampens, both in terms of “extent” as well as the “pattern” of the Ca2+-influx by other stimulus too in cells expressing TRPV4-Wt, suggesting that P4 crosstalk with the TRPV4-mediated Ca2+-signalling, both in quick and long-term manner. We propose that P4 crosstalk with TRPV4 might be relevant for both acute and chronic pain as well as for other health-related functions.

Queen of all herbs (Asparagus racemosus): an assessment of its botany, conventional utilization, phytochemistry and pharmacology

Shatavari (Asparagus racemosus), a member of the Asparagaceae family, is vital in Ayurveda since it may prevent and treat hundreds of ailments. It is known as "herb's queen."Its bioactive constituents include steroidal glycosides, saponins (primarily Shatavarins I, II, III and IV), polyphenols, flavonoids, alkaloids (racemosol) and vitamins. Shatavari is a popular shrub in folk and Ayurvedic medicine due to its sapogenin content, which is the precursor to many pharmacologically active steroids. Most of its components are medicinal, but roots, stems and leaves are the most essential. Shatavari "Rasayanas" boost immunity and infection resistance. Due to its phytochemicals, it is used to cure several illnesses. Due to its phytochemicals, it is used to cure several illnesses. Shatavari has many medicinal properties such as anti-spasmodic, anti-oxidant, anti-diabetic, anti-allergic, anti-malarial, protective, anti-neoplastic activities, immune response enhancement, anti-arthritic, anti-inflammatory, anti-periodic, anti-ulcerogenic action, immune modulatory antistress, anti-diarrheal, antidepressant infections, tuberculosis and so on. Commercial Shatavari extract medications are anti-leprotic, anti-abortifacient, antibacterial, antipyretic and analgesic. Shatavari root, leaf, flower and stem extracts treat dyspepsia, mental disorders, cough, bronchitis, throat and female reproductive system issues.

Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular Smooth Muscle and Eventual Cerebral Artery Dilation.

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β1 subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β1 provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone. Aldosterone can modify cerebral artery function independently of its effects outside the brain, yet BK involvement in aldosterone's cerebrovascular action and identification of channel subunits, possibly involved in steroid action, remains uninvestigated. Using microscale thermophoresis, we demonstrated that each subunit type presents two recognition sites for aldosterone: at 0.3 and ≥10 µM for α and at 0.3-1 µM and ≥100 µM for β1. Next, we probed aldosterone on SM BK activity and diameter of middle cerebral artery (MCA) isolated from β1-/- vs. wt mice. Data showed that β1 leftward-shifted aldosterone-induced BK activation, rendering EC50~3 μM and ECMAX ≥ 10 μM, at which BK activity increased by 20%. At similar concentrations, aldosterone mildly yet significantly dilated MCA independently of circulating and endothelial factors. Lastly, aldosterone-induced MCA dilation was lost in β1-/- mice. Therefore, β1 enables BK activation and MCA dilation by low µM aldosterone.