scholarly journals Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

2014 ◽  
Vol 28 (7) ◽  
pp. 999-1011 ◽  
Author(s):  
Rucha Patel ◽  
Jasmine Williams-Dautovich ◽  
Carolyn L. Cummins
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Drug Targets ◽  
Muscle Wasting ◽  
Hormone Receptors ◽  
Specific Level ◽  
Glucocorticoid Signaling ◽  
Unknown Protein ◽  
Glucocorticoid Response ◽  
Molecular Effects

The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas.

scholarly journals Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stefan Prekovic ◽  
Karianne Schuurman ◽  
Isabel Mayayo-Peralta ◽  
Anna G. Manjón ◽  
Mark Buijs ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Cancer Biology ◽  
Target Gene ◽  
Solid Cancer ◽  
Distal Enhancer ◽  
Glucocorticoid Response ◽  
Cell Dormancy ◽  
Glucocorticoid Action

AbstractThe glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

scholarly journals Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Mohamed A. Morsy ◽  
Snehal S. Patel ◽  
Azza A. K. El-Sheikh ◽  
Jignasa K. Savjani ◽  
Anroop B. Nair ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Tumor Necrosis ◽  
Serum Levels ◽  
Withaferin A ◽  
Boswellic Acid ◽  
Cotton Pellet ◽  
Anti Inflammatory ◽  
Necrosis Factor

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-α in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

scholarly journals The Glucocorticoid Receptor Polymorphism Landscape in Patients With Diamond Blackfan Anemia Reveals an Association Between Two Clinically Relevant Single Nucleotide Polymorphisms and Time to Diagnosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Annalisa Lonetti ◽  
Valentina Indio ◽  
Irma Dianzani ◽  
Ugo Ramenghi ◽  
Lydie Da Costa ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Glucocorticoid Receptor ◽  
Compensatory Mechanism ◽  
Nucleotide Polymorphisms ◽  
Disease Manifestation ◽  
Single Nucleotide ◽  
Diamond Blackfan Anemia ◽  
Glucocorticoid Response ◽  
Minor Alleles ◽  
Population Demographic

NR3C1, the gene encoding the glucocorticoid receptor, is polymorphic presenting numerous single nucleotide polymorphisms (SNPs) some of which are emerging as leading cause in the variability of manifestation and/or response to glucocorticoids in human diseases. Since 60–80% of patients with Diamond Blackfan anemia (DBA), an inherited pure red cell aplasia induced by mutations in ribosomal protein genes became transfusion independent upon treatment with glucocorticoids, we investigated whether clinically relevant NR3C1 SNPs are associated with disease manifestation in DBA. The eight SNPs rs10482605, rs10482616, rs7701443, rs6189/rs6190, rs860457, rs6198, rs6196, and rs33388/rs33389 were investigated in a cohort of 91 European DBA patients. Results were compared with those observed in healthy volunteers (n=37) or present in public genome databases of Italian and European populations. Although, cases vs. control analyses suggest that the frequency of some of the minor alleles is significantly altered in DBA patients with respect to healthy controls or to the Italian or other European registries, lack of consistency among the associations across different sets suggests that overall the frequency of these SNPs in DBA is not different from that of the general population. Demographic data (47 females and 31 males) and driver mutations (44 S and 29 L genes and eight no-known mutation) are known for 81 patients while glucocorticoid response is known, respectively, for 81 (36 responsive and 45 non-responsive) and age of disease onsets for 79 (55 before and 24 after 4months of age) patients. Neither gender nor leading mutations were associated with the minor alleles or with disease manifestation. In addition, none of the SNPs met the threshold in the response vs. non-responsive groups. However, two SNPs (rs6196 and rs860457) were enriched in patients manifesting the disease before 4months of age. Although the exact biomechanistical consequences of these SNPs are unknown, the fact that their configuration is consistent with that of regulatory regions suggests that they regulate changes in glucocorticoid response during ontogeny. This hypothesis was supported by phosphoproteomic profiling of erythroid cells expanded ex vivo indicating that glucocorticoids activate a ribosomal signature in cells from cord blood but not in those from adult blood, possibly providing a compensatory mechanism to the driving mutations observed in DBA before birth.

scholarly journals Acquired Glucocorticoid Resistance Due to Homologous Glucocorticoid Receptor Downregulation: A Modern Look at an Age-Old Problem

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2529
Author(s):  
Lee-Maine L. Spies ◽  
Nicolette J. D. Verhoog ◽  
Ann Louw
Keyword(s):  
Transcription Factor ◽  
Side Effects ◽  
Pharmaceutical Industry ◽  
Glucocorticoid Receptor ◽  
Steroid Hormones ◽  
Molecular Mechanisms ◽  
Protein Levels ◽  
Current Review ◽  
Role Players ◽  
Receptor Conformation

For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the onset of severe side-effects, chronic GC therapy often leads to the ligand-mediated downregulation of the GRα which, in turn, leads to a decrease in GC sensitivity, and effectively, the development of acquired GC resistance. Although the ligand-mediated downregulation of GRα is well documented, the precise factors which influence this process are not well understood and, thus, the development of an acquired GC resistance presents an ever-increasing challenge to the pharmaceutical industry. Recently, however, studies have correlated the dimerization status of the GRα with its ligand-mediated downregulation. Therefore, the current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC-mediated GRα downregulation.

scholarly journals Determining novel candidate anti-hepatocellular carcinoma drugs using interaction networks and molecular docking between drug targets and natural compounds of SiNiSan

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10745
Author(s):  
Qin Zhang ◽  
Zhangying Feng ◽  
Mengxi Gao ◽  
Liru Guo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Drug Targets ◽  
Cellular Response ◽  
Hormone Receptors ◽  
Enrichment Analysis ◽  
Stage Iii ◽  
Ppi Network ◽  
P53 Signaling

Background SiNiSan (SNS) is an ancient traditional Chinese medicine (TCM) used to treat liver and spleen deficiencies. We studied the unique advantages of using SNS to treat hepatocellular carcinoma (HCC) with multiple components and targets to determine its potential mechanism of action. Methods The active compounds from the individual herbs in the SNS formula and their targets were mined from Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). HCC-associated targets were collected from the TCGA and GEO databases and samples were collected from patients with stage III hepatocellular carcinoma. A compound-disease target network was constructed, visualized, and analyzed using Cytoscape software. We built a protein-protein interaction (PPI) network using the String database. We enriched and analyzed key targets using GSEA, GO, and KEGG in order to explore their functions. Autodock software was used to simulate the process of SNS molecules acting on HCC targets. Results A total of 113 candidate compounds were taken from SNS, and 64 of the same targets were chosen from HCC and SNS. The predominant targets genes were PTGS2, ESR1, CHEK1, CCNA2, NOS2 and AR; kaempferol and quercetin from SNS were the principal ingredients in HCC treatment. The compounds may work against HCC due to a cellular response to steroid hormones and histone phosphorylation. The P53 signaling pathway was significantly enriched in the gene set GSEA enrichment analysis and differential gene KEGG enrichment analysis. Conclusions Our results showed that the SNS component has a large number of stage III HCC targets. Among the targets, the sex hormone receptors, the AR and ESR1 genes, are the core targets of SNS component and the most active proteins in the PPI network. In addition, quercetin, which has the most targets, can act on the main targets (BAX, CDK1, CCNB1, SERPINE1, CHEK2, and IGFBP3) of the P53 pathway to treat HCC.

Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene

1990 ◽  
Vol 10 (9) ◽  
pp. 4712-4719
Author(s):  
E Imai ◽  
P E Stromstedt ◽  
P G Quinn ◽  
J Carlstedt-Duke ◽  
J A Gustafsson ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Binding ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Binding Region ◽  
Factor Binding ◽  
Response Unit ◽  
Accessory Factor ◽  
Glucocorticoid Response ◽  
Glucocorticoid Induction ◽  
Receptor Binding Region

The minimal DNA sequence required for glucocorticoid induction of the phosphoenolpyruvate carboxykinase (PEPCK) gene in H4IIE rat hepatoma cells was defined. This novel glucocorticoid response unit (GRU) spans about 110 base pairs (bp) and includes two receptor-binding elements plus two accessory factor-binding elements. Purified glucocorticoid receptor bound to two regions (GR1 and GR2) between -395 and -349 bp relative to the transcription start site. Factors in crude rat liver nuclear extract bound to DNA in the regions -455 to -431 and -420 to -403 bp, which are designated accessory factor 1 (AF1) and accessory factor 2 (AF2) elements, respectively. Gel retardation analysis revealed that at least two proteins bound to AF1 and that they were distinct from the protein(s) that bound to AF2. Various combinations of GR1, GR2, AF1, and AF2 were fused to the chloramphenicol acetyltransferase (CAT) reporter gene and cotransfected with a glucocorticoid receptor expression plasmid (pSVGR1) into H4IIE cells to identify the functional GRU. Neither the glucocorticoid receptor binding region nor the accessory factor binding region alone was sufficient to confer glucocorticoid responsiveness. The two components of the glucocorticoid receptor binding region functioned independently, and each accounted for half of the maximal response, provided the accessory factor elements were present. Similarly, deletion of either AF1 or AF2 diminished glucocorticoid induction of the PEPCK gene to approximately half of the maximum. We propose that the complex PEPCK gene GRU provides the stringent regulation required of this critical enzyme in liver.

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