scholarly journals Rapid vasodilation to raloxifene: role of oestrogen receptors and off-target effects

2017 ◽  
Vol 174 (22) ◽  
pp. 4201-4202
Author(s):  
Matthias Barton ◽  
Eric R Prossnitz
Keyword(s):  
Oestrogen Receptors ◽  
Target Effects

scholarly journals Specificity of RNAi, LNA and CRISPRi as loss-of-function methods in transcriptional analysis

2017 ◽  
Author(s):  
Lovorka Stojic ◽  
Aaron Lun ◽  
Jasmin Mangei ◽  
Patrice Mascalchi ◽  
Valentina Quarantotti ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Noncoding Rna ◽  
Specific Activity ◽  
Transcriptional Analysis ◽  
Clonal Variation ◽  
Loss Of Function ◽  
Negative Controls ◽  
Whole Transcriptome ◽  
Target Effects

ABSTRACTLoss-of-function (LOF) methods, such as RNA interference (RNAi), antisense oligonucleotides or CRISPR-based genome editing, provide unparalleled power for studying the biological function of genes of interest. When coupled with transcriptomic analyses, LOF methods allow researchers to dissect networks of transcriptional regulation. However, a major concern is nonspecific targeting, which involves depletion of transcripts other than those intended. The off-target effects of each of these common LOF methods have yet to be compared at the whole-transcriptome level. Here, we systematically and experimentally compared non-specific activity of RNAi, antisense oligonucleotides and CRISPR interference (CRISPRi). All three methods yielded non-negligible offtarget effects in gene expression, with CRISPRi exhibiting clonal variation in the transcriptional profile. As an illustrative example, we evaluated the performance of each method for deciphering the role of a long noncoding RNA (lncRNA) with unknown function. Although all LOF methods reduced expression of the candidate lncRNA, each method yielded different sets of differentially expressed genes upon knockdown as well as a different cellular phenotype. Therefore, to definitively confirm the functional role of a transcriptional regulator, we recommend the simultaneous use of at least two different LOF methods and the inclusion of multiple, specifically designed negative controls.

scholarly journals Oestrogen receptors and antioestrogen treatment of hormone-dependent tumours

2018 ◽  
Vol 49 (2) ◽  
pp. 91
Author(s):  
N. G. KOSTOMITSOPOULOS (Ν.Γ. ΚΩΣΤΟΜΗΤΣΟΠΟΥΛΟΣ)
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Sequences ◽  
Human Breast Cancer ◽  
Oestrogen Receptor ◽  
Specific Gene ◽  
Oestrogen Receptors ◽  
Human Breast ◽  
Potential Use

The oestrogen receptor is a ligand-activated transcription factor that modulates specific gene expression by binding to short DNA sequences. The study of the role of oestrogen receptor on the expression of the mitogenic actionof oestrogens and oncogenesis lead biomedical research in new approaches of the treatment of oestrogen-dependent tumors by using antioestrogens. Main mechanism of action of antioestrogens is the prevention of oestrogen action by blocking the binding of oestradiol to the oestrogen receptor. Tamoxifen, the most wellknown antioestrogen, is widely used as adjuvant therapy in all stages of human breast cancer. Recently interest is focused on the potential use of "pure" antioestrogens. The use of antioestrogens in veterinary oncology is also under discussion.

α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome?

2021 ◽  
Vol 134 (5) ◽  
pp. 792-808
Author(s):  
Grace Hogan ◽  
Pierce Geoghegan ◽  
Tomás P. Carroll ◽  
Jennifer Clarke ◽  
Oisín F. McElvaney ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Main Function ◽  
Alveolar Capillary ◽  
Target Effects ◽  
Antiprotease Activity ◽  
The Ideal

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar–capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.

scholarly journals Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

2019 ◽  
Vol 20 (24) ◽  
pp. 6358 ◽  
Author(s):  
Giuseppina Emanuela Grieco ◽  
Noemi Brusco ◽  
Giada Licata ◽  
Laura Nigi ◽  
Caterina Formichi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Delivery ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Delivery Methods ◽  
Cell Dysfunction ◽  
Single Cell Type ◽  
Chronic Hyperglycaemia ◽  
Target Effects

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases.

scholarly journals Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors

2011 ◽  
Vol 203 (1) ◽  
pp. 259-269 ◽  
Author(s):  
M. R. Meyer ◽  
D. J. Clegg ◽  
E. R. Prossnitz ◽  
M. Barton
Keyword(s):  
Insulin Resistance ◽  
Sex Differences ◽  
Oestrogen Receptors

scholarly journals Specific Protein Antigen Delivery to Human Langerhans Cells in Intact Skin

2021 ◽  
Vol 12 ◽  
Author(s):  
Mareike Rentzsch ◽  
Robert Wawrzinek ◽  
Claudia Zelle-Rieser ◽  
Helen Strandt ◽  
Lydia Bellmann ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Langerhans Cells ◽  
Specific Protein ◽  
Protein Antigen ◽  
Antigen Delivery ◽  
Model Protein ◽  
Skin Explants ◽  
Antigen Presenting ◽  
Target Effects

Immune modulating therapies and vaccines are in high demand, not least to the recent global spread of SARS-CoV2. To achieve efficient activation of the immune system, professional antigen presenting cells have proven to be key coordinators of such responses. Especially targeted approaches, actively directing antigens to specialized dendritic cells, promise to be more effective and accompanied by reduced payload due to less off-target effects. Although antibody and glycan-based targeting of receptors on dendritic cells have been employed, these are often expensive and time-consuming to manufacture or lack sufficient specificity. Thus, we applied a small-molecule ligand that specifically binds Langerin, a hallmark receptor on Langerhans cells, conjugated to a model protein antigen. Via microneedle injection, this construct was intradermally administered into intact human skin explants, selectively loading Langerhans cells in the epidermis. The ligand-mediated cellular uptake outpaces protein degradation resulting in intact antigen delivery. Due to the pivotal role of Langerhans cells in induction of immune responses, this approach of antigen-targeting of tissue-resident immune cells offers a novel way to deliver highly effective vaccines with minimally invasive administration.

scholarly journals Differential inhibition of rat and mouse microsome heme oxygenase by derivatives of imidazole and benzimidazole

2017 ◽  
Vol 95 (12) ◽  
pp. 1454-1461
Author(s):  
Maaike Hum ◽  
Brian E. McLaughlin ◽  
Xianqi Kong ◽  
Jason Z. Vlahakis ◽  
Dragic Vukomanovic ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Mammalian Species ◽  
Benzimidazole Derivative ◽  
Benzimidazole Derivatives ◽  
Response Curves ◽  
Physiological Processes ◽  
Brain Microsomes ◽  
Derivatives Of ◽  
Target Effects

Metalloporphyrin heme oxygenase (HO) inhibitors have made an important contribution to elucidating the role of HO in physiological processes. Nevertheless, their off-target effects have drawn substantial criticism, which prompted us to develop non-porphyrin, azole-based inhibitors of HO. These second-generation HO inhibitors were evaluated using spleen and brain microsomes from rats as native sources of HO-1 and HO-2, respectively. Recently, the use of azole-based inhibitors of HO has been extended to other mammalian species and, as a consequence, it will be important to characterize the inhibitors in these species. The goal of this study was to compare the inhibitory profile of imidazole- and benzimidazole-based inhibitors of HO in a breast-cancer-implanted mouse to that of an untreated rat. For spleen and brain microsomes from both species, HO protein expression was determined by Western blotting and concentration–response curves for imidazole- and benzimidazole-derivative inhibition of HO activity were determined using a headspace gas-chromatographic assay. It was found that the effects on HO activity by imidazole and benzimidazole derivatives were different between the 2 species and were not explained by differences in HO expression. Thus, the HO inhibitory profile should be determined for azole derivatives before they are used in mammalian species other than rats.

A possible role of clomiphene citrate in the control of pre-ovulatory LH surge during induction of ovulation

1985 ◽  
Vol 109 (1) ◽  
pp. 58-63 ◽  
Author(s):  
Naoki Terakawa ◽  
Ikuya Shimizu ◽  
Hirohisa Tsutsumi ◽  
Toshihiro Aono ◽  
Keishi Matsumoto
Keyword(s):  
Nuclear Receptor ◽  
Clomiphene Citrate ◽  
Ovariectomized Rats ◽  
Receptor Complex ◽  
Oestrogen Receptors ◽  
Lh Surge ◽  
Serum Lh ◽  
Lh Release

Abstract. A possible role of clomiphene citrate (clomiphene) in the control of ovulation in anovulatory women was investigated. Since a single ip administration of 5 μg oestradiol-17β (E2) to long-term ovariectomized rats did not induce LH surge, the following studies were designed to determine whether pretreatment with clomiphene followed by administration of E2 could induce LH surge in the ovariectomized rats. Changes in cytoplasmic and nuclear oestrogen receptors (ER) were also examined in the pituitaries of these animals. An ip injection of 200 μg clomiphene suppressed serum LH levels significantly for 72 h. The clomiphene injection rapidly caused an elevation of nuclear ER with a concomitant depletion of cytoplasmic ER level in the pituitary and the ER levels remained almost unchaged for 72 h. An administration of E2 12 or 24 h after the clomiphene injection had no significant effects on either the serum LH levels or the cytoplasmic and nuclear ER levels, compared with those induced by clomiphene alone. However, LH surge and the depletion of nuclear ER in the pituitary occurred 24 h later when E2 was injected 48 h after the clomiphene administration. The E2-induced LH release seems to be induced by a replacement of clomiphene by E2 on the nuclear receptor complex. These results suggest that clomiphene may exert actions directly on the pituitary gland to augment oestrogeninduced LH release.

scholarly journals Regulation of IRE1α by the small molecule inhibitor 4μ8c in hepatoma cells

2017 ◽  
Vol 4 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Claire Stewart ◽  
Andrea Estrada ◽  
Paul Kim ◽  
Dong Wang ◽  
Yuren Wei ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecule ◽  
Pancreatic Beta Cells ◽  
Cell Types ◽  
Small Molecule Inhibitor ◽  
Hepatoma Cells ◽  
Rnase Activity ◽  
Molecule Inhibitor ◽  
Target Effects

AbstractThe unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]. In the present study we utilized this inhibitor to examine the role of IRE1α RNase activity in hepatoma cells (H4IIE), specifically concentrating on cell proliferation and the identification of potential off target effects under both unstressed and stressed conditions. Experiments were performed in H4IIE hepatoma cells in the absence (control conditions (LG)) or presence (LG + Thapsigargin (Thap)) of ER stress. The presence of 4μ8c decreased IRE1α RNase activity, based on reduced splicing of X-box binding protein-1 (XBP1s) and regulated IRE1α-dependent decay of mRNA in both treatments and at concentrations ranging from 10-90 μM. Cell proliferation was significantly reduced at higher concentrations (> 60 μM 4μ8c) in unstressed cells and displayed a dose-response relationship with 4μ8c in both treatments. The presence of 4μ8c did not promote cytoxicity in either of the treatment conditions but higher concentrations of the inhibitor (60 μM) were associated with apparent off-target or compensatory responses that were not observed at 10 μM. Overall, the small-molecule inhibitor, 4μ8c is an effective inhibitor of IRE1α RNase activity in H4IIE cells. Potential off-target effects associated with this inhibitor require the use of multiple inhibitor concentrations in all experiments.

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