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PloS One 2015One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their...
One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their maturation program at lesions. To identify key regulators of myelin gene expression acting at the last stages of OPC maturation we developed a drug repositioning strategy based on the mouse immortalized oligodendrocyte (OL) cell line Oli-neu brought to the premyelination stage by stably expressing a key factor regulating the last stages of OL maturation. The Prestwick Chemical Library of 1,200 FDA-approved compound(s) was repositioned at three dosages based on the induction of Myelin Basic Protein (MBP) expression. Drug hits were further validated using dosage-dependent reproducibility tests and biochemical assays. The glucocorticoid class of compounds was the most highly represented and we found that they can be divided in three groups according to their efficacy on MBP up-regulation. Since target identification is crucial before bringing compounds to the clinic, we searched for common targets of the primary screen hits based on their known chemical-target interactomes, and the pathways predicted by top ranking compounds were validated using specific inhibitors. Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. Further, RxRγ activation is required for MBP expression upon Halcinonide and Clobetasol treatment. These data indicate Clobetasol and Halcinonide as potential promyelinating drugs and also provide a mechanistic understanding of their mode of action in the pathway leading to myelination in OPCs. Furthermore, our classification of glucocorticoids with respect to MBP expression provides important novel insights into their effects in the CNS and a rational criteria for their choice in combinatorial therapies in de-myelinating diseases.
Topics: Animals; Anti-Inflammatory Agents; Cell Line; Clobetasol; Cytoskeletal Proteins; Drug Repositioning; Gene Expression; Halcinonide; Immunoblotting; Mice; Microscopy, Fluorescence; Muscle Proteins; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Retinoid X Receptor gamma; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors
PubMed: 26658258
DOI: 10.1371/journal.pone.0144550 -
Vitamins and Hormones 2011The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the... (Review)
Review
The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the cerebellum and hippocampus. It has been reported that exposure to glucocorticoids can impair neurogenesis in both adults and children. Glucocorticoids are known to bind with high affinity to intracellular receptors. Glucocorticoid blood levels are normally regulated by environmental stresses, but because of their clinical utility, exogenous glucocorticoids are frequently administered in drug formulations. Consequently, concerns have arisen about the consequences of glucocorticoid use on neurogenesis and health, especially in the pediatric population. In this article, we will review recent findings that a select number of related glucocorticoids, halcinonide, fluticasone propionate, clobetasol propionate, and fluocinonide, also bind the hedgehog pathway receptor Smoothened. We will discuss their pharmacology and also a most surprising result; that this select group of compounds, which includes FDA approved drugs, unlike typical glucocorticoids such as dexamethasone, stimulate stem cell growth, and thus enhance neurogenesis.
Topics: Adult Stem Cells; Animals; Glucocorticoids; Hedgehog Proteins; Humans; Neural Stem Cells; Neurogenesis; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor
PubMed: 22127244
DOI: 10.1016/B978-0-12-386015-6.00030-5 -
The Journal of Clinical and Aesthetic... Apr 2011When treating patients with extensive dermatitis, total body surface area affected must be considered when prescribing topical medication. Halcinonide 0.1% cream, a...
UNLABELLED
When treating patients with extensive dermatitis, total body surface area affected must be considered when prescribing topical medication. Halcinonide 0.1% cream, a class 2 topical corticosteroid, is now available in a 216g jar. This large size is convenient and cost effective for patients with large-area dermatoses.
OBJECTIVES
The objectives of this study were to determine the efficacy and patient acceptance of halcinonide in 216g jars for the treatment of large-area dermatoses.
DESIGN
This study was an open-label, noncomparator trial evaluating the clinical outcomes and acceptability of halcinonide in 216g jars. Halcinonide was prescribed twice daily for up to 28 days.
MEASUREMENT
Severity of dermatoses was based on investigator observations at the baseline visit and again after 28 days. Patient satisfaction was evaluated based on a questionnaire completed at the conclusion of the study.
RESULTS
Total enrollment was 40 patients. Dermatoses affected an average of 12 percent body surface area. At baseline, all patients exhibited dermatoses rated as severe or moderate. Nearly half of patients were completely cleared or almost cleared by 28 days, with all patients noting at least some improvement. Most patients agreed that they liked the way the product spread on the skin (94.7%), and more than 80 percent found that it was neither sticky nor greasy. In more than 90 percent of cases, the investigator reported that halcinonide provided a shorter duration of therapy versus triamcinolone one-pound jars.
CONCLUSION
Halcinonide 0.1% cream in 216g jars is effective and convenient for patients with large-area dermatoses.
PubMed: 21532875
DOI: No ID Found -
Pharmaceutics Sep 2021The potencies of topical corticosteroid products have mainly been classified using clinical data but in some instances, the US Food and Drug Administration's (FDA's)...
The potencies of topical corticosteroid products have mainly been classified using clinical data but in some instances, the US Food and Drug Administration's (FDA's) vasoconstrictor assay (VCA) to assess the skin blanching response has also been used. However, the reported skin blanching response data were often based on a single visual reading and lack information on the dose (amount/quantity) or dose duration. Although several lists classifying potencies of various topical corticosteroid products have been published, the inherent potencies of topical corticosteroid raw materials used as active pharmaceutical ingredients (APIs) have not been investigated. The objective was to rank the inherent potencies of topical corticosteroid APIs and to standardize dosing such that the relevant compounds could be compared on a normalized molar basis. The potencies of clobetasol propionate, halcinonide, mometasone furoate, and fluocinolone acetonide were compared using the resulting data following the fitting of the relevant response data to the model where mometasone furoate > fluocinolone acetonide = clobetasol propionate > halcinonide. This ranking lists the respective inherent potencies of the APIs, which will facilitate the choice of a suitable candidate for incorporation into an appropriate topical corticosteroid product for a specific clinical indication.
PubMed: 34575532
DOI: 10.3390/pharmaceutics13091456 -
Blood Cancer Journal Jun 2018Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse....
Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.
Topics: Apoptosis; Biomarkers; Biomarkers, Tumor; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Computational Biology; Cytarabine; Drug Discovery; Drug Screening Assays, Antitumor; Gene Expression Profiling; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Neoplastic Stem Cells; Transcriptome
PubMed: 29921955
DOI: 10.1038/s41408-018-0087-2 -
Clinical, Cosmetic and Investigational... 2022Lichen sclerosis (LS) is an insidious, chronic, relapsing skin disease characterized by atrophic, porcelain-appearing plaques. It usually arises in the anogenital area,...
Lichen sclerosis (LS) is an insidious, chronic, relapsing skin disease characterized by atrophic, porcelain-appearing plaques. It usually arises in the anogenital area, but some cases can present in extragenital regions with a variety of presentations, including a bullous variant. Topical corticosteroids are a first-line therapy and are usually the most effective treatment to induce remission of LS. However, there is a subset of patients that does not respond well to topical steroids. Herein, we report an extragenital bullous LS case successfully treated with a fractional CO laser (FxCO) and subsequent wet dressing of halcinonide solution.
PubMed: 35300434
DOI: 10.2147/CCID.S355111 -
Proceedings of the National Academy of... May 2010Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened...
Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impeded by a lack of US Food and Drug Administration (FDA)-approved Smo agonists. Using a high-content screen with cells expressing Smo receptors and a beta-arrestin2-GFP reporter, we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. These drugs demonstrated an ability to bind Smo, promote Smo internalization, activate Gli, and stimulate the proliferation of primary neuronal precursor cells alone and synergistically in the presence of Sonic Hedgehog protein. Halcinonide, fluticasone, clobetasol, and fluocinonide provide an unprecedented opportunity to develop unique clinical strategies to treat Hedgehog-dependent illnesses.
Topics: Androstadienes; Arrestins; Blotting, Western; Cell Line; Cell Proliferation; Clobetasol; Fluocinonide; Fluticasone; Glucocorticoids; Green Fluorescent Proteins; Halcinonide; Hedgehog Proteins; Humans; Molecular Structure; Receptors, G-Protein-Coupled; Regenerative Medicine; Signal Transduction; Smoothened Receptor; Stem Cells; beta-Arrestins
PubMed: 20439738
DOI: 10.1073/pnas.0910712107 -
The Journal of Investigative Dermatology Mar 1976Formulations of a number of steroids were evaluated after topical application in a reversed passive Arthus test (RPA) in rabbits. Four 21-chlorosteroids in the same...
Formulations of a number of steroids were evaluated after topical application in a reversed passive Arthus test (RPA) in rabbits. Four 21-chlorosteroids in the same cream base were investigated. The preparations of SQ 18,566 (halcinonide) and SQ 20,811 showed anti-edema activity, but those of SQ 15,361 and SQ 20,589 were less active. Ointment formulations of halcinonide also reduced edema in the RPA. These results, coupled with previously reported clinical data, suggest that the RPA might be utilized to distinguish good from poor formulations of anti-inflammatory steroids prior to screening tests or clinical trials in humans.
Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Arthus Reaction; Glucocorticoids; Halcinonide; Inflammation; Injections, Intradermal; Ointments; Pregnadienetriols; Pregnenediones; Rabbits; Steroids, Chlorinated; Triamcinolone Acetonide
PubMed: 129493
DOI: 10.1111/1523-1747.ep12481898 -
Infection, Genetics and Evolution :... Dec 2020The recent outbreak of COVID-19 has become a global health concern. There are currently no effective treatment strategies and vaccines for the treatment or prevention of...
AIMS
The recent outbreak of COVID-19 has become a global health concern. There are currently no effective treatment strategies and vaccines for the treatment or prevention of this fatal disease. The current study aims to determine promising treatment options for the COVID-19 through a computational drug repurposing approach.
MATERIALS AND METHODS
In this study, we focus on differentially expressed genes (DEGs), detected in SARS-CoV-2 infected cell lines including "the primary human lung epithelial cell line NHBE" and "the transformed lung alveolar cell line A549". Next, the identified DEGs are used in the connectivity map (CMap) analysis to identify similarly acting therapeutic candidates. Furthermore, to interpret lists of DEGs, pathway enrichment and protein network analysis are performed. Genes are categorized into easily interpretable pathways based on their biological functions, and overrepresentation of each pathway is tested in comparison to what is expected randomly.
KEY FINDINGS
The results suggest the effectiveness of lansoprazole, folic acid, sulfamonomethoxine, tolnaftate, diclofenamide, halcinonide, saquinavir, metronidazole, ebselen, lidocaine and benzocaine, histone deacetylase (HDAC) inhibitors, heat shock protein 90 (HSP90) inhibitors, and many other clinically approved drugs as potent drugs against COVID-19 outbreak.
SIGNIFICANCE
Making new drugs remain a lengthy process, so the drug repurposing approach provides an insight into the therapeutics that might be helpful in this pandemic. In this study, pathway enrichment and protein network analysis are also performed, and the effectiveness of some drugs obtained from the CMap analysis has been investigated according to previous researches.
Topics: A549 Cells; Antiviral Agents; COVID-19; Cell Line, Tumor; Drug Repositioning; Humans; Pandemics; Protein Interaction Maps; SARS-CoV-2; Transcriptome
PubMed: 33130005
DOI: 10.1016/j.meegid.2020.104610 -
Annals of Transplantation May 2016BACKGROUND Our aim was to explore the mechanism of post-transplant organ function decrease induced by brain death (BD) and discover a potential candidate drug for...
BACKGROUND Our aim was to explore the mechanism of post-transplant organ function decrease induced by brain death (BD) and discover a potential candidate drug for improving the survival and organ function after BD. MATERIAL AND METHODS The microarray data developed from the liver tissues after BD were further analyzed by bioinformatics methods. The differentially expressed genes (DEGs) were computationally predicted and the DEGs that involved biological functions were explored by gene ontology (GO) analysis. The candidate agents that could induce the reverse gene signature were predicted based on the Connectivity Map (CMap) database. RESULTS There were total 1374 DEGs, including 589 up-regulated genes and 785 down-regulated genes. Function analysis showed that DEGs were mainly enriched in biological process-related GO terms, such as regulation of transcription, DNA-dependent, inflammatory response, and regulation of phosphorus metabolic process. The down-regulated genes were significantly enriched in transcription factor activity and transcription regulator activity-related molecular function. The down-regulated GO terms exhibited close interaction with each other. CONCLUSIONS The organ function decrease may be attributed by transcription alteration, inflammation response, and metabolic alteration in liver after BD. Spaglumic acid and halcinonide may be potential drugs for preventing organ damage during the BD process.
Topics: Brain Death; Computational Biology; Dipeptides; Gene Expression Profiling; Gene Ontology; Graft Survival; Halcinonide; Humans; Liver; Liver Transplantation; Oligonucleotide Array Sequence Analysis; Tissue Donors
PubMed: 27170053
DOI: 10.12659/aot.897454