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Biochemical Pharmacology Jul 1988Following chronic administration of corticosteroids in vivo, a number of complications occur, which mainly involve the metabolism of connective tissue cells. Therefore,...
Following chronic administration of corticosteroids in vivo, a number of complications occur, which mainly involve the metabolism of connective tissue cells. Therefore, several attempts have been made to develop corticosteroids, which show less pronounced side effects. Fibroblasts were kept in monolayer cultures and were exposed to corticosteroids demonstrating similar anti-inflammatory activity (prednicarbate, desoximetasone). Chemotaxis of fibroblasts was studied over 4 hr, protein and collagen synthesis were estimated using proteinchemical methods and also by dot blot hybridization. Corticosteroids used in a high dosage (10 microM) affected all biosynthetic capacities of the investigated fibroblasts. Protein synthesis and production of collagen types I and III were reduced and a similar decrease of mRNA levels for collagen type I could be found indicating an influence on the pretranslational control. In the same concentrations desoximetasone was much more active than prednicarbate. Fibroblast migration was dosage dependently inhibited from 10(-9) M to 10(-5) M for desoximetasone, while incubation with prednicarbate did not cause a reduction of the chemotactic response at concentrations lower than 10(-7) M. These data suggest that modifications of corticosteroids might result in a dissociation of some of their biological activities and can specifically influence their effects on biosynthetic capacities of fibroblasts.
Topics: Adrenal Cortex Hormones; Cells, Cultured; Chemotaxis; Collagen; Fibroblasts; Humans; RNA, Messenger
PubMed: 3395353
DOI: 10.1016/0006-2952(88)90034-2 -
Experimental Cell Research Oct 2020SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to...
BACKGROUND
SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach.
METHODS
In the present investigation, we evaluated the effects of SARS-CoV on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analyzed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV, SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses.
RESULTS
The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV infection.
CONCLUSIONS
Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment.
Topics: Bronchi; COVID-19; Carcinoembryonic Antigen; Coronavirus Infections; Drug Discovery; Dyneins; GPI-Linked Proteins; Gene Regulatory Networks; Granulocyte Colony-Stimulating Factor; Humans; Immunity, Innate; Machine Learning; Pandemics; Pneumonia, Viral; Respiratory Mucosa; Transcriptome; Up-Regulation
PubMed: 32735892
DOI: 10.1016/j.yexcr.2020.112204 -
Biochemical Pharmacology Mar 2005Tristetraprolin (TTP) is a factor that regulates mRNA stability and the expression of certain inflammatory genes. In the present study, we found that TTP expression was...
Tristetraprolin (TTP) is a factor that regulates mRNA stability and the expression of certain inflammatory genes. In the present study, we found that TTP expression was increased in macrophages exposed to bacterial lipopolysaccharide (LPS). Dexamethasone and dissociated steroid RU24858 inhibited LPS-induced TTP protein and mRNA expression and the inhibitory effect was reversed by a glucocorticoid receptor antagonist mifepristone. Histone deacetylase inhibitors trichostatin A (TSA) and apicidin reduced the inhibitory effect of dexamethasone and RU24858 on TTP expression, but the glucocorticoids did not alter TTP mRNA half-life. These results suggest that anti-inflammatory steroids reduce TTP expression in activated macrophages by a glucocorticoid response element (GRE)-independent mechanism, possibly through histone deacetylation and transcriptional silencing.
Topics: Animals; Cell Line; DNA-Binding Proteins; Desoximetasone; Dexamethasone; Gene Expression Regulation; Histone Deacetylases; Hydroxycorticosteroids; Immediate-Early Proteins; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; RNA, Messenger; Tristetraprolin
PubMed: 15710351
DOI: 10.1016/j.bcp.2004.11.027 -
Die Pharmazie Jan 1998Growth/differentiation factor-5 (GDF-5) is a new member of the transforming growth factor-beta (TGF-beta) superfamily of multifunctional peptide growth factors that...
Growth/differentiation factor-5 (GDF-5) is a new member of the transforming growth factor-beta (TGF-beta) superfamily of multifunctional peptide growth factors that appear to mediate many key events in cell growth and development. The effects of GDF-5 and other growth factors (epidermal growth factor, EGF; TGF-beta 1) on the proliferation of human keratinocytes and fibroblasts compared with desoximetasone and calcipotriol have been investigated. The proliferation rate was determined by a hemocytometer, MTT assay and the incorporation of [3H]-thymidine. Moreover, cell cycle analyses were performed and the influence on interleukin-1 alpha (IL-1 alpha) production in keratinocytes was measured by enzyme-linked immunosorbent assay (ELISA) because of its pronounced proinflammatory effect. In keratinocytes, GDF-5 stimulated cell proliferation to a minor extent. The drug already proved to be effective at very low concentrations (0.1 ng/ml). Growth stimulatory effects with EGF have been observed only in keratinocyte basal medium (KBM), but not in keratinocyte growth medium (KGM). TGF-beta 1 markedly inhibited the proliferation of keratinocytes at concentrations > 1 ng/ml. Calcipotriol and desoximetasone also showed a dose-dependent cell growth inhibition in epidermal cell cultures. IL-1 alpha synthesis was greatly suppressed by calcipotriol 10(-8)-10(-6) M. EGF at 10 ng/ml, in contrast, strongly stimulated IL-1 alpha production. Neither GDF-5 nor TGF-beta 1 had a significant effect on IL-1 alpha production in keratinocyte monolayer cultures. In fibroblasts, GDF-5 induced very weak antiproliferative effects. Calcipotriol and desoximetasone also inhibited cell growth in fibroblast cultures whereas proliferation and DNA synthesis were strongly stimulated by 1 ng/ml EGF. There was, however, a contradiction between TGF-beta 1 results on fibroblasts. Whereas TGF-beta 1 increased proliferation in cell number determination and in the thymidine incorporation assay, MTT assays showed slight antiproliferative effects. Due to these controversial results, in addition cell cycle analysis was employed. TGF-beta 1 led to an increased S phase, which indicates a stimulation of cell division. The different results obtained with the MTT test suggest that TGF-beta 1 may stimulate cell division of fibroblasts not only by increasing the S phase, but also by shortening the G1 phase of the cell cycle.
Topics: Cell Cycle; Cell Division; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Growth Substances; Humans; Interleukin-1; Keratinocytes; Skin; Tetrazolium Salts; Thiazoles; Thymidine
PubMed: 9476258
DOI: No ID Found -
Eye (London, England) 1993Steroid creams applied topically to the skin are routinely used in the treatment of many dermatoses. Their use on the face in severe atopic eczema is relatively common....
Steroid creams applied topically to the skin are routinely used in the treatment of many dermatoses. Their use on the face in severe atopic eczema is relatively common. We report a series of three patients who whilst using topical facial steroids developed advanced glaucoma. A further two cases of ocular hypertension secondary to topical facial steroids are also described. This is the first series of cases to be reported demonstrating the potentially blinding complications of topical facial steroids. Recommendations are made with regard to screening such patients for glaucoma.
Topics: Administration, Topical; Adolescent; Adult; Anti-Inflammatory Agents; Clobetasol; Dermatitis, Atopic; Desoximetasone; Facial Dermatoses; Female; Glaucoma; Humans; Hydrocortisone; Male; Ocular Hypertension; Prednisolone; Vision Disorders; Visual Acuity
PubMed: 8287990
DOI: 10.1038/eye.1993.152 -
Pharmaceutical Research Dec 1997Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD),... (Comparative Study)
Comparative Study
PURPOSE
Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), betamethasone (BM) and desoximetasone (DM) by evaluating their effects on epidermal and dermal cells. Synopsis of pharmacokinetic and pharmacodynamic studies, possibly explaining the improved benefit-risk ratio of prednicarbate.
METHODS
Isolated foreskin keratinocytes were used to investigate the influence on epidermal inflammatory processes, dermal fibroblasts of the same origin to study antiproliferative activities of glucocorticoids. Interleukins were measured by ELISA-assay, the influence on II-1 alpha-production also on mRNA-level by RNAse protection assay. Proliferation was assessed by 3H thymidine incorporation and biodegradation by HPLC/UV-absorption. Cell viability was controlled by MTT assay.
RESULTS
In keratinocytes, inflammation was induced by TNF alpha, resulting in an increased II-1 alpha synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p < or = 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1 alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation effects. In agreement with the previous experiment, the antiinflammatory potency of native PC was confirmed. In fibroblasts, II-1 alpha and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II-1 alpha and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p < or = 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymidine incorporation. More pronounced antiproliferative features were observed with BM, PEC and especially BMV.
CONCLUSIONS
Correlating antiphlogistic effects in keratinocytes (suppression of II-1 alpha) with antiproliferative effects in fibroblasts (suppression of II-1 alpha and II-6), the improved benefit-risk ratio of PC compared to conventional glucocorticoids does not result only from distinct drug metabolism in the skin but also from a specific influence on the cytokine network.
Topics: Administration, Topical; Anti-Inflammatory Agents; Betamethasone Valerate; Cell Division; Cells, Cultured; Desoximetasone; Fibroblasts; Glucocorticoids; Humans; Interleukin-1; Interleukin-6; Keratinocytes; Prednisolone; RNA, Messenger; Skin; Thymidine
PubMed: 9453063
DOI: 10.1023/a:1012183914011 -
Acta Dermatovenerologica Alpina,... Jun 2021Hypopigmented mycosis fungoides (HMF) is a rare variant of patch stage MF, which is often misdiagnosed. A 35-year-old male presented with non-pruritic white patches on...
Hypopigmented mycosis fungoides (HMF) is a rare variant of patch stage MF, which is often misdiagnosed. A 35-year-old male presented with non-pruritic white patches on his chest that had been present for 10 years. The patient had previously been treated for leprosy without any improvement. Physical examination showed well-defined multiple hypopigmented patches and macules on the chest, posterior trunk, and gluteus, with some lesions exhibiting anhidrosis and central erythema. The result of sensibility examination was unclear. Slit-skin-smear examination for acid-fast bacilli and anti-phenolic-glycolipid-1 examination were negative. Histopathological examination showed Pautrier microabscesses. The patient was diagnosed with HMF and was treated with 16 mg methylprednisolone b.i.d., topical application of desoximetasone, and 1% methoxsalen lotion followed by sun exposure. A significant improvement was observed during the following 6 months. This case shows that HMF needs to be considered in patients presenting with chronic unexplained hypopigmented patches to avoid unnecessary treatment and progression to more advanced stages.
Topics: Adrenal Cortex Hormones; Adult; Humans; Hypopigmentation; Leprosy; Male; Mycosis Fungoides; Skin Neoplasms
PubMed: 34169706
DOI: No ID Found -
Experimental and Therapeutic Medicine May 2021Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation,...
Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1β, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.
PubMed: 33747183
DOI: 10.3892/etm.2021.9876 -
Dermatitis : Contact, Atopic,... 2017Corticosteroids may cause delayed hypersensitivity. On the basis of structure, the following 4 groups of corticosteroids are recognized: A, B, C, and D (subdivided into...
INTRODUCTION
Corticosteroids may cause delayed hypersensitivity. On the basis of structure, the following 4 groups of corticosteroids are recognized: A, B, C, and D (subdivided into D1 and D2). More recently, a newer classification system subdivides corticosteroids into groups 1, 2, and 3. Cross-reactions are unpredictable. The objective of this study was to describe positive patch test and co-reaction patterns to corticosteroids.
METHODS AND RESULTS
A retrospective analysis of 17,978 patients patch tested by the North American Contact Dermatitis Group between 2007 and 2014 was performed. Corticosteroids tested during this period included the following: tixocortol-21-pivalate 1.0% petroleum (pet), budesonide 0.1% pet, triamcinolone acetonide 1.0% pet, desoximetasone 1.0% pet, clobetasol-17-propionate 1.0% pet, and hydrocortisone-17-butyrate (HC-17-B) 1.0% (pet and alcohol). Overall, 4.12% (n = 741) of patients had 1 or more positive reactions to corticosteroids. Tixocortol-21-pivalate positivity was the most common (2.26%), followed by budesonide (0.87%), HC-17-B (0.43%), clobetasol-17-proprionate (0.32%), and desoximetasone (0.16%). Reaction strength was strong (++ or +++) in almost twice as many tixocortol and budesonide reactions (>64%) as compared with the other 3 corticosteroids (<34.5%). Of the patients with positive corticosteroid reactions (n = 741), most (70.7%) had sensitivity to only 1 corticosteroid. Co-reactivity was highest between desoximetasone and budesonide.
CONCLUSIONS
Sensitivity to corticosteroids is important. Consistent with other studies, the highest frequency of corticosteroid positivity was seen in group A (tixocortol-21-pivalate), followed by group B (budesonide) and D2 (HC-17-B). Co-reactivity varied; more studies are needed to fully understand structural cross-reactivity.
Topics: Adrenal Cortex Hormones; Anti-Allergic Agents; Anti-Inflammatory Agents; Dermatitis, Contact; Drug Eruptions; Female; Humans; Hydrocortisone; Male; North America; Patch Tests; Retrospective Studies
PubMed: 28002236
DOI: 10.1097/DER.0000000000000251 -
Internal Medicine (Tokyo, Japan) 2008A 54-year-old man experienced weight gain. He was diagnosed as having hyperglycemia, hypertension and liver damage. Liver biopsy showed steatohepatitis. We initially...
A 54-year-old man experienced weight gain. He was diagnosed as having hyperglycemia, hypertension and liver damage. Liver biopsy showed steatohepatitis. We initially suspected him as having hyperadrenocorticism. However, both adrenocorticotropic hormone and cortisol levels were low. Later, it was revealed that he took medicine to relieve his gonalgia. His hyperglycemia, hypertension and liver damage improved after he discontinued taking the medicine. An analysis of this medicine showed that it contained desoximetasone, a glucocorticoid compound that had not been approved for medical use in Japan. To adequately diagnose clinical conditions, it is necessary to survey the patient's medicinal history in detail.
Topics: Adrenocortical Hyperfunction; Arthralgia; Chemical and Drug Induced Liver Injury; Desoximetasone; Fatty Liver; Glucocorticoids; Humans; Knee Joint; Male; Middle Aged; Self Medication
PubMed: 18591846
DOI: 10.2169/internalmedicine.47.0988