Overcoming steroid unresponsiveness in airways disease

2009 ◽  
Vol 37 (4) ◽  
pp. 824-829 ◽  
Author(s):  
Ian M. Adcock ◽  
Pai-Chien Chou ◽  
Andrew Durham ◽  
Paul Ford
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Chronic Obstructive ◽  
Management Problem ◽  
Activator Protein 1 ◽  
Obstructive Pulmonary Disease ◽  
Asthmatic Patients ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
High Doses

Most of the patients with asthma are found to be successfully treated with conventional therapy. However, there are a small proportion of asthmatic patients who fail to respond to corticosteroids even at high doses or with supplementary therapy. In addition, even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD (chronic obstructive pulmonary disease) and only a small effect in reducing exacerbations. Corticosteroid-insensitivity therefore presents a profound management problem. Corticosteroids act through a cytosolic receptor [GR (glucocorticoid receptor)], which is activated and translocates to the nucleus. Once in the nucleus, it either binds to DNA and switches on the expression of anti-inflammatory genes or represses the activity of distinct signalling pathways such as NF-κB (nuclear factor κB), AP-1 (activator protein-1) or MAPKs (mitogen-activated protein kinases). This latter step requires the recruitment of co-repressor molecules. A failure to respond to corticosteroids may therefore result from lack of binding to GR, reduced GR expression, lack of co-repressor activity or enhanced activation of inflammatory pathways. These events can be modulated by oxidative stress or high levels of inflammatory cytokines, which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases.

scholarly journals 20-Hydroxy-3-Oxolupan-28-Oic Acid Attenuates Inflammatory Responses by Regulating PI3K–Akt and MAPKs Signaling Pathways in LPS-Stimulated RAW264.7 Macrophages

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 386 ◽  
Author(s):  
Yufeng Cao ◽  
Fu Li ◽  
Yanyan Luo ◽  
Liang Zhang ◽  
Shuya Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

20-Hydroxy-3-oxolupan-28-oic acid (HOA), a lupane-type triterpene, was obtained from the leaves of Mahonia bealei, which is described in the Chinese Pharmacopeia as a remedy for inflammation and related diseases. The anti-inflammatory mechanisms of HOA, however, have not yet been fully elucidated. Therefore, the objective of this study was to characterize the molecular mechanisms of HOA in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. HOA suppressed the release of nitric oxide (NO), pro-inflammatory cytokine tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 macrophages without affecting cell viability. Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis indicated that HOA also suppressed the gene expression of inducible NO synthase (iNOS), TNF-α, and IL-6. Further analyses demonstrated that HOA inhibited the phosphorylation of upstream signaling molecules, including p85, PDK1, Akt, IκBα, ERK, and JNK, as well as the nuclear translocation of nuclear factor κB (NF-κB) p65. Interestingly, HOA had no effect on the LPS-induced nuclear translocation of activator protein 1 (AP-1). Taken together, these results suggest that HOA inhibits the production of cytokine by downregulating iNOS, TNF-α, and IL-6 gene expression via the downregulation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs), and the inhibition of NF-κB activation. Our findings indicate that HOA could potentially be used as an anti-inflammatory agent for medical use.

scholarly journals δ-Tocotrienol, Isolated from Rice Bran, Exerts an Anti-Inflammatory Effect via MAPKs and PPARs Signaling Pathways in Lipopolysaccharide-Stimulated Macrophages

2018 ◽  
Vol 19 (10) ◽  
pp. 3022 ◽  
Author(s):  
Junjun Shen ◽  
Tao Yang ◽  
Youzhi Xu ◽  
Yi Luo ◽  
Xinyue Zhong ◽  
...  
Keyword(s):  
Rice Bran ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Activator Protein 1 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Inflammatory Effect

δ-Tocotrienol, an important component of vitamin E, has been reported to possess some physiological functions, such as anticancer and anti-inflammation, however their molecular mechanisms are not clear. In this study, δ-tocotrienol was isolated and purified from rice bran. The anti-inflammatory effect and mechanism of δ-tocotrienol against lipopolysaccharides (LPS) activated pro-inflammatory mediator expressions in RAW264.7 cells were investigated. Results showed that δ-tocotrienol significantly inhibited LPS-stimulated nitric oxide (NO) and proinflammatory cytokine (TNF-α, IFN-γ, IL-1β and IL-6) production and blocked the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 (ERK1/2). δ-Tocotrienol repressed the transcriptional activations and translocations of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), which were closely related with downregulated cytokine expressions. Meanwhile, δ-tocotrienol also affected the PPAR signal pathway and exerted an anti-inflammatory effect. Taken together, our data showed that δ-tocotrienol inhibited inflammation via mitogen-activated protein kinase (MAPK) and peroxisome proliferator-activated receptor (PPAR) signalings in LPS-stimulated macrophages.

scholarly journals In Vitro Anti-Inflammatory and Skin Moisturizing Properties of Pilea martini (Levl.) Hand.-Mazz. Extracts

2020 ◽  
Vol 15 (11) ◽  
pp. 1934578X2096786
Author(s):  
Jieun Choi ◽  
Young Yun Jung ◽  
In Jin Ha ◽  
Seung Ho Baek ◽  
Zhiyun Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Prostaglandin E ◽  
Activator Protein 1 ◽  
Serine Palmitoyltransferase ◽  
Raw264.7 Macrophages ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

The in vitro anti-inflammatory and skin moisturizing activities of Pilea martini (Levl.) Hand.-Mazz. were investigated on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and human immortalized keratinocytes. Chromatographic analysis was performed to identify the chemical composition of the extracts. Pilea martini extracts significantly suppressed LPS-induced nitric oxide, prostaglandin E2, interleukin 6, and tumor necrosis factor α production in dose-dependent manners. In addition, the extracts inhibited LPS-induced inducible nitric oxide synthase and cyclooxygenase-2 proteins and their mRNA expression through causing a downregulation of nuclear factor-κB, activator protein 1, and mitogen-activated protein kinase signaling cascades. The extracts increased the production of hyaluronic acid levels and enhanced the expression levels of both filaggrin and serine palmitoyltransferase regulation. Liquid chromatography-mass spectroscopy analysis showed that the extracts contained 6 different compounds (malic acid, tryptophan, chlorogenic acid, caffeic acid, p-coumaric acid, and isoquercetin) that may contribute to their bioactivities. Taken together, Pilea martini extract showed remarkable promise as an anti-inflammatory and moisturizing agent.

Anti-inflammatory Actions of Glucocorticoids: Molecular Mechanisms

1998 ◽  
Vol 94 (6) ◽  
pp. 557-572 ◽  
Author(s):  
Peter J. Barnes
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Glucocorticoid Receptors ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Inflammatory Genes ◽  
Anti Inflammatory

1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this antiinflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents. 2. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for antiinflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the widespread anti-inflammatory actions of glucocorticoids. 3. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes (cytokines, enzymes, receptors and adhesion molecules). This cannot be due to a direct interaction between glucocorticoid receptors and GRE, as these binding sites are absent from the promoter regions of most inflammatory genes. It is more likely to be due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors, such as nuclear factor-κB and activator protein-1, which regulate the inflammatory gene expression. 4. It is increasingly recognized that glucocorticoids change the chromatin structure. Glucocorticoid receptors also interact with CREB-binding protein (CBP), which acts as a co-activator of transcription, binding several other transcription factors that compete for binding sites on this molecule. Increased transcription is associated with uncoiling of DNA wound around histone and this is secondary to acetylation of the histone residues by the enzymic action of CBP. Glucocorticoids may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression. 5. Rarely patients with chronic inflammatory diseases fail to respond to glucocorticoids, although endocrine function of steroids is preserved. This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). ‘Dissociated’ steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-κB, are also targets for novel anti-inflammatory therapies.

scholarly journals Immunological and toxicological risk assessment of e-cigarettes

2018 ◽  
Vol 27 (147) ◽  
pp. 170119 ◽  
Author(s):  
Gagandeep Kaur ◽  
Rakeysha Pinkston ◽  
Benathel Mclemore ◽  
Waneene C. Dorsey ◽  
Sanjay Batra
Keyword(s):  
Tobacco Smoke ◽  
Prolonged Exposure ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Mitogen Activated Protein ◽  
Immunological Effects ◽  
Contradictory Evidence

Knowledge of the long-term toxicological and immunological effects of e-cigarette (e-cig) aerosols remains elusive due to the relatively short existence of vaping. Therefore, we performed a systematic search of articles published in public databases and analysed the research evidence in order to provide critical information regarding e-cig safety. Electronic nicotine delivery systems (or e-cigs) are an alternative to traditional cigarettes for the delivery of nicotine and are typically filled with glycerol or propylene glycol-based solutions known as e-liquids. Though present in lower quantities, e-cig aerosols are known to contain many of the harmful chemicals found in tobacco smoke. However, due to the paucity of experimental data and contradictory evidence, it is difficult to draw conclusive outcomes regarding toxicological, immunological and clinical impacts of e-cig aerosols. Excessive vaping has been reported to induce inflammatory responses including mitogen-activated protein kinase, Janus tyrosine kinase/signal transducer and activator of transcription and nuclear factor-κB signalling, similar to that induced by tobacco smoke. Based on recent evidence, prolonged exposure to some constituents of e-cig aerosols might result in respiratory complications such as asthma, chronic obstructive pulmonary disease and inflammation. Future studies are warranted that focus on establishing correlations between e-cig types, generations and e-liquid flavours and immunological and toxicological profiles to broaden our understanding about the effects of vaping.

The effect of glucocorticoids in combination with azithromycin or theophylline on cytokine production by NK and NKT-like blood cells of patients with chronic obstructive pulmonary disease

2021 ◽  
Vol 67 (4) ◽  
pp. 352-359
Author(s):  
A.G. Kadushkin ◽  
A.D. Tahanovich ◽  
L.V. Movchan ◽  
T.S. Kolesnikova ◽  
A.V. Khadasouskaya ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Nk Cells ◽  
Pulmonary Disease ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Anti Inflammatory

Chronic obstructive pulmonary disease (COPD) is characterized by reduced sensitivity of cells to the anti-inflammatory effects of glucocorticoids (GCs). Azithromycin and a low dose theophylline have a significant impact on molecular mechanisms leading to corticosteroid resistance. The aim of this study was to evaluate the ability of azithromycin and theophylline to enhance the anti-inflammatory effects of GCs on the production of cytokines by NK and NKT-like blood cells of COPD patients. Whole blood cells from COPD patients (n=21) were incubated in the presence of budesonide (10 nM), azithromycin (10 μg/mL), theophylline (1 μM), or their combinations and stimulated with phorbol myristate acetate (50 ng/mL). Intracellular production of proinflammatory cytokines in NK (CD3-CD56+) and NKT-like (CD3+CD56+) blood cells was analyzed by flow cytometry. Budesonide reduced synthesis of interleukin 4 (IL-4), CXCL8, tumor necrosis factor α (TNFα) by NK and NKT-like cells, as well as production of interferon γ (IFNγ) by NK cells. Azithromycin suppressed production of IL-4 and CXCL8 by NK and NKT-like cells, and theophylline inhibited IL-4 synthesis by these lymphocytes. The combination of azithromycin and budesonide had a more pronounced inhibitory effect on the production of IL-4 and CXCL8 by NK and NKT-like cells than the effect of these drugs alone. The combination of theophylline and budesonide suppressed synthesis of IL-4 and CXCL8 by NK and NKT-like cells, as well as the production of TNFα and IFNγ by NK cells stronger than budesonide alone. The obtained results demonstrate the benefits for the combined use of GCs with theophylline at a low dose or azithromycin to suppress the inflammatory process in patients with COPD.

scholarly journals Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis

2015 ◽  
Vol 24 (137) ◽  
pp. 451-461 ◽  
Author(s):  
Mario Cazzola ◽  
Luigino Calzetta ◽  
Clive Page ◽  
Josè Jardim ◽  
Alexander G. Chuchalin ◽  
...  
Keyword(s):  
Relative Risk ◽  
Airway Obstruction ◽  
Chronic Bronchitis ◽  
Meta Analysis ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Regular Treatment ◽  
Copd Exacerbations ◽  
Copd Patients ◽  
High Doses

In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤600 mg per day) and high (>600 mg per day) doses of NAC.The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n=1933; placebo or controls n=2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66–0.84; p<0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68–0.82; p=0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89–0.97; p=0.40; high doses relative risk 1.11, 95% CI 0.89–1.39; p=0.58).The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient.

Bronchodilator and anti-inflammatory therapy of chronic obstructive pulmonary disease from the position of interchangeability

2021 ◽  
Vol 31 (4) ◽  
pp. 518-529
Author(s):  
E. A. Orlova ◽  
I. P. Dorfman ◽  
M. A. Orlov ◽  
A. K. Andreeva ◽  
M. A. Abdullaev
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Generic Drugs ◽  
The State ◽  
Chronic Obstructive ◽  
Anticholinergic Drugs ◽  
Adherence To Treatment ◽  
Obstructive Pulmonary Disease ◽  
State Register ◽  
Anti Inflammatory

The choice of drugs used to treat patients with chronic obstructive pulmonary disease (COPD) (inhaled β-agonists, M-anticholinergic drugs, inhaled corticosteroids (ICS)) in view of their interchangeability is reviewed in this article. This aspect is especially important for clinicians when choosing an effective and safe treatment for COPD and for increasing patient adherence to treatment.The aim of this study was to assess the ratio of the number of reference (original), interchangeable, and generic drugs used in COPD.Methods. In accordance with the Russian clinical guidelines 2018 and GOLD 2019, modern drugs for the treatment of COPD with bronchodilator and anti-inflammatory activity were selected. All trade names of the corresponding drugs for each international non-proprietary name (INN) In the State Register of Medicines website were considered. The information on the availability of reference (original) drugs and the corresponding interchangeable products, as well as their presence in the List of vital and essential drugs was analyzed.Results. A large number of generic prodcuts are registered in the State Register of Medicines, and only a few of them are interchangeable with the corresponding reference (original) drug.Conclusion. The analysis will help widen the doctors’ choice of interchangeable drugs in treatment of COPD with an equivalent effect and safety of reference drugs, as well as to increase the patients’ adherence to treatment.

Sign in / Sign up

Export Citation Format

Share Document