scholarly journals Disease- and treatment-associated acquired glucocorticoid resistance

2018 ◽  
Vol 7 (12) ◽  
pp. R328-R349 ◽  
Author(s):  
Legh Wilkinson ◽  
Nicolette J D Verhoog ◽  
Ann Louw
Keyword(s):  
Glucocorticoid Receptor ◽  
Disease Progression ◽  
Side Effect ◽  
Molecular Mechanisms ◽  
Current Understanding ◽  
Side Effect Profile ◽  
Major Threat ◽  
Development Of Resistance ◽  
Current Review ◽  
Over Time

The development of resistance to glucocorticoids (GCs) in therapeutic regimens poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor α (GRα) underlie this resistance. Many studies have detailed how alterations in GRα function lead to diminished GC sensitivity; however, the current review highlights the wealth of data concerning reductions in the GRα pool, mediated by disease-associated and treatment-associated effects, which contribute to a significant decrease in GC sensitivity. Additionally, the current understanding of the molecular mechanisms involved in driving reductions in the GRα pool is discussed. After highlighting the importance of maintaining the level of the GRα pool to combat GC resistance, we present current strategies and argue that future strategies to prevent GC resistance should involve biased ligands with a predisposition for reduced GR dimerization, a strategy originally proposed as the SEMOGRAM–SEDIGRAM concept to reduce the side-effect profile of GCs.

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.

Impact of cetuximab on chemoradiation use in older patients with locally advanced head and neck cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6594-6594 ◽  
Author(s):  
Shrujal S. Baxi ◽  
Eric Jeffrey Sherman ◽  
Coral L Atoria ◽  
Nancy Y. Lee ◽  
David G. Pfister ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Side Effect ◽  
Locally Advanced ◽  
Definitive Treatment ◽  
Side Effect Profile ◽  
Advanced Head ◽  
The Impact ◽  
Over Time

6594 Background: The benefit of chemoradiation (CTRT) in the treatment of locally advanced head and neck cancer (LAHNC) declines in older and sicker patients. In 2006, the FDA approved cetuximab in LAHNC. Cetuximab with radiation has a perceived lower side effect profile compared to standard chemotherapies used in CTRT. Our objective was to examine the impact of cetuximab on the use of CTRT in elderly patients with LAHNC. Methods: We identified adults aged 66 and older diagnosed with LAHNC between 1999 and 2007 in the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Treatment was categorized as CTRT or other based on Medicare claims within 6 months of diagnosis. We excluded patients who did not receive definitive treatment. In patients who had CTRT, we identified use of cetuximab based on drug-specific billing codes. We assessed trends in the use of CTRT over the entire study period and in the use of cetuximab since 2006. We examined the influence of age and comorbidity on the likelihood of receiving CTRT before and after 2006 adjusting for clinical and demographic factors. Results: We identified 4,809 patients with LAHNC. One-fourth were ≥80 years and almost a fifth had a Charlson comorbidity score (CCS) of ≥2. Overall more than 20% of patients received CTRT. The use of CTRT more than tripled over time, from 10% of patients diagnosed in 1999 to 38% in 2007 (p<0.0001 for trend). Of the 336 patients who had CTRT since 2006, 45% received cetuximab. Prior to 2006, patients ≥80 years or those with a CCS of ≥2 were significantly less likely to be treated with CTRT compared to younger patients or those with a CCS of 0. In patients diagnosed in 2006 or later, age and comorbidity no longer predicted the likelihood of receiving CTRT. Conclusions: In this population-based cohort of older adults, the use of CTRT increased substantially over time. The availability of cetuximab, with a perceived gentler side effect profile, may have increased the use of CTRT, especially in older and sicker patients. [Table: see text]

scholarly journals Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile

2018 ◽  
Vol 61 (5) ◽  
pp. 1785-1799 ◽  
Author(s):  
Lena Ripa ◽  
Karl Edman ◽  
Matthew Dearman ◽  
Goran Edenro ◽  
Ramon Hendrickx ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Side Effect ◽  
Side Effect Profile ◽  
Oral Glucocorticoid ◽  
Receptor Modulator

Schizophrenia

2020 ◽  
pp. 115-128
Author(s):  
David V. Braitman ◽  
Juan R. Bustillo
Keyword(s):  
Mental Illness ◽  
Effective Treatment ◽  
Side Effect ◽  
Antipsychotic Drugs ◽  
Molecular Mechanisms ◽  
Brain Volume ◽  
Chronic Mental Illness ◽  
Side Effect Profile ◽  
Unknown Aetiology ◽  
Common Variants

Schizophrenia is a serious, chronic mental illness of unknown aetiology for which there is presently no cure. However, over a century’s worth of research has resulted in important pathophysiological and therapeutic findings. Though strongly heritable, schizophrenia is a highly polygenic illness involving very small effects across hundreds of common variants. Small reductions in brain volume have been repeatedly documented, as well as an increment in striatal dopaminergic release. The most reliably effective treatment involves agents that block dopamine D2 receptors in the striatum, which though similarly efficacious, vary in terms of their side-effect profile. Only one drug, clozapine, has been found to be effective in schizophrenia patients who fail with other antipsychotic drugs. There is clearly a need for a deeper understanding of the molecular mechanisms underlying this debilitating illness.

Valproic Acid:

1999 ◽  
Vol 16 (2) ◽  
pp. 130-136 ◽  
Author(s):  
Sayonara Beatriz Ranciaro Fagundes
Keyword(s):  
Health Care ◽  
Valproic Acid ◽  
Antiepileptic Drug ◽  
Detailed Analysis ◽  
Side Effect ◽  
Side Effect Profile ◽  
Care Givers

Clinical pharmacologists, neurologists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug when determining which drug is best for a given patient.The purpose of this study was to investigate valproic acid with a detailed analysis of the different reports.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

scholarly journals Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marjan Talebi ◽  
Mohsen Talebi ◽  
Tahereh Farkhondeh ◽  
Jesus Simal-Gandara ◽  
Dalia M. Kopustinskiene ◽  
...  
Keyword(s):  
Blood Cells ◽  
Molecular Mechanisms ◽  
Web Of Science ◽  
Experimental Studies ◽  
Protective Effects ◽  
Pharmacological Activities ◽  
Current Review ◽  
Mesh Terms ◽  
Online Databases ◽  
Anti Cancer

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies. Graphic abstract

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