scholarly journals Corticosteroid-insensitive asthma: molecular mechanisms

2003 ◽  
Vol 178 (3) ◽  
pp. 347-355 ◽  
Author(s):  
IM Adcock ◽  
SJ Lane
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Alternative Therapies ◽  
Chronic Inflammatory Diseases ◽  
Asthmatic Patients ◽  
Inflammatory Bowel ◽  
Therapeutic Problem ◽  
Care Costs ◽  
Corticosteroid Response ◽  
Insight Into

Corticosteroids are the most potent anti-inflammatory agents used to treat chronic inflammatory diseases such as bronchial asthma. However, there are a small number (<5%) of asthmatic patients who do not respond well, or at all, to corticosteroid therapy - the corticosteroid-resistant and corticosteroid-dependent patients. Although this phenomenon is relatively uncommon, it poses a difficult therapeutic problem because few alternative therapies are available and these patients account for >50% of the health care costs of asthma. If the mechanisms for corticosteroid insensitivity are understood they may, in turn, provide insight into the key mechanism of corticosteroid action and allow a rational way to treat these individuals whose disease tends to be severe. Corticosteroid insensitivity is not limited to asthma and is a feature of other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Thus, elucidation of the cause for the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases.

scholarly journals Effects of Anti-Cytokine Antibodies on Gut Barrier Function

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Fang Liu ◽  
Seul A. Lee ◽  
Stephen M. Riordan ◽  
Li Zhang ◽  
Lixin Zhu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Barrier Function ◽  
Inflammatory Diseases ◽  
Immunomodulatory Effects ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Chronic Inflammatory Diseases ◽  
Gut Barrier Function ◽  
Inflammatory Bowel

Anti-cytokine antibodies are used in treating chronic inflammatory diseases and autoimmune diseases such as inflammatory bowel disease and rheumatic diseases. Patients with these diseases often have a compromised gut barrier function, suggesting that anti-cytokine antibodies may contribute to the re-establishment of gut barrier integrity, in addition to their immunomodulatory effects. This paper reviews the effects of anti-cytokine antibodies on gut barrier function and their mechanisms.

scholarly journals Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1107
Author(s):  
Emilie Logie ◽  
Wim Vanden Berghe
Keyword(s):  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Withaferin A ◽  
Related Factor ◽  
Nuclear Factor ◽  
Pharmaceutical Drugs ◽  
In Vivo Models ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory

Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

scholarly journals Curcumin and Intestinal Inflammatory Diseases: Molecular Mechanisms of Protection

2019 ◽  
Vol 20 (8) ◽  
pp. 1912 ◽  
Author(s):  
Kathryn Burge ◽  
Aarthi Gunasekaran ◽  
Jeffrey Eckert ◽  
Hala Chaaban
Keyword(s):  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Immunological Response ◽  
Intestinal Microbiome ◽  
Intestinal Barrier Function ◽  
Dietary Antigens ◽  
Inflammatory Bowel ◽  
Intestinal Inflammatory Disease

Intestinal inflammatory diseases, such as Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis, are becoming increasingly prevalent. While knowledge of the pathogenesis of these related diseases is currently incomplete, each of these conditions is thought to involve a dysfunctional, or overstated, host immunological response to both bacteria and dietary antigens, resulting in unchecked intestinal inflammation and, often, alterations in the intestinal microbiome. This inflammation can result in an impaired intestinal barrier allowing for bacterial translocation, potentially resulting in systemic inflammation and, in severe cases, sepsis. Chronic inflammation of this nature, in the case of inflammatory bowel disease, can even spur cancer growth in the longer-term. Recent research has indicated certain natural products with anti-inflammatory properties, such as curcumin, can help tame the inflammation involved in intestinal inflammatory diseases, thus improving intestinal barrier function, and potentially, clinical outcomes. In this review, we explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its antimicrobial and immunomodulatory properties, as well as its potential to alter the intestinal microbiome. Curcumin may play a significant role in intestinal inflammatory disease treatment in the future, particularly as an adjuvant therapy.

scholarly journals Health Implications of High Dietary Omega-6 Polyunsaturated Fatty Acids

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
E. Patterson ◽  
R. Wall ◽  
G. F. Fitzgerald ◽  
R. P. Ross ◽  
C. Stanton
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Inflammatory Diseases ◽  
Lipid Mediator ◽  
Omega 3 ◽  
Nonalcoholic Fatty Liver ◽  
Chronic Inflammatory Diseases ◽  
Signalling Molecules ◽  
Omega 6 ◽  
Inflammatory Bowel

Omega-6 (n-6) polyunsaturated fatty acids (PUFA) (e.g., arachidonic acid (AA)) and omega-3 (n-3) PUFA (e.g., eicosapentaenoic acid (EPA)) are precursors to potent lipid mediator signalling molecules, termed “eicosanoids,” which have important roles in the regulation of inflammation. In general, eicosanoids derived from n-6 PUFA are proinflammatory while eicosanoids derived from n-3 PUFA are anti-inflammatory. Dietary changes over the past few decades in the intake of n-6 and n-3 PUFA show striking increases in the (n-6) to (n-3) ratio (~15 : 1), which are associated with greater metabolism of the n-6 PUFA compared with n-3 PUFA. Coinciding with this increase in the ratio of (n-6) : (n-3) PUFA are increases in chronic inflammatory diseases such as nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, obesity, inflammatory bowel disease (IBD), rheumatoid arthritis, and Alzheimer's disease (AD). By increasing the ratio of (n-3) : (n-6) PUFA in the Western diet, reductions may be achieved in the incidence of these chronic inflammatory diseases.

scholarly journals Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

2021 ◽  
Author(s):  
Ilya Korsunsky ◽  
Kevin Wei ◽  
Mathilde Pohin ◽  
Edy Y. Kim ◽  
Francesca Barone ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Bowel Disease ◽  
Single Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Chronic Inflammatory Diseases ◽  
Single Cell Rna Sequencing ◽  
Inflammatory Bowel ◽  
Novel Therapeutic

SummaryPro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren’s syndrome, and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases.

Long term azathioprine fails to prevent onset of multiple sclerosis: report of two cases

2000 ◽  
Vol 6 (5) ◽  
pp. 362-363 ◽  
Author(s):  
C S Constantinescu ◽  
A Whiteley ◽  
L D Blumhardt
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Immunosuppressive Drug ◽  
Chronic Inflammatory Diseases ◽  
Definite Multiple Sclerosis ◽  
Clinically Definite Multiple Sclerosis ◽  
Inflammatory Bowel

Azathioprine is an immunosuppressive drug widely used in the treatment of chronic inflammatory diseases, including Multiple Sclerosis (MS). We report two patients who developed the first manifestations of clinically definite multiple sclerosis while on long term (3.5 and 10 years, respectively) treatment with azathioprine for Crohn's disease. Both patients developed the first MS symptoms during a quiescent phase of their inflammatory bowel disease. These cases show that long term azathioprine, while possibly maintaining inflammatory bowel disease under control, could not prevent the onset of MS.

scholarly journals Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

2020 ◽  
Author(s):  
Gong Qin ◽  
Kim Robinson ◽  
Xu Chenrui ◽  
Zhang Jiawen ◽  
Boo Zhao Zhi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inner Core ◽  
Inflammatory Diseases ◽  
Structural Features ◽  
Structural Basis ◽  
Card Domain ◽  
Domain Interactions ◽  
Cultured Human Cells ◽  
Insight Into

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIINDUPA rings. Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIINDUPA, which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance

2015 ◽  
Vol 12 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Deepa K. Ingawale ◽  
Satish K. Mandlik ◽  
Snehal S. Patel
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Platelet Activating Factor ◽  
Enzyme Modulation ◽  
New Strategy ◽  
Acid Metabolites ◽  
Inflammatory Proteins ◽  
Anti Inflammatory ◽  
Therapeutic Problem ◽  
Inflammatory Action

AbstractGlucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC–GR complex with the receptor and exert their actions. On activation the GC–GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.

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