scholarly journals Antithrombin and Its Role in Host Defense and Inflammation

2021 ◽  
Vol 22 (8) ◽  
pp. 4283
Author(s):  
Christine Schlömmer ◽  
Anna Brandtner ◽  
Mirjam Bachler
Keyword(s):  
Cell Walls ◽  
Inflammatory Diseases ◽  
Antibacterial Properties ◽  
Coagulation System ◽  
Peptide Fragments ◽  
Inflammatory Signaling ◽  
Surface Receptors ◽  
Inflammatory Conditions ◽  
Randomized Control

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

Hyperferritinaemia: An Iron Sword of Autoimmunity

2019 ◽  
Vol 25 (27) ◽  
pp. 2909-2918 ◽  
Author(s):  
Joanna Giemza-Stokłosa ◽  
Md. Asiful Islam ◽  
Przemysław J. Kotyla
Keyword(s):  
Immune Response ◽  
Macrophage Activation ◽  
Inflammatory Diseases ◽  
Acute Phase Reactant ◽  
Catastrophic Antiphospholipid Syndrome ◽  
Inflammatory Conditions ◽  
Phase Reactant ◽  
Signalling Molecule ◽  
Cytokine Synthesis

Background:: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods:: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results:: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion:: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

scholarly journals Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Hernán F. Peñaloza ◽  
Rick van der Geest ◽  
Joel A. Ybe ◽  
Theodore J. Standiford ◽  
Janet S. Lee
Keyword(s):  
Infectious Diseases ◽  
Lung Diseases ◽  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inflammatory Conditions ◽  
Inflammatory Processes

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

scholarly journals Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved off C5 domain (endotrophin)

2021 ◽  
Author(s):  
Matthias Przyklenk ◽  
Stefanie Elisabeth Heumueller ◽  
Steffen Luetke ◽  
Gerhard Sengle ◽  
Manuel Koch ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Physiological Role ◽  
Potential Interaction ◽  
Anthrax Toxin ◽  
Close Relative ◽  
Collagen Vi ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Toxin Receptor

The widely expressed microfibril-forming collagen VI is subject to proteolytic cleavage and it has been proposed that the cleaved off C-terminal Kunitz domain (C5) of the α3 chain is an adipokine important for tumor progression and fibrosis. Under the name endotrophin the C5 fragment has also been shown to be a potent biomarker for fibro-inflammatory diseases. However, the biochemical mechanisms behind endotrophin activity have not been investigated. In earlier studies, the anthrax toxin receptor 1 was found to bind to C5, but this potential interaction has not been further studied. Given the proposed physiological role of endotrophin we aimed to determine how the endotrophin signal is transmitted to the recipient cells. Surprisingly, we could not detect any interaction between endotrophin and anthrax toxin receptor 1 or its close relative, anthrax toxin receptor 2. Moreover, we could not detect binding of fully assembled collagen VI to either anthrax toxin receptor. We also performed similar experiments with the collagen VI surface receptor NG2 (CSPG4). We could confirm that NG2 is a collagen VI receptor that binds to assembled collagen VI, but not to the cleaved C5/endotrophin. A cellular receptor for C5/endotrophin therefore still remains elusive.

Toll-Like Receptor 4 (TLR4) and AMPK Relevance in Cardiovascular Disease

2021 ◽  
Author(s):  
Haleh Vaez ◽  
Hamid Soraya ◽  
Alireza Garjani ◽  
Tooba Gholikhani
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Inflammatory Conditions ◽  
Immune Mediated ◽  
Energy Sensor

Toll-like receptors (TLRs) are essential receptors of the innate immune system, playing a significant role in cardiovascular diseases. TLR4, with the highest expression among TLRs in the heart, has been investigated extensively for its critical role in different myocardial inflammatory conditions. Studies suggest that inhibition of TLR4 signaling pathways reduces inflammatory responses and even prevents additional injuries to the already damaged myocardium. Recent research results have led to a hypothesis that there may be a relation between TLR4 expression and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in various inflammatory conditions, including cardiovascular diseases. AMPK, as a cellular energy sensor, has been reported to show anti-inflammatory effects in various models of inflammatory diseases. AMPK, in addition to its physiological acts in the heart, plays an essential role in myocardial ischemia and hypoxia by activating various energy production pathways. Herein we will discuss the role of TLR4 and AMPK in cardiovascular diseases and a possible relation between TLRs and AMPK as a novel therapeutic target. In our opinion, AMPK-related TLR modulators will find application in treating different immune-mediated inflammatory disorders, especially inflammatory cardiac diseases, and present an option that will be widely used in clinical practice in the future.

An overview of high-mobility group box 1, a potent pro-inflammatory cytokine in asthma

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Farzaneh Kianian ◽  
Mehri Kadkhodaee ◽  
Hamid Reza Sadeghipour ◽  
Seyed Morteza Karimian ◽  
Behjat Seifi
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Diseases ◽  
High Mobility ◽  
Chronic Respiratory Disease ◽  
High Mobility Group ◽  
High Morbidity ◽  
Surface Receptors ◽  
Nucleosome Formation ◽  
Central Characteristic

AbstractHigh-mobility group box 1 (HMGB1), also called amphoterin, HMG1 and p30, is a highly conserved protein between different species that has various functions in nucleus such as stabilization of nucleosome formation, facilitation of deoxyribonucleic acid (DNA) bending and increasing the DNA transcription, replication and repair. It has also been indicated that HMGB1 acts as a potent pro-inflammatory cytokine with increasing concentrations in acute and chronic inflammatory diseases. Asthma is a common chronic respiratory disease associated with high morbidity and mortality rates. One central characteristic in its pathogenesis is airway inflammation. Considering the inflammatory role of HMGB1 and importance of inflammation in asthma pathogenesis, a better understanding of this protein is vital. This review describes the structure, cell surface receptors, signaling pathways and intracellular and extracellular functions of HMGB1, but also focuses on its inflammatory role in asthma. Moreover, this manuscript reviews experimental and clinical studies that investigated the pathologic role of HMGB1.

scholarly journals Natural Products for Antithrombosis

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Cen Chen ◽  
Feng-Qing Yang ◽  
Qian Zhang ◽  
Feng-Qin Wang ◽  
Yuan-Jia Hu ◽  
...  
Keyword(s):  
Natural Products ◽  
Thrombus Formation ◽  
Coagulation System ◽  
Bioactive Components ◽  
Flow Conditions ◽  
Paper Briefly ◽  
Inflammatory Conditions ◽  
Antiplatelet Aggregation ◽  
Thrombotic Diseases

Thrombosis is considered to be closely related to several diseases such as atherosclerosis, ischemic heart disease and stroke, as well as rheumatoid arthritis, hyperuricemia, and various inflammatory conditions. More and more studies have been focused on understanding the mechanism of molecular and cellular basis of thrombus formation as well as preventing thrombosis for the treatment of thrombotic diseases. In reality, there is considerable interest in the role of natural products and their bioactive components in the prevention and treatment of thrombosis related disorders. This paper briefly describes the mechanisms of thrombus formation on three aspects, including coagulation system, platelet activation, and aggregation, and change of blood flow conditions. Furthermore, the natural products for antithrombosis by anticoagulation, antiplatelet aggregation, and fibrinolysis were summarized, respectively.

scholarly journals On the Role of the Immunoproteasome in Protein Homeostasis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3216
Author(s):  
Michael Basler ◽  
Marcus Groettrup
Keyword(s):  
Inflammatory Diseases ◽  
Protein Homeostasis ◽  
Cellular Processes ◽  
Inflammatory Conditions ◽  
Histocompatibility Complex ◽  
Species Formation ◽  
Preclinical Animal Models ◽  
Prime Function ◽  
In Cells

Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.

Dietary Supplements for Arthritis and other Inflammatory Conditions: Key Role of Mast Cells and Benefit of Combining Anti-Inflammatory and Proteoglycan Products

2003 ◽  
Vol 1 (1) ◽  
pp. 1-8 ◽  
Author(s):  
T. C. Theoharides
Keyword(s):  
Mast Cells ◽  
Chondroitin Sulfate ◽  
Dietary Supplements ◽  
Inflammatory Diseases ◽  
Scientific Evidence ◽  
Common Source ◽  
Inflammatory Conditions ◽  
Considerable Morbidity ◽  
Inflammatory Molecules

Arthritis is estimated to affect over 30% of all adults and all the available drugs add considerable morbidity and mortality of their own. A recent therapeutic approach targets the mast cells that are currently considered critical in a variety of inflammatory diseases, especially arthritis. Mast cells could be activated by many immune and neural triggers, as well as by many food substances and drugs leading to secretion of numerous vasoactive and inflammatory molecules. Recent studies have shown that mast cells can be inhibited by certain naturally occurring flavonoids, such as quercetin, and the sulfated proteoglycan chondroitin sulfate. Glucosamine and chondroitin are present in many dietary supplements, but neither the source nor the purity of the active substances is listed; moreover, these formulations do not permit sufficient absorption, due to the high molecular weight and negative charge. Moreover, a common source of chondroitin sulfate is cow trachea with the risk of spongioform encephalopathy (mad cow disease). A new series of dietary supplements (Algonot-Plus®) are based on published scientific evidence and combine quercetin, glucosamine sulfate and chondroitin sulfate of high purity in formulations that include kernel olive oil to increase absorption of the inhibitory substances.

Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders

2019 ◽  
Vol 20 (4) ◽  
pp. 367-379 ◽  
Author(s):  
Rakesh Kumar Singh ◽  
Abul Kalam Najmi
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Critical Factor ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Conditions ◽  
Targeted Inhibition ◽  
Chronic Airway

Objective: The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiology of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. Background: MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a critical factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the production and release of these cytokine molecules. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. Results: The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. Conclusion: Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.

scholarly journals APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling

2020 ◽  
Vol 28 (5) ◽  
pp. 1223-1235
Author(s):  
A. L. Cross ◽  
J. Hawkes ◽  
H. L. Wright ◽  
R. J. Moots ◽  
S. W. Edwards
Keyword(s):  
Inflammatory Diseases ◽  
Cell Signalling ◽  
Neutrophil Function ◽  
Receptor Expression ◽  
Bacterial Killing ◽  
Surface Receptors ◽  
Cell Functions ◽  
Inflammatory Conditions ◽  
Neutrophil Degranulation ◽  
Surface Receptor

Abstract Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10–1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.

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