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

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.

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Hyperferritinaemia: An Iron Sword of Autoimmunity

Current Pharmaceutical Design ◽

10.2174/1381612825666190709202804 ◽

2019 ◽

Vol 25 (27) ◽

pp. 2909-2918 ◽

Cited By ~ 4

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.

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Infiltration of Mast Cells in Scalp Biopsies of Patients with Alopecia Areata or Androgenic Alopecia Versus Healthy Individuals: A Case-Control Study

Galen Medical Journal ◽

10.31661/gmj.v9i0.1962 ◽

2020 ◽

Vol 9 ◽

pp. 1962

Author(s):

Soheila Nasiri ◽

Alireza Salehi ◽

Azadeh Rakhshan

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Alopecia Areata ◽

Inflammatory Diseases ◽

Androgenic Alopecia ◽

Cell Counts ◽

Healthy Control ◽

Over 40 Years ◽

Control Study

Background: Alopecia areata (AA) and androgenic alopecia (AGA) are the most common types of alopecias. Recently, the role of mast cells in inflammatory diseases has become the focus of many studies. However, few studies have been conducted on their role in AA and AGA. Therefore, our study aimed to quantitatively evaluate the presence of mast cells in the AA and AGA specimens.Materials and Methods: Three groups of AA, AGA, and healthy control were studied (each group with 20 subjects). Patients were randomly selected from those referred to the dermatology clinics of Shahid Beheshti University. Specimens were obtained from the scalp, and perifollicular and perivascular areas were investigated. Results: Significantly higher perifollicular and perivascular mast cell counts were seen in both AGA and AA groups compared to healthy control (P<0.001 for both). Moreover, AA patients had more frequent perivascular mast cells than the AGA group (P=0.042). Among patients aged <40 years, perifollicular and perivascular mast cell counts were not significantly different among the three groups; however, subjects over 40 years of age in both groups had significantly more perifollicular and perivascular mast cells than healthy participants. There was a significant positive correlation between disease severity and mast cell counts in both perifollicular and perivascular areas in AA patients (P=0.001 for both). Conclusion: There was a significantly increased infiltration of mast cells in AA and AGA patients, and this increase was age and severity dependent. Moreover, the increase in mast cell proliferation is more dominant in AA patients. [GMJ.2020;9:e1962]

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Antithrombin and Its Role in Host Defense and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22084283 ◽

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.

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Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Cells ◽

10.3390/cells10112906 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2906

Author(s):

Hiroyuki Ogasawara ◽

Masato Noguchi

Keyword(s):

Mast Cells ◽

Immunoglobulin E ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Neuromuscular Blocking ◽

Drug Induced ◽

Functional Studies ◽

Inflammatory Conditions ◽

Functional Analyses

Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.754702 ◽

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.

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

Advanced Pharmaceutical Bulletin ◽

10.34172/apb.2023.004 ◽

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.

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Essential role of EP3 subtype in prostaglandin E2-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix

AJP Cell Physiology ◽

10.1152/ajpcell.00218.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. C1427-C1433 ◽

Cited By ~ 9

Author(s):

Mariko Sakanaka ◽

Satoshi Tanaka ◽

Yukihiko Sugimoto ◽

Atsushi Ichikawa

Keyword(s):

Mast Cells ◽

Immune Responses ◽

Cell Function ◽

Critical Role ◽

Pivotal Role ◽

Receptor Subtypes ◽

Inflammatory Conditions ◽

Peritoneal Mast Cells ◽

Line P

Accumulating evidence has indicated that mast cells can modulate a wide variety of immune responses. Migration and adhesion play a critical role in regulation of tissue mast cell function, in particular, under inflammatory conditions. We previously demonstrated that prostaglandin (PG) E2 stimulates adhesion of a mouse mastocytoma cell line, P-815, to the Arg-Gly-Asp (RGD)-enriched matrix through cooperation between two PGE2 receptor subtypes: EP3 and EP4 (Hatae N, Kita A, Tanaka S, Sugimoto Y, Ichikawa A. J Biol Chem 278: 17977–17981, 2003). We here investigated PGE2-induced adhesion of IL-3-dependent bone marrow-derived cultured mast cells (BMMCs). In contrast to the elevated cAMP-dependent adhesion of P-815 cells, EP3-mediated Ca2+ mobilization plays a pivotal role in PGE2-induced adhesion of BMMCs. Adhesion and Ca2+ mobilization induced by PGE2 were abolished in the Ptger3−/− BMMCs and were significantly suppressed by treatment with pertussis toxin, a phospholipase C inhibitor, U-73122, and a store-operated Ca2+ channel inhibitor, SKF 36965, indicating the involvement of Gi-mediated Ca2+ influx. We then investigated PGE2-induced adhesion of peritoneal mast cells to the RGD-enriched matrix. EP3 subtype was found to be the dominant PGE receptor that expresses in mouse peritoneal mast cells. PGE2 induced adhesion of the peritoneal mast cells of the Ptger3+/+ mice, but not that of the Ptger3−/− mice. In rat peritoneal mast cells, PGE2 or an EP3 agonist stimulated both Ca2+ mobilization and adhesion to the RGD-enriched matrix. These results suggested that the EP3 subtype plays a pivotal role in PGE2-induced adhesion of murine mast cells to the RGD-enriched matrix through Ca2+ mobilization.

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On the Role of the Immunoproteasome in Protein Homeostasis

Cells ◽

10.3390/cells10113216 ◽

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.

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Phytochemicals as Novel Therapeutic Strategies for NLRP3 Inflammasome-Related Neurological, Metabolic, and Inflammatory Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20122876 ◽

2019 ◽

Vol 20 (12) ◽

pp. 2876 ◽

Cited By ~ 23

Author(s):

Carolina Pellegrini ◽

Matteo Fornai ◽

Luca Antonioli ◽

Corrado Blandizzi ◽

Vincenzo Calderone

Keyword(s):

Type 2 Diabetes ◽

Nlrp3 Inflammasome ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Scientific Evidence ◽

Pyrin Domain ◽

Novel Therapeutic Strategies

Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout). Intensive research efforts are being made to achieve an integrated view about the pathophysiological role of NLRP3 inflammasome pathways in such disorders. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome by phytochemicals could represent a promising molecular target for the therapeutic management of neurological, psychiatric, metabolic, and inflammatory diseases. The present review article has been intended to provide an integrated and critical overview of the available clinical and experimental evidence about the role of NLRP3 inflammasome in the pathophysiology of neurological, psychiatric, metabolic, and inflammatory diseases, including PD, AD, MS, depression, obesity, type 2 diabetes, arthritis, and intestinal inflammation. Special attention has been paid to highlight and critically discuss current scientific evidence on the effects of phytochemicals on NLRP3 inflammasome pathways and their potential in counteracting central neuroinflammation, metabolic alterations, and immune/inflammatory responses in such diseases.

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