scholarly journals Comprehensive Detection of Isopeptides between Human Tissue Transglutaminase and Gluten Peptides

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2263 ◽  
Author(s):  
Lexhaller ◽  
Ludwig ◽  
Scherf
Keyword(s):  
Inflammatory Diseases ◽  
Tissue Transglutaminase ◽  
Model System ◽  
Molecular Structures ◽  
Molar Ratios ◽  
Gluten Peptides ◽  
Gluten Peptide ◽  
Lysine Residues ◽  
Key Factor ◽  
Peptide Complexes

Celiac disease (CD) is a chronic inflammation of the small intestine triggered by the ingestion of gluten in genetically predisposed individuals. Tissue transglutaminase (TG2) is a key factor in CD pathogenesis, because it catalyzes both the deamidation of specific glutamine residues and the formation of covalent Nε-(γ-glutamyl)-lysine isopeptide crosslinks resulting in TG2–gluten peptide complexes. These complexes are thought to activate B cells causing the secretion of anti-TG2 autoantibodies that serve as diagnostic markers for CD, although their pathogenic role remains unclear. To gain more insight into the molecular structures of TG2-gluten peptide complexes, we used different proteomics software tools that enable the comprehensive identification of isopeptides. Thus, 34 different isopeptides involving 20 TG2 lysine residues were identified in a model system, only six of which were previously known. Additionally, 36 isopeptides of TG2-TG2 multimers were detected. Experiments with different TG2-gluten peptide molar ratios revealed the most preferred lysine residues involved in isopeptide crosslinking. Expanding the model system to three gluten peptides with more glutamine residues allowed the localization of the preferred glutamine crosslinking sites. These new insights into the structure of TG2-gluten peptide complexes may help clarify the role of extracellular TG2 in CD autoimmunity and in other inflammatory diseases.

scholarly journals Photoprotective Properties of Eumelanin: Computational Insights into the Photophysics of a Catechol:Quinone Heterodimer Model System

Photochem ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 26-37
Author(s):  
Victoria C. Frederick ◽  
Thomas A. Ashy ◽  
Barbara Marchetti ◽  
Michael N. R. Ashfold ◽  
Tolga N. V. Karsili
Keyword(s):  
Ground State ◽  
Sandwich Structure ◽  
Computational Study ◽  
Minimum Energy ◽  
Carbonyl Oxygen ◽  
Model System ◽  
Molecular Structures ◽  
Uv Damage ◽  
Chromosomal Dna ◽  
Relevant Model

Melanins are skin-centered molecular structures that block harmful UV radiation from the sun and help protect chromosomal DNA from UV damage. Understanding the photodynamics of the chromophores that make up eumelanin is therefore paramount. This manuscript presents a multi-reference computational study of the mechanisms responsible for the experimentally observed photostability of a melanin-relevant model heterodimer comprising a catechol (C)–benzoquinone (Q) pair. The present results validate a recently proposed photoinduced intermolecular transfer of an H atom from an OH moiety of C to a carbonyl-oxygen atom of the Q. Photoexcitation of the ground state C:Q heterodimer (which has a π-stacked “sandwich” structure) results in population of a locally excited ππ* state (on Q), which develops increasing charge-transfer (biradical) character as it evolves to a “hinged” minimum energy geometry and drives proton transfer (i.e., net H atom transfer) from C to Q. The study provides further insights into excited state decay mechanisms that could contribute to the photostability afforded by the bulk polymeric structure of eumelanin.

scholarly journals Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

2020 ◽  
Author(s):  
Zohreh Jadali
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Relevant Literature ◽  
Regulatory Mechanisms ◽  
Immune Mediated ◽  
Key Factor ◽  
Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

scholarly journals Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

2020 ◽  
Vol 21 (15) ◽  
pp. 5472
Author(s):  
Yuliya V. Markina ◽  
Elena V. Gerasimova ◽  
Alexander M. Markin ◽  
Victor Y. Glanz ◽  
Wei-Kai Wu ◽  
...  
Keyword(s):  
Single Molecule ◽  
Inflammatory Diseases ◽  
Effector Proteins ◽  
Molecular Structures ◽  
Common Mechanism ◽  
Post Translational Modification ◽  
Effector Functions ◽  
Humoral Immune ◽  
Inflammatory Action

Immunoglobulins are the potent effector proteins of the humoral immune response. In the course of evolution, immunoglobulins have formed extremely diverse types of molecular structures with antigen-recognizing, antigen-binding, and effector functions embedded in a single molecule. Polysaccharide moiety of immunoglobulins plays the essential role in immunoglobulin functioning. There is growing evidence that the carbohydrate composition of immunoglobulin-linked glycans, and especially their terminal sialic acid residues, provide a key effect on the effector functions of immunoglobulins. Possibly, sialylation of Fc glycan is a common mechanism of IgG anti-inflammatory action in vivo. Thus, the post-translational modification (glycosylation) of immunoglobulins opens up significant possibilities in the diagnosis of both immunological and inflammatory disorders and in their therapies. This review is focused on the analysis of glycosylation of immunoglobulins, which can be a promising addition to improve existing strategies for the diagnosis and treatment of various immuno-inflammatory diseases.

scholarly journals Identification of tissue transglutaminase-reactive lysine residues in glyceraldehyde-3-phosphate dehydrogenase

2009 ◽  
Vol 11 (1) ◽  
pp. 137-146
Author(s):  
Stefania Orru ◽  
Margherita Ruoppolo ◽  
Simona Francese ◽  
Luigi Vitagliano ◽  
Gennaro Marino ◽  
...  
Keyword(s):  
Tissue Transglutaminase ◽  
Lysine Residues

scholarly journals Biological Functions of Interleukin-21 and Its Role in Inflammation

2007 ◽  
Vol 7 ◽  
pp. 1715-1735 ◽  
Author(s):  
Martin Pelletier ◽  
Denis Girard
Keyword(s):  
Potential Role ◽  
Inflammatory Diseases ◽  
Antitumor Agent ◽  
Biological Functions ◽  
Key Factor ◽  
Autoimmune And Inflammatory Diseases ◽  
Activated T Lymphocytes ◽  
Inflammatory Bowel ◽  
Interleukin 21 ◽  
Therapeutic Tools

Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, is mainly produced by activated T lymphocytes, particularly the inflammatory Th17subset, and is believed to be a key factor in the transition between innate and acquired immunity. In the last few years, this cytokine has been shown to modulate the functions of T, B, and NK cells, as well as cells of myeloid origin. In addition, it was demonstrated that IL-21 is a potent antitumor agent, making it a promising candidate for the development of therapeutic tools. IL-21 has also been associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review will summarize the biological functions of IL-21 and its potential role in inflammation.

scholarly journals Synthesis and characterization of novel 1,2,3-triazole-bridged oxime polyurethanes obtained from an isomannide derivative

2021 ◽  
Vol 40 (1) ◽  
pp. 67
Author(s):  
Fatih Bayrak ◽  
Ayhan Oral ◽  
Kadir Ay
Keyword(s):  
Electron Microscopy ◽  
Surface Characteristics ◽  
Molecular Structures ◽  
Hexamethylene Diisocyanate ◽  
Synthesis And Characterization ◽  
1H And 13C Nmr ◽  
Molecular Weights ◽  
Molar Ratios ◽  
Scanning Electron

Polyurethanes (PUs) are synthesized by the reaction of diisocyanates and diols and are widely used in furniture foams, thermal insulation, coatings, and adhesives. In this work, a 1,2,3-triazole-bridged dioxime (compound 6) as a diol source was synthesized from isomannide via tosylation, azidation, and cyclization-addition and used in the syntheses of new PUs. A new carbohydrate-based linear P-1 was synthesized by the reaction of 6 and 1,6-hexamethylene diisocyanate (1,6-HMDI). Besides, three new linear PUs (P-2, P-3, and P-4) were synthesized by the reaction of 6, isomannide compound (used in different molar ratios), and 1,6-HMDI. The thermal properties of the new PUs were determined by thermogravimetry (TG), their molecular structures were characterized by FTIR, 1H- and 13C-NMR, and the molecular weights of some polymers were determined by GPC/SEC. Additionally, the surface characteristics of the synthesized PUs were examined via scanning electron microscopy (SEM).

scholarly journals S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1706
Author(s):  
Chi-Ho Lee ◽  
Ji Woong Choi
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Receptor Subtype ◽  
Inflammasome Activation ◽  
Mouse Bone Marrow ◽  
Nlrp3 Inflammasome Activation ◽  
Key Factor ◽  
Signaling Axis ◽  
Sphingosine 1 Phosphate ◽  
Effector Pathways

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.

scholarly journals A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Melinda Y. Hardy ◽  
Gautam Goel ◽  
Amy K. Russell ◽  
Swee Lin G. Chen Yi Mei ◽  
Gregor J. E. Brown ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Whole Blood ◽  
Cd4 T Cells ◽  
Phase 2 ◽  
Cytokine Release ◽  
Gluten Peptides ◽  
Gluten Peptide ◽  
Phase 2 Clinical Trial ◽  
Ifn Γ

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.

Curcumin-C3 Complexed with α-, β-cyclodextrin Exhibits Antibacterial and Antioxidant Properties Suitable for Cancer Treatments

2020 ◽  
Vol 20 (12) ◽  
pp. 988-1001 ◽  
Author(s):  
Desu N. K. Reddy ◽  
Ramya Kumar ◽  
Shao-Pin Wang ◽  
Fu-Yung Huang
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Diseases ◽  
Curcuma Longa ◽  
Antioxidant Properties ◽  
Preventive Treatment ◽  
Entrapment Efficiency ◽  
Cancer Treatments ◽  
Molar Ratios ◽  
Transmission Electron ◽  
Wide Range

Background: The curcumin-C3 (cur-C3) complex obtained from Curcuma longa rhizome is a combination of three curcuminoids, namely, curcumin, dimethoxycurcumin, and bisdemethoxycurcumin. Cur and curcuminoids have been extensively researched for their wide range of therapeutic properties against inflammatory diseases, diabetes, and cancer. Objective: In spite of their extensive medicinal properties, cur and curcuminoids have poor solubility and bioavailability due to their hydrophobicity. This limitation can be overcome by complexing cur-C3 with natural cyclic oligosaccharides, such as Cyclodextrin (CD). Methods: In this study, cur-C3 and CD (α, β) inclusion complexes (ICs) were prepared with different molar ratios and characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy, X-ray diffraction, and transmission electron microscopy. Results: The cur-C3 cyclodextrin ICs showed an increased entrapment efficiency of 97.8% and improved antioxidant activity compared to cur and can be used as an antioxidant to reduce cancer-related oxidative stress. Additionally, α- CD ICs of curcumin-C3 caused an increase in growth inhibition of Staphylococcus aureus. Conclusion: Our findings suggest that both α- and β-CDs are suitable carriers for cur-C3 and can be used as an effective treatment for cancer-associated oxidative stress and as a preventive treatment for nosocomial infections and pneumonia.

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