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New Molecular Mechanisms and Markers in Inflammatory Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 19298

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Special Issue Editors

Dr. Galliera Emanuela Rita

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Guest Editor

Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
Interests: inflammation; inflammatory disorders; biomarkers; molecular mechanism of inflammation; molecular signaling
Special Issues, Collections and Topics in MDPI journals

Dr. Elena Vianello

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Guest Editor

Special Issue Information

Dear Colleagues,

Inflammation importantly participates in host defences against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases, ranging from cancer to biomechanical injuries and from chronic to acute disorders. For this reason, the discovery of new inflammation-linked biomarkers is the goal of many studies focused on the pathogenesis, the diagnosis, the prognosis, and the therapeutical approaches of inflammatory-associated comorbidities. The intent of this Special Issue is to present research papers and reviews focused on the new biomarkers of inflammatory-associated disorders, which highlight the molecular mechanisms of inflammation in the onset and progression of pathological states like cancer, immune diseases, cardiovascular-associated disorders, metabolic diseases, and all other pathological states linked to inflammation. This knowledge should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of diseases associated with inflammatory status.

Dr. Galliera Emanuela Rita
Dr. Elena Vianello
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

inflammation
inflammatory disorders
biomarkers
molecular mechanism of inflammation
molecular signaling

Published Papers (9 papers)

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Research

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14 pages, 937 KiB

Open AccessArticle

Relevance of Biomarkers in Serum vs. Synovial Fluid in Patients with Knee Osteoarthritis

by Stefania Kalogera, Mylène P. Jansen, Anne-Christine Bay-Jensen, Peder Frederiksen, Morten A. Karsdal, Christian S. Thudium and Simon C. Mastbergen

Int. J. Mol. Sci. 2023, 24(11), 9483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119483 - 30 May 2023

Cited by 3 | Viewed by 1698

Abstract

The association between structural changes and pain sensation in osteoarthritis (OA) remains unclear. Joint deterioration in OA leads to the release of protein fragments that can either systemically (serum) or locally (synovial fluid; SF) be targeted as biomarkers and describe structural changes and potentially pain. Biomarkers of collagen type I (C1M), type II (C2M), type III (C3M), type X (C10C), and aggrecan (ARGS) degradation were measured in the serum and SF of knee OA patients. Spearman’s rank correlation was used to assess the correlation of the biomarkers’ levels between serum and SF. Linear regression adjusted for confounders was used to evaluate the associations between the biomarkers’ levels and clinical outcomes. The serum C1M levels were negatively associated with subchondral bone density. The serum C2M levels were negatively associated with KL grade and positively associated with minimum joint space width (minJSW). The C10C levels in SF were negatively associated with minJSW and positively associated with KL grade and osteophyte area. Lastly, the serum C2M and C3M levels were negatively associated with pain outcomes. Most of the biomarkers seemed to mainly be associated with structural outcomes. The overall biomarkers of extracellular matrix (ECM) remodeling in serum and SF may provide different information and reflect different pathogenic processes. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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14 pages, 1322 KiB

Open AccessArticle

Canine Mammary Neoplasia Induces Variations in the Peripheral Blood Levels of CD20, CD45RA, and CD99

by Makchit Galadima, Iuliia Kotova, Ronny Schmidt, Josep Pastor, Christoph Schröder, Joan Enric Rodríguez-Gil and Maria Montserrat Rivera del Alamo

Int. J. Mol. Sci. 2023, 24(11), 9222; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119222 - 25 May 2023

Cited by 1 | Viewed by 1556

Abstract

The idea of using tumour biomarkers as diagnostic tools is progressively increasing. Of these, serum biomarkers are of particular interest, as they can provide rapid results. In the present study, serum samples from 26 bitches diagnosed with mammary tumours, plus 4 healthy bitches, were obtained. The samples were analysed using CD antibody microarrays targeting 90 CD surface markers and 56 cytokines/chemokines. A total of five CD proteins, namely CD20, CD45RA, CD53, CD59, and CD99, were selected and further analysed, utilizing immunoblotting techniques to validate the microarray results. CD45RA showed a significantly lower abundance in the serum samples from the bitches carrying mammary neoplasia in comparison to the healthy animals. Regarding CD99, the serum samples from the neoplastic bitches showed it in a significantly higher abundance than those from the healthy patients. Finally, CD20 showed a significantly higher abundance in bitches carrying a malignant mammary tumour in comparison to healthy patients, but no differential expression between malignant and benign tumours was observed. According to these results, both CD99 and CD45RA are indicators of mammary tumour presence, but without distinguishing between malignant and benign. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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19 pages, 3055 KiB

Open AccessArticle

Mutations in the Vicinity of the IRAK3 Guanylate Cyclase Center Impact Its Subcellular Localization and Ability to Modulate Inflammatory Signaling in Immortalized Cell Lines

by Ilona Turek, Trang H. Nguyen, Charles Galea, Isaiah Abad, Lubna Freihat, David T. Manallack, Tony Velkov and Helen Irving

Int. J. Mol. Sci. 2023, 24(10), 8572; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108572 - 10 May 2023

Cited by 3 | Viewed by 1890

Abstract

Interleukin-1 receptor-associated kinase 3 (IRAK3) modulates the magnitude of cellular responses to ligands perceived by interleukin-1 receptors (IL-1Rs) and Toll-like receptors (TLRs), leading to decreases in pro-inflammatory cytokines and suppressed inflammation. The molecular mechanism of IRAK3’s action remains unknown. IRAK3 functions as a guanylate cyclase, and its cGMP product suppresses lipopolysaccharide (LPS)-induced nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activity. To understand the implications of this phenomenon, we expanded the structure–function analyses of IRAK3 through site-directed mutagenesis of amino acids known or predicted to impact different activities of IRAK3. We verified the capacity of the mutated IRAK3 variants to generate cGMP in vitro and revealed residues in and in the vicinity of its GC catalytic center that impact the LPS-induced NFκB activity in immortalized cell lines in the absence or presence of an exogenous membrane-permeable cGMP analog. Mutant IRAK3 variants with reduced cGMP generating capacity and differential regulation of NFκB activity influence subcellular localization of IRAK3 in HEK293T cells and fail to rescue IRAK3 function in IRAK3 knock-out THP-1 monocytes stimulated with LPS unless the cGMP analog is present. Together, our results shed new light on the mechanism by which IRAK3 and its enzymatic product control the downstream signaling, affecting inflammatory responses in immortalized cell lines. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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17 pages, 7001 KiB

Open AccessArticle

Unveiling IL-33/ST2 Pathway Unbalance in Cardiac Remodeling Due to Obesity in Zucker Fatty Rats

by Clementina Sitzia, Elena Vianello, Elena Dozio, Marta Kalousová, Tomáš Zima, Stefano Brizzola, Paola Roccabianca, Gabriella Tedeschi, John Lamont, Lorenza Tacchini and Massimiliano Marco Corsi-Romanelli

Int. J. Mol. Sci. 2023, 24(3), 1991; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031991 - 19 Jan 2023

Viewed by 2405

Abstract

Obesity is an epidemic condition linked to cardiovascular disease severity and mortality. Fat localization and type represent cardiovascular risk estimators. Importantly, visceral fat secretes adipokines known to promote low-grade inflammation that, in turn, modulate its secretome and cardiac metabolism. In this regard, IL-33 regulates the functions of various immune cells through ST2 binding and—following its role as an immune sensor to infection and stress—is involved in the pro-fibrotic remodeling of the myocardium. Here we further investigated the IL-33/ST2 effects on cardiac remodeling in obesity, focusing on molecular pathways linking adipose-derived IL-33 to the development of fibrosis or hypertrophy. We analyzed the Zucker Fatty rat model, and we developed in vitro models to mimic the adipose and myocardial relationship. We demonstrated a dysregulation of IL-33/ST2 signaling in both adipose and cardiac tissue, where they affected Epac proteins and myocardial gene expression, linked to pro-fibrotic signatures. In Zucker rats, pro-fibrotic effects were counteracted by ghrelin-induced IL-33 secretion, whose release influenced transcription factor expression and ST2 isoforms balance regulation. Finally, the effect of IL-33 signaling is dependent on several factors, such as cell types’ origin and the balancing of ST2 isoforms. Noteworthy, it is reasonable to state that considering IL-33 to have a unique protective role should be considered over-simplistic. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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11 pages, 1612 KiB

Open AccessArticle

A Highly Sensitive Biomarker of Type II Collagen C-Terminal Pro-Peptide Associated with Cartilage Formation

by Helena Port, Anne-Christine Bay-Jensen, Yi He, Morten A. Karsdal, Thorbjørn Gantzel, Christian S. Thudium and Signe Holm Nielsen

Int. J. Mol. Sci. 2023, 24(1), 454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010454 - 27 Dec 2022

Cited by 1 | Viewed by 1902

Abstract

The type II collagen C-terminal pro-peptide is one of the most abundant polypeptides in cartilage. The purpose of this study was to develop a competitive chemiluminescence enzyme-linked immunosorbent assay, CALC2, targeting this pro-peptide as a marker of cartilage formation. Technical assay parameters were evaluated. CALC2 level was measured after in vitro cleavage of recombinant type II collagen with bone morphogenetic protein-1 (BMP-1) and treatment of ex vivo human osteoarthritis (OA) cartilage explant model (HEX) with insulin-like growth factor-1 (IGF-1). Serum CALC2 levels were assessed in 18 patients with rheumatoid arthritis (RA), 19 patients with ankylosing spondylitis (AS), and 18 age- and sex-matched controls in cohort 1 and 8 patients with OA and 14 age- and sex-matched controls in cohort 2. Type II collagen cleavage with BMP-1 increased the CALC2 level. IGF-1 treatment increased the CALC2 levels in HEX compared with the untreated explants (p < 0.05). Results were confirmed using Western blot analysis. CALC2 levels were decreased in the patients with RA and AS compared with the healthy controls (p = 0.01 and p = 0.02, respectively). These findings indicate that CALC2 may be a novel biomarker of type II collagen formation. However, further preclinical and clinical studies are required to validate these findings. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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16 pages, 2123 KiB

Open AccessArticle

Molecular Fingerprint of Human Pathological Synoviocytes in Response to Extractive Sulfated and Biofermentative Unsulfated Chondroitins

by Valentina Vassallo, Antonietta Stellavato, Rosita Russo, Donatella Cimini, Mariangela Valletta, Alberto Alfano, Paolo Vincenzo Pedone, Angela Chambery and Chiara Schiraldi

Int. J. Mol. Sci. 2022, 23(24), 15865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415865 - 14 Dec 2022

Cited by 8 | Viewed by 1400

Abstract

Pharma-grade extractive chondroitin sulfate (CS) is widely used for osteoarthritis (OA) treatment. Recently, unsulfated biofermentative chondroitin (BC) proved positive effects in OA in vitro model. This study, based on primary pathological human synoviocytes, aimed to analyze, by a multiplex assay, a panel of OA-related biomarkers in response to short-term treatments with bovine (CS_b), pig (CS_p) and fish (CS_f) chondroitins, in comparison to BC. As expected, all samples had anti-inflammatory properties, however CS_b, CS_f and especially BC affected more cytokines and chemokines. Based on these results and molecular weight similarity, CS_f and BC were selected to further explore the synoviocytes’ response. In fact, Western blot analyses showed CS_f and BC were comparable, downregulating OA-related biomarkers such as the proteins mTOR, NF-kB, PTX-3 and COMP-2. Proteomic analyses, performed by applying a nano-LC-MS/MS TMT isobaric labelling-based approach, displayed the modulation of both common and distinct molecules to chondroitin treatments. Thus, CS_f and BC modulated the biological mediators involved in the inflammation cascade, matrix degradation/remodeling, glycosaminoglycans’ synthesis and cellular homeostasis. This study helps in shedding light on different molecular mechanisms related to OA disease that may be potentially affected not only by animal-source chondroitin sulfate but also by unsulfated biofermentative chondroitin. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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17 pages, 2760 KiB

Open AccessArticle

Regulation of Neuroinflammatory Signaling by PPARγ Agonist in Mouse Model of Diabetes

by Iwona Piątkowska-Chmiel, Mariola Herbet, Monika Gawrońska-Grzywacz and Jarosław Dudka

Int. J. Mol. Sci. 2022, 23(10), 5502; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105502 - 14 May 2022

Cited by 10 | Viewed by 2138

Abstract

Many relevant studies, as well as clinical practice, confirm that untreated diabetes predisposes the development of neuroinflammation and cognitive impairment. Having regard for the fact that PPARγ are widely distributed in the brain and PPARγ ligands may regulate the inflammatory process, the anti-inflammatory potential of the PPARγ agonist, pioglitazone, was assessed in a mouse model of neuroinflammation related with diabetes. In this regard, the biochemical and molecular indicators of neuroinflammation were determined in the hippocampus and prefrontal cortex of diabetes mice. The levels of cytokines (IL-1β, IL-6, and TNF) and the expression of genes (Tnfrsf1a and Cav1) were measured. In addition, behavioral tests such as the open field test, the hole-board test, and the novel object recognition test were conducted. A 14-day treatment with pioglitazone significantly decreased IL-6 and TNFα levels in the prefrontal cortex and led to the downregulation of Tnfrsf1a expression and the upregulation of Cav1 expression in both brain regions of diabetic mice. Pioglitazone, by targeting neuroinflammatory signaling, improved memory and exploratory activity in behavioral tests. The present study provided a potential theoretical basis and therapeutic target for the treatment of neuroinflammation associated with diabetes. Pioglitazone may provide a promising therapeutic strategy in diabetes patients with muffled of behavioral activity. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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20 pages, 6465 KiB

Open AccessArticle

A Wide-Proteome Analysis to Identify Molecular Pathways Involved in Kidney Response to High-Fat Diet in Mice

by Elena Dozio, Elisa Maffioli, Elena Vianello, Simona Nonnis, Francesca Grassi Scalvini, Leonardo Spatola, Paola Roccabianca, Gabriella Tedeschi and Massimiliano Marco Corsi Romanelli

Int. J. Mol. Sci. 2022, 23(7), 3809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073809 - 30 Mar 2022

Cited by 1 | Viewed by 2211

Abstract

The etiopathogenesis of obesity-related chronic kidney disease (CKD) is still scarcely understood. To this aim, we assessed the effect of high-fat diet (HF) on molecular pathways leading to organ damage, steatosis, and fibrosis. Six-week-old male C57BL/6N mice were fed HF diet or normal chow for 20 weeks. Kidneys were collected for genomic, proteomic, histological studies, and lipid quantification. The main findings were as follows: (1) HF diet activated specific pathways leading to fibrosis and increased fatty acid metabolism; (2) HF diet promoted a metabolic shift of lipid metabolism from peroxisomes to mitochondria; (3) no signs of lipid accumulation and/or fibrosis were observed, histologically; (4) the early signs of kidney damage seemed to be related to changes in membrane protein expression; (5) the proto-oncogene MYC was one of the upstream transcriptional regulators of changes occurring in protein expression. These results demonstrated the potential usefulness of specific selected molecules as early markers of renal injury in HF, while histomorphological changes become visible later in obesity-related CDK. The integration of these information with data from biological fluids could help the identification of biomarkers useful for the early detection and prevention of tissue damage in clinical practice. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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Review

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49 pages, 1915 KiB

Open AccessReview

GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review

by Roberto De Masi and Stefania Orlando

Int. J. Mol. Sci. 2022, 23(13), 7373; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137373 - 1 Jul 2022

Cited by 4 | Viewed by 2839

Abstract

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc₃Man₉GlcNAc₂ highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders)

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