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New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition

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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 (20 October 2024) | Viewed by 10471

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Dr. Galliera Emanuela Rita

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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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Dear Colleagues,

Inflammation participates in hosts’ 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 inflammation-associated comorbidities. The intent of this Special Issue is to present research papers and reviews focused on new biomarkers of inflammation-associated disorders, which highlight their molecular mechanisms during the onset and progression of pathological states such as cancer, immune diseases, cardiovascular-associated disorders, metabolic diseases, and all other pathological states linked to inflammation. This knowledge should facilitate 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 inflammation.

Dr. Galliera Emanuela Rita
Dr. Elena Vianello
Guest Editors

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Keywords

inflammation
inflammatory disorders
biomarkers
molecular mechanism of inflammation
molecular signaling

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Published Papers (8 papers)

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Research

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22 pages, 77884 KiB

Open AccessArticle

Interconnected Pathways: Exploring Inflammation, Pain, and Cognitive Decline in Osteoarthritis

by Mihails Tarasovs, Sandra Skuja, Simons Svirskis, Liba Sokolovska, Andris Vikmanis, Aivars Lejnieks, Yehuda Shoenfeld and Valerija Groma

Int. J. Mol. Sci. 2024, 25(22), 11918; https://doi.org/10.3390/ijms252211918 - 6 Nov 2024

Viewed by 445

Abstract

The relationship among inflammation, pain, and cognitive decline in osteoarthritis (OA) patients is complex and has not been sufficiently explored; therefore, we undertook this research to evaluate how OA-related inflammation and pain affect cognitive functions, as well as to examine the potential of urinary markers as indicators of these conditions. This study examined fifty OA patients through clinical and cognitive assessments, morphological analyses, urinary biomarkers, and bioinformatics. Morphologically, 24% of patients had moderate to high synovial inflammation, which was significantly correlated with depressive symptoms, pain intensity, and self-reported anxiety. The Montreal Cognitive Assessment indicated minimal decline in most patients but showed negative correlations with age and inflammation severity. Urinary TNF-α and TGF-β1 levels positively correlated with body mass index and pain and synovitis score and immune cell infiltration, respectively. In contrast, cartilage oligomeric matrix protein and C-telopeptides of type II collagen showed inverse correlations with pain duration and cognitive function, respectively. Distinct patient clusters with higher inflammation were identified and were associated with reported pain and depressive symptoms. Urinary TNF-α and TGF-β1 can serve as biomarkers reflecting inflammation and disease severity in OA. This study suggests that synovial inflammation may be linked to mental and cognitive health in some patient cohorts. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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13 pages, 1092 KiB

Open AccessArticle

Systemic Inflammation Across Metabolic Obesity Phenotypes: A Cross-Sectional Study of Korean Adults Using High-Sensitivity C-Reactive Protein as a Biomarker

by Seong-Uk Baek and Jin-Ha Yoon

Int. J. Mol. Sci. 2024, 25(21), 11540; https://doi.org/10.3390/ijms252111540 - 27 Oct 2024

Viewed by 538

Abstract

Chronic systemic inflammation is a hallmark of obesity. This cross-sectional study aimed to investigate the association between metabolic obesity phenotypes and inflammatory markers in Korean adults (N = 21,112; mean age: 50.9 ± 16.6). Metabolic obesity phenotypes were categorized into metabolically healthy non-obesity (MHNO), metabolically unhealthy non-obesity (MUNO), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO) based on body mass index and the presence of any metabolic abnormalities. High-sensitivity C-reactive protein (hs-CRP) levels were measured. Multiple linear regression was used to determine the association between obesity phenotypes and hs-CRP levels. In the male sample, compared to the MHNO type, the MUNO, MHO, and MUO types were associated with a 22.3% (95% confidence interval; CI: 14.7–30.3%), 15.8% (95% CI: 2.6–30.7%), and 12.5% (95% CI: 3.0–22.9%) increase in the hs-CRP levels, respectively. The association between metabolic obesity types and hs-CRP levels was stronger among the female sample; compared to the MHNO type, the MUNO, MHO, and MUO types were associated with a 30.2% (95% CI: 22.8–38.2%), 16.0% (95% CI: 6.5–26.4%), and 22.8% (95% CI: 13.6–32.8%) increase in the hs-CRP levels, respectively. Our findings indicate a varying profile of systemic inflammation across different metabolic obesity phenotypes. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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17 pages, 3068 KiB

Open AccessArticle

Specific microRNA Profile Associated with Inflammation and Lipid Metabolism for Stratifying Allergic Asthma Severity

by Andrea Escolar-Peña, María Isabel Delgado-Dolset, Carmela Pablo-Torres, Carlos Tarin, Leticia Mera-Berriatua, María del Pilar Cuesta Apausa, Heleia González Cuervo, Rinku Sharma, Alvin T. Kho, Kelan G. Tantisira, Michael J. McGeachie, Rocio Rebollido-Rios, Domingo Barber, Teresa Carrillo, Elena Izquierdo and María M. Escribese

Int. J. Mol. Sci. 2024, 25(17), 9425; https://doi.org/10.3390/ijms25179425 - 30 Aug 2024

Cited by 1 | Viewed by 933

Abstract

The mechanisms underlying severe allergic asthma are complex and unknown, meaning it is a challenge to provide the most appropriate treatment. This study aimed to identify novel biomarkers for stratifying allergic asthmatic patients according to severity, and to uncover the biological mechanisms that lead to the development of the severe uncontrolled phenotype. By using miRNA PCR panels, we analyzed the expression of 752 miRNAs in serum samples from control subjects (n = 15) and mild (n = 11) and severe uncontrolled (n = 10) allergic asthmatic patients. We identified 40 differentially expressed miRNAs between severe uncontrolled and mild allergic asthmatic patients. Functional enrichment analysis revealed signatures related to inflammation, angiogenesis, lipid metabolism and mRNA regulation. A random forest classifier trained with DE miRNAs achieved a high accuracy of 97% for severe uncontrolled patient stratification. Validation of the identified biomarkers was performed on a subset of allergic asthmatic patients from the CAMP cohort at Brigham and Women’s Hospital, Harvard Medical School. Four of these miRNAs (hsa-miR-99b-5p, hsa-miR-451a, hsa-miR-326 and hsa-miR-505-3p) were validated, pointing towards their potential as biomarkers for stratifying allergic asthmatic patients by severity and providing insights into severe uncontrolled asthma molecular pathways. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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13 pages, 1804 KiB

Open AccessCommunication

TNF-α/Stearate Induced H3K9/18 Histone Acetylation Amplifies IL-6 Expression in 3T3-L1 Mouse Adipocytes

by Fatemah Bahman, Areej Al-Roub, Nadeem Akhter, Ashraf Al Madhoun, Ajit Wilson, Nourah Almansour, Fatema Al-Rashed, Sardar Sindhu, Fahd Al-Mulla and Rasheed Ahmad

Int. J. Mol. Sci. 2024, 25(12), 6776; https://doi.org/10.3390/ijms25126776 - 20 Jun 2024

Cited by 1 | Viewed by 1077

Abstract

Extensive evidence supports the connection between obesity-induced inflammation and the heightened expression of IL-6 adipose tissues. However, the mechanism underlying the IL-6 exacerbation in the adipose tissue remains unclear. There is general agreement that TNF-α and stearate concentrations are mildly elevated in adipose tissue in the state of obesity. We hypothesize that TNF-α and stearate co-treatment induce the increased expression of IL-6 in mouse adipocytes. We therefore aimed to determine IL-6 gene expression and protein production by TNF-α/stearate treated adipocytes and investigated the mechanism involved. To test our hypothesis, 3T3-L1 mouse preadipocytes were treated with TNF-α, stearate, or TNF-α/stearate. IL-6 gene expression was assessed by quantitative real-time qPCR. IL-6 protein production secreted in the cell culture media was determined by ELISA. Acetylation of histone was analyzed by Western blotting. Il6 region-associated histone H3 lysine 9/18 acetylation (H3K9/18Ac) was determined by ChIP-qPCR. 3T3-L1 mouse preadipocytes were co-challenged with TNF-α and stearate for 24 h, which led to significantly increased IL-6 gene expression (81 ± 2.1 Fold) compared to controls stimulated with either TNF-α (38 ± 0.5 Fold; p = 0.002) or stearate (56 ± 2.0 Fold; p = 0.013). As expected, co-treatment of adipocytes with TNF-α and stearate significantly increased protein production (338 ± 11 pg/mL) compared to controls stimulated with either TNF-α (28 ± 0.60 pg/mL; p = 0.001) or stearate (53 ± 0.20 pg/mL, p = 0.0015). Inhibition of histone acetyltransferases (HATs) with anacardic acid or curcumin significantly reduced the IL-6 gene expression and protein production by adipocytes. Conversely, TSA-induced acetylation substituted the stimulatory effect of TNF-α or stearate in their synergistic interaction for driving IL-6 gene expression and protein production. Mechanistically, TNF-α/stearate co-stimulation increased the promoter-associated histone H3 lysine 9/18 acetylation (H3K9/18Ac), rendering a transcriptionally permissive state that favored IL-6 expression at the transcriptional and translational levels. Our data represent a TNF-α/stearate cooperativity model driving IL-6 expression in 3T3-L1 cells via the H3K9/18Ac-dependent mechanism, with implications for adipose IL-6 exacerbations in obesity. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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20 pages, 3749 KiB

Open AccessArticle

Serological Antibodies against Kidney, Liver, and Spleen Membrane Antigens as Potential Biomarkers in Patients with Immune Disorders

by Leidi Hernandez-Suarez, Eguzkiñe Diez-Martin, June Egiguren-Ortiz, Roberto Fernandez, Aitor Etxebarria, Egoitz Astigarraga, Cristina Miguelez, Andoni Ramirez-Garcia and Gabriel Barreda-Gómez

Int. J. Mol. Sci. 2024, 25(4), 2025; https://doi.org/10.3390/ijms25042025 - 7 Feb 2024

Cited by 1 | Viewed by 1566

Abstract

Immune disorders arise from complex genetic and environmental factors, which lead to dysregulation at the cellular and inflammatory levels and cause tissue damage. Recent research highlights the crucial role of reactive antibodies in autoimmune diseases and graft rejection, but their complex determination poses challenges for clinical use. Therefore, our study aimed to ascertain whether the presence of reactive antibodies against membrane antigens in tissues from both animal models and humans could serve as biomarkers in patients with autoimmune disorders. To address this issue, we examined the binding profile of serological antibodies against a diverse panel of cell membranes from the spleen, liver, and kidney tissues of monkeys, rats, and humans. After developing the cell membrane microarrays, human sera were immunologically assayed. The study was first conducted on sera from two groups, healthy subjects and patients with inflammatory and autoimmune disorders, and then optimized for kidney transplant patient sera. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in patients’ serum as potential biomarkers of immune disorders. However, it is important to note that these results need to be verified in further studies with a larger sample size to confirm their relevance. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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16 pages, 1479 KiB

Open AccessArticle

Patterns of IgA Autoantibody Generation, Inflammatory Responses and Extracellular Matrix Metabolism in Patients with Alcohol Use Disorder

by Onni Niemelä, Aini Bloigu, Risto Bloigu, Ulla Nivukoski, Johanna Kultti and Heidi Pohjasniemi

Int. J. Mol. Sci. 2023, 24(17), 13124; https://doi.org/10.3390/ijms241713124 - 23 Aug 2023

Cited by 1 | Viewed by 1547

Abstract

Recent data have emphasized the role of inflammation and intestinal immunoglobulin A (IgA) responses in the pathogenesis of alcoholic liver disease (ALD). In order to further explore such associations, we compared IgA titers against antigens targeted to ethanol metabolites and tissue transglutaminase with pro- and anti-inflammatory mediators of inflammation, markers of liver status, transferrin protein desialylation and extracellular matrix metabolism in alcohol-dependent patients with or without liver disease and in healthy controls. Serum IgAs against protein adducts with acetaldehyde (HbAch-IgA), the first metabolite of ethanol, and tissue transglutaminase (tTG-IgA), desialylated transferrin (CDT), pro- and anti-inflammatory cytokines, markers of liver status (GT, ALP) and extracellular matrix metabolism (PIIINP, PINP, hyaluronic acid, ICTP and CTx) were measured in alcohol-dependent patients with (n = 83) or without (n = 105) liver disease and 88 healthy controls representing either moderate drinkers or abstainers. In ALD patients, both tTG-IgA and HbAch-IgA titers were significantly higher than those in the alcoholics without liver disease (p < 0.0005 for tTG-IgA, p = 0.006 for Hb-Ach-IgA) or in healthy controls (p < 0.0005 for both comparisons). The HbAch-IgA levels in the alcoholics without liver disease also exceeded those found in healthy controls (p = 0.0008). In ROC analyses, anti-tTG-antibodies showed an excellent discriminative value in differentiating between ALD patients and healthy controls (AUC = 0.95, p < 0.0005). Significant correlations emerged between tTG-IgAs and HbAch-IgAs (r_s = 0.462, p < 0.0005), CDT (r_s = 0.413, p < 0.0001), GT (r_s = 0.487, p < 0.0001), alkaline phosphatase (r_s = 0.466, p < 0.0001), serum markers of fibrogenesis: PIIINP (r_s = 0.634, p < 0.0001), hyaluronic acid (r_s = 0.575, p < 0.0001), ICTP (r_s = 0.482, p < 0.0001), pro-inflammatory cytokines IL-6 (r_s = 0.581, p < 0.0001), IL-8 (r_s = 0.535, p < 0.0001) and TNF-α (r_s = 0.591, p < 0.0001), whereas significant inverse correlations were observed with serum TGF-β (r_s = −0.366, p < 0.0001) and CTx, a marker of collagen degradation (r_s = −0.495, p < 0.0001). The data indicate that the induction of IgA immune responses toward ethanol metabolites and tissue transglutaminaseis a characteristic feature of patients with AUD and coincides with the activation of inflammation, extracellular matrix remodeling and the generation of aberrantly glycosylated proteins. These processes appear to work in concert in the sequence of events leading from heavy drinking to ALD. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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Review

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17 pages, 1656 KiB

Open AccessReview

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance—A Narrative Review

by Maria Mirabelli, Roberta Misiti, Luciana Sicilia, Francesco S. Brunetti, Eusebio Chiefari, Antonio Brunetti and Daniela P. Foti

Int. J. Mol. Sci. 2024, 25(18), 9802; https://doi.org/10.3390/ijms25189802 - 11 Sep 2024

Cited by 1 | Viewed by 1240

Abstract

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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16 pages, 6569 KiB

Open AccessReview

Crosstalk between Dysfunctional Mitochondria and Proinflammatory Responses during Viral Infections

by Zitao Sun, Yanjin Wang, Xin Jin, Su Li and Hua-Ji Qiu

Int. J. Mol. Sci. 2024, 25(17), 9206; https://doi.org/10.3390/ijms25179206 - 24 Aug 2024

Viewed by 1918

Abstract

Mitochondria play pivotal roles in sustaining various biological functions including energy metabolism, cellular signaling transduction, and innate immune responses. Viruses exploit cellular metabolic synthesis to facilitate viral replication, potentially disrupting mitochondrial functions and subsequently eliciting a cascade of proinflammatory responses in host cells. Additionally, the disruption of mitochondrial membranes is involved in immune regulation. During viral infections, mitochondria orchestrate innate immune responses through the generation of reactive oxygen species (ROS) and the release of mitochondrial DNA, which serves as an effective defense mechanism against virus invasion. The targeting of mitochondrial damage may represent a novel approach to antiviral intervention. This review summarizes the regulatory mechanism underlying proinflammatory response induced by mitochondrial damage during viral infections, providing new insights for antiviral strategies. Full article

(This article belongs to the Special Issue New Molecular Mechanisms and Markers in Inflammatory Disorders, 2nd Edition)

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