Biomedicines

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10 pages, 493 KB

Open AccessArticle

IL-15, IL-18 and IL-21 Along the Stress–Smoking–Periodontal Health Axis: A Cross-Sectional Study in Mexican Adults

by Carmen Celina Alonso-Sánchez, Juan Manuel Guzmán-Flores, Julieta Sarai Becerra-Ruiz, Celia Guerrero-Velázquez, María Luisa Ramírez-de los Santos, Edgar Iván López-Pulido and Saúl Ramírez-de los Santos

Biomedicines 2026, 14(1), 114; https://doi.org/10.3390/biomedicines14010114 - 6 Jan 2026

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Abstract

From a psychoneuroimmunology standpoint, stress and cigarette smoking are plausible modulators of periodontal inflammation through neuroendocrine–immune pathways and cytokine networks. Interleukin-18 (IL-1 family), interleukin-21 (common γ-chain cytokine), and interleukin-15 (tissue-resident lymphocyte activation/homeostasis) are mechanistically relevant candidates to characterize in relation to these exposures. [...] Read more.

From a psychoneuroimmunology standpoint, stress and cigarette smoking are plausible modulators of periodontal inflammation through neuroendocrine–immune pathways and cytokine networks. Interleukin-18 (IL-1 family), interleukin-21 (common γ-chain cytokine), and interleukin-15 (tissue-resident lymphocyte activation/homeostasis) are mechanistically relevant candidates to characterize in relation to these exposures. We aimed to quantify serum IL-15, IL-18, and IL-21 and examine their associations with stress, smoking, and periodontal status in Mexican adults. Methods: Cross-sectional study (n = 65; 18–60 years; 70.8% female). Smoking status (23.1% smokers) and periodontal status were recorded; due to low periodontitis frequency (n = 3), periodontal status was analyzed as healthy (23.1%) versus periodontal disease (76.9%; gingivitis + periodontitis). Stress was assessed using the 18-item Symptomatic Stress Questionnaire and dichotomized as no/low stress (0–10; 52.3%) versus pathological stress (11–54; 47.7%). Systolic and diastolic blood pressure were recorded. IL-15, IL-18, and IL-21 were measured in serum by immunoassay. Analyses used medians (IQR), Mann–Whitney U tests with rank-biserial effect sizes, and exploratory Benjamini–Hochberg false discovery rate (FDR) adjustment across the nine primary cytokine-by-contrast tests; correlations with age and diastolic blood pressure were exploratory. Results: Cytokine distributions were right-skewed, particularly for IL-21. Across smoking, stress, and periodontal-status contrasts, no comparison met q < 0.05 after FDR adjustment. Effect-size patterns were heterogeneous rather than uniformly monotonic across exposures (e.g., IL-18 showed higher central tendency in healthy vs. periodontal disease; IL-21 showed higher central tendency in no/low stress vs. pathological stress), indicating substantial inter-individual variability in circulating cytokines within this cohort. Conclusions: In this exploratory cross-sectional sample, serum IL-15, IL-18, and IL-21 did not show robust, multiplicity-resistant differences by smoking, stress, or periodontal status. The findings provide a transparent description of distributional properties and hypothesis-generating patterns that motivate larger, longitudinal studies with repeated cytokine sampling, standardized periodontal assessment, and improved control of key confounders to clarify the relevance of these cytokines to periodontal inflammation under behavioral exposures. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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13 pages, 440 KB

Open AccessArticle

Blood Immunophenotyping in Prediction of Gestational Hypertensive Conditions

by Almagul Kurmanova, Altynay Nurmakova, Damilya Salimbayeva, Gulfiruz Urazbayeva, Gaukhar Kurmanova, Natalya Kravtsova, Zhanar Kypshakbayeva and Madina Khalmirzaeva

Biomedicines 2025, 13(12), 3122; https://doi.org/10.3390/biomedicines13123122 - 18 Dec 2025

Cited by 1 | Viewed by 727

Abstract

Background: Hypertensive conditions during pregnancy, such as preeclampsia (PE), are multisystem obstetric complications, accompanied by changes in the immunological status. Although several types of immune cells are involved in pathogenesis of preeclampsia, such as regulatory T cells, macrophages, natural killer cells, and [...] Read more.

Background: Hypertensive conditions during pregnancy, such as preeclampsia (PE), are multisystem obstetric complications, accompanied by changes in the immunological status. Although several types of immune cells are involved in pathogenesis of preeclampsia, such as regulatory T cells, macrophages, natural killer cells, and neutrophils, most studies have focused on the concentration of circulating cytokines. Much less is known about intracellular cytokine production at the level of individual groups of peripheral blood immune cells. This gap limits our understanding of the early immunological changes that precede the clinical manifestation of the disease. Thus, the study of intracellular cytokine production in various leukocyte populations may provide new biomarkers for predicting preeclampsia. Objectives: To test the hypothesis that women with preeclampsia exhibit distinct intracellular cytokine profiles in specific peripheral blood immune cell subsets compared with normotensive pregnant women, and to assess whether these differences could serve as potential biomarkers for disease prediction. Methods: The study included a total of 78 pregnant women admitted to labor with physiological pregnancy (n = 32) and with gestational hypertension (GH) (n = 39) and PE (n = 7). The multicolor immunophenotyping with intracellular cytokine production of TNF, GM-CSF, IGF and receptor VEGFR-2 by different immunocompetent cell types was evaluated on a BD FACS CALIBUR flow cytometer. Results: Flow cytometry revealed a marked increase in the proportion of CD8⁺ GM-CSF⁺, CD56⁺VEGFR2⁺, CD14⁺IL-10⁺, and CD19⁺IGF⁺ cells in both hypertensive groups versus controls (p < 0.001). In contrast, CD56⁺TNF⁺ levels were significantly reduced (p < 0.001). For differentiating PE from GH, CD56+VEGFR2+ and CD19+IGF+ should be prioritized (AUC~0.66–0.78) with good specificity and moderate sensitivity. Conclusions: These data will not only expand existing knowledge about the role of intracellular cytokines in the pathogenesis of preeclampsia, but will also help to obtain new markers for predicting preeclampsia. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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14 pages, 1698 KB

Open AccessArticle

Tacrolimus Inhibits Human Tenon’s Fibroblast Migration, Proliferation, and Transdifferentiation

by Woojune Hur, Jeongeun Park, Jae-Hyuck Lee, Ho-Seok Chung, Jin-A Shin, Hun Lee, Hungwon Tchah and Jae-Yong Kim

Biomedicines 2025, 13(12), 2956; https://doi.org/10.3390/biomedicines13122956 - 1 Dec 2025

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Abstract

Background/Objectives: We aimed to investigate the effects of tacrolimus on human Tenon’s fibroblast (HTF) migration, proliferation, and transdifferentiation in vitro. Methods: HTF cells were subcultured and serum-starved for 24 h before being treated with 10 ng/mL tacrolimus. After 1 h, 30 [...] Read more.

Background/Objectives: We aimed to investigate the effects of tacrolimus on human Tenon’s fibroblast (HTF) migration, proliferation, and transdifferentiation in vitro. Methods: HTF cells were subcultured and serum-starved for 24 h before being treated with 10 ng/mL tacrolimus. After 1 h, 30 ng/mL platelet-derived growth factor (PDGF) or 10 ng/mL transforming growth factor beta-1 (TGF-β1) was administered to the HTFs. Migration, proliferation, and transdifferentiation were assessed using WST-1 assays, scratch-induced directional wounding, and western blot analysis. The involvement of the TGF-β signaling pathway was examined via western blotting to measure phosphorylated Smad2, Smad3, ERK, and Akt levels. Results: TGF-β1 and PDGF enhanced HTF migration, proliferation, and transdifferentiation, whereas tacrolimus inhibited these effects. Tacrolimus also inhibited the TGF-β1-induced upregulation of phosphorylated Smad2 and Smad3, suggesting its inhibitory effects occur through TGF-β1 signaling. Conclusions: Overall, tacrolimus can inhibit PDGF- and TGF-β1-induced HTF migration, proliferation, and transdifferentiation, primarily through the Smad-dependent TGF-β signaling pathway. To develop a new therapeutic modality, further longitudinal in vivo studies and human clinical trials are warranted. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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15 pages, 1869 KB

Open AccessArticle

Enhanced mTORC1 Signaling in Inflammatory Monocytes Links Systemic Inflammation to Cardiovascular Disease in Rheumatoid Arthritis

by Claudio Karsulovic, Fabian Tempio, Mercedes Lopez, Julia Guerrero, Ka Wei Katty Joo Hu and Annelise Goecke

Biomedicines 2025, 13(11), 2578; https://doi.org/10.3390/biomedicines13112578 - 22 Oct 2025

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Abstract

Background/Objectives: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA), not fully explained by traditional risk factors and disease activity alone. This study explored the relationship between circulating monocyte subsets, inflammatory cytokine profiles, and Mammalian Target of [...] Read more.

Background/Objectives: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA), not fully explained by traditional risk factors and disease activity alone. This study explored the relationship between circulating monocyte subsets, inflammatory cytokine profiles, and Mammalian Target of Rapamycin Complex (mTORC) signaling in RA patients with and without a history of CVD. Methods: Peripheral blood mononuclear cells from 9 RA patients with prior CVD, 9 carefully matched RA controls without CVD, and 6 healthy controls were analyzed by flow cytometry. Matching was rigorously conducted across clinically relevant variables, including age, sex, blood pressure, lipid profile, smoking status, RA duration, disease activity, Disease-Modifying Anti-Rheumatic Drug (DMARD) failures, and steroid use. Monocyte subsets were classified as inflammatory (CD14⁺HLA-DR⁺CCR2⁺) and non-inflammatory (CD14⁺CD163⁺CCR2⁻). Results: RA-CVD⁺ patients exhibited higher frequencies of inflammatory monocytes and elevated intracellular levels of Interleukin 1 β (IL-1β) and Interleukin 6 (IL-6) compared to RA-CVD⁻ patients and healthy controls. mTORC activation, assessed by phosphorylation of S6 Ribosomal Protein (S6Rp), was significantly increased in inflammatory monocytes from RA-CVD⁺ patients. Conclusions: S6Rp correlated with IL-1β and IL-6 levels only in the RA-CVD⁺ group, suggesting a link between mTORC activity and inflammatory monocyte function. Notably, these inflammatory features did not correlate with disease activity scores or disease duration. We observed increased mTORC1 signaling in inflammatory monocytes in RA-CVD⁺ patients, suggesting a potential association with cardiovascular comorbidity. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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21 pages, 1078 KB

Open AccessArticle

sTREM-1, HMGB1, CRP, PCT, sCD14-ST, IL-6, IL-10, sHLA-G, and Vitamin D in Relation to Clinical Scores and Survival in SIRS/Sepsis

by Michaela Kopcova, Anna Dobisova, Magda Suchankova, Elena Tibenska, Kinga Szaboova, Juraj Koutun and Maria Bucova

Biomedicines 2025, 13(10), 2481; https://doi.org/10.3390/biomedicines13102481 - 11 Oct 2025

Cited by 2 | Viewed by 1632

Abstract

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and remains a major cause of mortality in intensive care units. Methods: We analyzed plasma levels of sTREM-1, CRP, PCT, sCD14-ST, HMGB1, IL-6, IL-10, vitamin D (VD), [...] Read more.

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and remains a major cause of mortality in intensive care units. Methods: We analyzed plasma levels of sTREM-1, CRP, PCT, sCD14-ST, HMGB1, IL-6, IL-10, vitamin D (VD), and sHLA-G in patients with SIRS/sepsis, and assessed their relationships with APACHE II, SOFA scores, and survival. Results: Septic patients showed significantly elevated sTREM-1, CRP, PCT, sCD14-ST, and higher neutrophil-to-lymphocyte ratio, while VD levels were markedly reduced. Logistic regression identified CRP and PCT as the strongest univariate predictors of sepsis, but after adjustment for age, sex, BMI, and comorbidities, CRP lost significance, whereas VD and sCD14-ST remained independent predictors. Prognostically, higher IL-10 levels significantly correlated with 7- and 28-day mortality and with SOFA scores, while higher VD concentrations predicted better survival. Conclusion: CRP, PCT, and sCD14-ST are reliable diagnostic biomarkers of sepsis, with sTREM-1 providing additional value for disease monitoring. After adjustment for clinical covariates, VD emerged as an independent protective factor, whereas elevated IL-10 significantly predicted 7- and 28-day mortality. These findings underscore the utility of combining inflammatory and immunoregulatory biomarkers to improve sepsis diagnostics and prognostication, warranting validation in larger multicenter cohorts. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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17 pages, 3426 KB

Open AccessArticle

Effects of Platelet-Rich Fibrin on In Vitro Periodontal Ligament Cell Functions

by Pablo Cores Ziskoven, Andressa Vilas Boas Nogueira, Jean-Claude Imber, Philipp Bani, Charlott Luise Hell, Jens Weusmann and James Deschner

Biomedicines 2025, 13(10), 2360; https://doi.org/10.3390/biomedicines13102360 - 26 Sep 2025

Cited by 1 | Viewed by 1108

Abstract

Background: Periodontitis is a chronic inflammatory disease that leads to tooth loosening and ultimately tooth loss. Regenerative approaches employing bioactive substances aim to restore lost tissues. Platelet-rich fibrin (PRF) is a simple and cost-effective option, but its effects on periodontal ligament (PDL) cells [...] Read more.

Background: Periodontitis is a chronic inflammatory disease that leads to tooth loosening and ultimately tooth loss. Regenerative approaches employing bioactive substances aim to restore lost tissues. Platelet-rich fibrin (PRF) is a simple and cost-effective option, but its effects on periodontal ligament (PDL) cells under inflammatory conditions remain unclear. Objectives: This study investigated the stimulating effects of platelet-rich fibrin on molecules crucial for periodontal wound healing and tissue remodelling in periodontal ligament (PDL) cells, under normal and inflammatory conditions mimicked by TNF-α. Methods The stimulating effects of different concentrations of PRF on the gene expression of VEGF, BMP2, COX2, TNF-α, and SPP1 were analysed by real-time PCR and ELISA. In addition, the possible modulating effects of TNF-α, a pro-inflammatory cytokine associated with periodontitis, on PRF-induced effects were studied. Furthermore, cell viability, proliferation, and migration were investigated. Results: A 2–3-fold dose-dependent increase in the expression of all the aforementioned genes by PRF was observed at 24 h and 48 h. Additional incubation with TNF-α did not lead to any significant modulation of PRF-induced expression patterns, indicating that the effects of PRF were not compromised in an inflammatory environment. Functionally, PRF caused a significant 35% increase in cell migration between 24 h and 48 h, which was again not affected by a pro-inflammatory condition. Cell viability and proliferation remained largely unaffected by PRF, irrespective of the presence of TNF-α or not. Conclusions: The results suggest that PRF can promote initial periodontal wound healing even in an inflammatory environment by stimulating the expression of cytokines, growth factors and markers of osteogenic differentiation such as VEGF, BMP2 and SPP1, which are involved in angiogenesis, tissue remodelling, and/or cell migration. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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14 pages, 659 KB

Open AccessArticle

Anti-Inflammatory and Immunomodulatory Effects of 2-(3-Acetyl-5-(4-Chlorophenyl)-2-Methyl-1H-Pyrrol-1-yl)-3-Phenylpropanoic Acid

by Hristina Zlatanova-Tenisheva and Stanislava Vladimirova

Biomedicines 2025, 13(8), 2003; https://doi.org/10.3390/biomedicines13082003 - 18 Aug 2025

Cited by 2 | Viewed by 1873

Abstract

Background: The pursuit of novel anti-inflammatory agents with enhanced efficacy and safety is crucial. Pyrrole-containing compounds, integral to many NSAIDs, exhibit promising anti-inflammatory properties. Compound 3f (2-(3-acetyl-5-(4-chlorophenyl)-2-methyl-1H-pyrrol-1-yl)-3-phenylpropanoic acid), a pyrrole derivative structurally inspired by the COX-2 selective inhibitor celecoxib, was evaluated [...] Read more.

Background: The pursuit of novel anti-inflammatory agents with enhanced efficacy and safety is crucial. Pyrrole-containing compounds, integral to many NSAIDs, exhibit promising anti-inflammatory properties. Compound 3f (2-(3-acetyl-5-(4-chlorophenyl)-2-methyl-1H-pyrrol-1-yl)-3-phenylpropanoic acid), a pyrrole derivative structurally inspired by the COX-2 selective inhibitor celecoxib, was evaluated for its anti-inflammatory and immunomodulatory effects. Methods: Anti-inflammatory activity was assessed in a carrageenan-induced paw edema model in Wistar rats. Compound 3f was administered intraperitoneally at 10, 20, and 40 mg/kg, either as a single dose or daily for 14 days. Diclofenac (25 mg/kg) served as the reference. Edema volume was measured by plethysmometry. Systemic inflammation was induced by lipopolysaccharide (LPS), and serum levels of the pro-inflammatory cytokine TNF-α and anti-inflammatory cytokines IL-10 and TGF-β1 were quantified by ELISA following single and repeated administration of compound 3f. Results: Single-dose administration of compound 3f at 20 mg/kg significantly reduced paw edema at 2 h (p = 0.001). After 14 days, all tested doses significantly inhibited paw edema at all time points (p < 0.001). In the LPS-induced systemic inflammation model, repeated treatment with 40 mg/kg of compound 3f significantly decreased serum TNF-α (p = 0.032). TGF-β1 levels increased significantly after both single and repeated doses (p = 0.002 and p = 0.045, respectively), while IL-10 levels remained unaffected. Conclusions: Compound 3f exhibits potent anti-inflammatory activity, particularly after repeated dosing, reflected by reduced local edema and systemic TNF-α suppression. The marked elevation of TGF-β1 indicates a potential immunomodulatory mechanism, selectively modulating cytokine profiles without altering IL-10. These findings support compound 3f as a promising candidate for targeted anti-inflammatory therapy involving cytokine regulation. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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Review

Jump to: Research, Other

22 pages, 2660 KB

Open AccessReview

Hepatocarcinogenesis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Roles of Interleukin-10 and Transcriptomic Insights into IL-10 Signaling Rewiring

by Helena Solleiro-Villavicencio, Lucía Angélica Méndez-García, Itzel Baltazar-Pérez, Pablo Fernando Pineda-Pérez and Ana Alfaro-Cruz

Biomedicines 2026, 14(5), 1093; https://doi.org/10.3390/biomedicines14051093 - 12 May 2026

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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16 pages, 742 KB

Open AccessReview

The Role of Cytokines in Vascular Endothelial Glycocalyx Integrity and Impairment Following Open-Heart Surgery

by Lara Batičić, Božena Ćurko-Cofek, Gordana Taleska Štupica, Matej Jenko, Marko Zdravković, Lea Cofek, Antea Krsek, Tanja Batinac, Danijel Knežević, Marino Damić, Mia Šestan, Aleksandra Ljubačev, Maja Šoštarič and Vlatka Sotošek

Biomedicines 2026, 14(4), 837; https://doi.org/10.3390/biomedicines14040837 - 7 Apr 2026

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Abstract

Open-heart surgery with cardiopulmonary bypass (CPB) is a high-risk procedure with significant morbidity and mortality. CPB, tissue injury, blood loss, endotoxemia and ischemia–reperfusion injury induce a pronounced systemic inflammatory response, leading to endothelial glycocalyx (EG) damage and vascular endothelial dysfunction. Consequently, immune cells, [...] Read more.

Open-heart surgery with cardiopulmonary bypass (CPB) is a high-risk procedure with significant morbidity and mortality. CPB, tissue injury, blood loss, endotoxemia and ischemia–reperfusion injury induce a pronounced systemic inflammatory response, leading to endothelial glycocalyx (EG) damage and vascular endothelial dysfunction. Consequently, immune cells, reactive oxygen species, and enzymes gain free access to vascular endothelial cells, resulting in their dysfunction and enhancing inflammation, vascular permeability, and microvascular impairment. EG degradation is most commonly assessed by measuring the circulating levels of its degradation products. Additionally, CPB triggers an early inflammatory response that is characterized by the secretion of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor alpha, and IL-18, which play roles in initiating the process of EG injury. EG damage is further propagated by the sustained release of cytokines, inhibiting the regeneration of the glycocalyx layer. Heparanase and matrix metalloproteinases are enzymatic pathways involved in cytokine-mediated EG degradation after cardiac surgery, and the balance between the pro- and anti-inflammatory cytokines determines the magnitude and duration of the inflammatory response and EG impairment, which correlates with adverse clinical outcomes, including myocardial dysfunction, acute lung and kidney injury, neurological complications, and prolonged need for intensive care. Thus, identifying patients with an exaggerated cytokine response could potentially provide more personalized therapy based on the circulating biomarkers of EG shedding, and cytokine-directed preservation of EG represents a promising therapeutic strategy in vascular dysfunction prevention during and after open-heart surgery. In this review, we summarize the current knowledge on cytokine-mediated EG impairment following open-heart surgery with CPB. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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14 pages, 1172 KB

Open AccessReview

IL-10–STAT3-Dependent Transcriptional Regulation in Microglia: Alzheimer’s Disease and Neuroinflammation

by Mi Eun Kim and Jun Sik Lee

Biomedicines 2026, 14(4), 826; https://doi.org/10.3390/biomedicines14040826 - 5 Apr 2026

Cited by 1 | Viewed by 760

Abstract

Interleukin-10 (IL-10) is a key immunoregulatory cytokine that suppresses inflammatory gene transcription in myeloid cells through signal transducer and activator of transcription 3 (STAT3). In Alzheimer’s disease and neuroinflammation, microglia express IL10ra and exhibit STAT3 Tyr705 phosphorylation following IL-10 stimulation, indicating IL-10 receptor-dependent [...] Read more.

Interleukin-10 (IL-10) is a key immunoregulatory cytokine that suppresses inflammatory gene transcription in myeloid cells through signal transducer and activator of transcription 3 (STAT3). In Alzheimer’s disease and neuroinflammation, microglia express IL10ra and exhibit STAT3 Tyr705 phosphorylation following IL-10 stimulation, indicating IL-10 receptor-dependent STAT3 activation. Recent studies demonstrate that IL-10 induces promoter-selective STAT3-dependent transcriptional regulation in microglia through chromatin-associated mechanisms, whereas gp130-dependent cytokines activate STAT3 to induce transcription of defined target genes, including Socs3 and Ccl5. Following IL-10 receptor activation, STAT3 binds regulatory regions of inflammatory genes, including Il1b, Tnf, Il6, and Nlrp3, with reduced RNA polymerase II and NF-κB binding. IL-10-dependent transcriptional repression involves formation of a nuclear SHIP1–STAT3 complex, localization of histone deacetylase (HDAC)1 and HDAC2 to H3K4me1-enriched enhancer regions, reduced H3K27ac, and decreased chromatin accessibility at regulatory regions of inflammatory genes. IL-10-activated STAT3 induces Socs3, which regulates JAK1 and TYK2 activity and STAT3 phosphorylation. Impairment of IL-10 receptor signaling in microglia is associated with increased inflammatory gene expression, enhanced inflammasome-related transcription, demyelination, and amyloid accumulation. This review focuses on IL-10–STAT3-dependent transcriptional regulation in microglia, including receptor signaling, chromatin-associated mechanisms, and disease-associated gene expression in Alzheimer’s disease and neuroinflammation. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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19 pages, 1955 KB

Open AccessReview

Extracorporeal Cytokine Adsorption in Acute Cardiovascular Care: Pathophysiological Insights and Clinical Perspectives

by Klevis Mihali, Lukas Harbaum, Birgit Markus, Georgios Chatzis, Nikolaos Patsalis, Styliani Syntila, Bernhard Schieffer and Julian Kreutz

Biomedicines 2026, 14(2), 360; https://doi.org/10.3390/biomedicines14020360 - 4 Feb 2026

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Abstract

Background: Cardiogenic shock (CS) and post-cardiac arrest syndrome (PCAS) are frequently associated with a systemic inflammatory response resulting from ischemia–reperfusion injury, endothelial dysfunction, and microcirculatory impairment. This inflammatory biology may be further amplified by temporary mechanical circulatory support (tMCS) through blood–surface interactions [...] Read more.

Background: Cardiogenic shock (CS) and post-cardiac arrest syndrome (PCAS) are frequently associated with a systemic inflammatory response resulting from ischemia–reperfusion injury, endothelial dysfunction, and microcirculatory impairment. This inflammatory biology may be further amplified by temporary mechanical circulatory support (tMCS) through blood–surface interactions and shear-related hemolysis. Extracorporeal cytokine adsorption has therefore been proposed as an adjunctive strategy to attenuate hyperinflammation and facilitate shock reversal in selected patients. Methods: We conducted a narrative review, guided by a targeted PubMed and Scopus search and reference screening, to summarize the current pathophysiological concepts and clinical evidence on extracorporeal cytokine adsorption in CS-, PCAS-, and tMCS-supported states. Results: Across porous polymer hemoadsorption cartridges (e.g., CytoSorb^®), membrane-based or hybrid filters with adsorptive properties (e.g., oXiris^®), and selective approaches targeting inflammatory mediators (e.g., PentraSorb^® CRP), available studies most consistently report short-term physiological effects, including reduced vasopressor demand, improved metabolic stabilization, and modulation of inflammatory markers. However, evidence of benefits to clinically relevant endpoints remains inconsistent in various clinical settings, and randomized data are limited. Conclusions: Extracorporeal cytokine adsorption is a biologically plausible adjunct in inflammation-driven acute cardiovascular syndromes, but current evidence does not support routine use. Phenotype-guided patient selection, early timing, and adequately powered, mechanism-informed randomized trials are required to define clinical efficacy and safety in defined patient populations. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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31 pages, 2225 KB

Open AccessReview

Interferons in Autoimmunity: From Loss of Tolerance to Chronic Inflammation

by Grigore Mihaescu, Gratiela Gradisteanu Pircalabioru, Claudiu Natanael Roznovan, Lia-Mara Ditu, Mihaela Maria Comanici and Octavian Savu

Biomedicines 2025, 13(10), 2472; https://doi.org/10.3390/biomedicines13102472 - 11 Oct 2025

Cited by 6 | Viewed by 3122

Abstract

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current [...] Read more.

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current data on IFN biology, their immunoregulatory and pathogenic mechanisms, and their contributions to distinct AD phenotypes. We conducted a comprehensive review of peer-reviewed literature on IFNs and autoimmune diseases, focusing on publications indexed in PubMed and Scopus. Studies on molecular pathways, immune cell interactions, disease-specific IFN signatures, and clinical correlations were included. Data were extracted and thematically organized by IFN type, signaling pathway, and disease context, with emphasis on rheumatic and systemic autoimmune disorders. Across systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, idiopathic inflammatory myopathies, multiple sclerosis, type 1 diabetes, psoriasis, and inflammatory bowel diseases, IFNs were consistently associated with aberrant activation of pattern recognition receptors, sustained expression of interferon-stimulated genes (ISGs), and dysregulated T cell and B cell responses. Type I IFNs often preceded clinical onset, suggesting a triggering role, whereas type II and III IFNs modulated disease course and severity. Notably, IFNs exhibited dual immunostimulatory and immunosuppressive effects, contingent on tissue context, cytokine milieu, and disease stage. IFNs are central mediators in autoimmune pathogenesis, functioning as both initiators and amplifiers of chronic inflammation. Deciphering the context-dependent effects of IFN signaling may inform targeted therapeutic strategies and advance precision immunomodulation in autoimmune diseases. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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21 pages, 2253 KB

Open AccessReview

Role of the Th2-like Immune Response in Obesity: IL-4 as a Metabolic Regulator and IL-13 as an Effector of Muscle Energy Metabolism

by Lucía A. Méndez-García, Helena Solleiro-Villavicencio, Nallely Bueno-Hernández, Arturo Cérbulo-Vázquez, Galileo Escobedo, Marcela Esquivel-Velázquez and Miguel A. Fonseca-Sánchez

Biomedicines 2025, 13(9), 2208; https://doi.org/10.3390/biomedicines13092208 - 9 Sep 2025

Cited by 4 | Viewed by 2305

Abstract

The Th2 immune response, associated with allergic diseases and helminth infections, has emerged as a significant modulator of metabolic processes in adipose and liver tissues. Th2 cytokines, such as IL-4, IL-5, and IL-13, regulate energy metabolism, insulin resistance, and obesity-related issues. IL-4 and [...] Read more.

The Th2 immune response, associated with allergic diseases and helminth infections, has emerged as a significant modulator of metabolic processes in adipose and liver tissues. Th2 cytokines, such as IL-4, IL-5, and IL-13, regulate energy metabolism, insulin resistance, and obesity-related issues. IL-4 and IL-13 play significant roles, while IL-5 mainly recruits eosinophils in visceral fat. IL-4 influences lipid metabolism via STAT6, promoting adipogenesis, lipolysis, and reducing leptin levels, thereby improving insulin resistance or inducing white adipose browning in the absence of leptin. IL-13 affects glucose metabolism by lowering gluconeogenesis and enhancing glucose control and increases energy expenditure in muscles during exercise via STAT3. Emerging therapies include recombinant cytokines, exosomes, and monoclonal antibodies targeting IL-4/IL-13 or IL-5, which are mostly approved for the treatment of allergic diseases. Their use in metabolic disorders is largely unexplored. Overall, Th2 cytokines are promising targets for obesity and metabolic diseases but require dedicated trials to assess benefits and risks. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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Role of Cytokines in Breast Cancer: A Systematic Review and Meta-Analysis

by Sebastian Ciurescu, Victor Buciu, Denis Șerban, Florina Borozan, Larisa Tomescu, Ionuț Marcel Cobec, Diana Gabriela Ilaș and Ioan Sas

Biomedicines 2025, 13(9), 2203; https://doi.org/10.3390/biomedicines13092203 - 9 Sep 2025

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Abstract

Background/Objectives: Cytokines play a fundamental role in the tumor microenvironment, influencing breast cancer progression, metastasis, and therapeutic resistance. The objective of this systematic review and meta-analysis was to evaluate the prognostic impact and therapeutic relevance of key cytokines in breast cancer, based [...] Read more.

Background/Objectives: Cytokines play a fundamental role in the tumor microenvironment, influencing breast cancer progression, metastasis, and therapeutic resistance. The objective of this systematic review and meta-analysis was to evaluate the prognostic impact and therapeutic relevance of key cytokines in breast cancer, based on human studies published between 2015 and 2025. Methods: We systematically searched PubMed, Web of Science, and Scopus for eligible studies reporting on cytokine expression and clinical outcomes in breast cancer. Inclusion criteria were based on the PRISMA framework, focusing on human cohorts and excluding in vitro or animal models. Data were extracted on cytokine types, measurement methods, patient population, and outcomes. Meta-analyses were performed using random-effects models for cytokines with sufficient data, notably IL-6 and TNF-α. Results: Twenty-three studies were included. Elevated IL-6 was consistently associated with poor overall survival (pooled HR = 2.25, 95% CI 1.83–2.76), while high TNF-α levels showed a trend toward worse outcomes but without statistical significance. IL-1β, IL-8, and IL-10 were also linked to increased metastasis and reduced response to therapy. Immunosuppressive cytokines such as IL-10 and TGF-β facilitated tumor immune evasion, while IL-17 promoted inflammation and angiogenesis. Cytokines such as IL-12 and IFN-γ were associated with improved immune responses and a favorable prognosis. Conclusions: Cytokines are central mediators of breast cancer progression and immune regulation. Elevated levels of pro-inflammatory and immunosuppressive cytokines correlate with poor outcomes and may serve as prognostic biomarkers and therapeutic targets. Their integration into personalized treatment strategies holds significant clinical potential but requires further prospective validation and biomarker standardization. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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Open AccessSystematic Review

Preclinical Evidence of Curcuma longa Linn. as a Functional Food in the Management of Metabolic Syndrome: A Systematic Review and Meta-Analysis of Rodent Studies

by Samuel Abiodun Kehinde, Zahid Naeem Qaisrani, Rinrada Pattanayaiying, Wai Phyo Lin, Bo Bo Lay, Khin Yadanar Phyo, Myat Mon San, Nurulhusna Awaeloh, Sasithon Aunsorn, Ran Kitkangplu and Sasitorn Chusri

Biomedicines 2025, 13(8), 1911; https://doi.org/10.3390/biomedicines13081911 - 5 Aug 2025

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Background/Objectives: Metabolic syndrome (MetS) is a multifactorial condition characterized by abdominal obesity, dyslipidemia, insulin resistance, hypertension, and chronic inflammation. As its global prevalence rises, there is increasing interest in natural, multi-targeted approaches to manage MetS. Curcuma longa Linn. (turmeric), especially its active [...] Read more.

Background/Objectives: Metabolic syndrome (MetS) is a multifactorial condition characterized by abdominal obesity, dyslipidemia, insulin resistance, hypertension, and chronic inflammation. As its global prevalence rises, there is increasing interest in natural, multi-targeted approaches to manage MetS. Curcuma longa Linn. (turmeric), especially its active compound curcumin, has shown therapeutic promise in preclinical studies. This systematic review and meta-analysis evaluated the effects of Curcuma longa and its derivatives on MetS-related outcomes in rodent models. Methods: A comprehensive search was conducted across six databases (PubMed, Scopus, AMED, LILACS, MDPI, and Google Scholar), yielding 47 eligible in vivo studies. Data were extracted on key metabolic, inflammatory, and oxidative stress markers and analyzed using random-effects models. Results were presented as mean differences (MD) with 95% confidence intervals (CI). Results: Meta-analysis showed that curcumin significantly reduced body weight (rats: MD = −42.10; mice: MD = −2.91), blood glucose (rats: MD = −55.59; mice: MD = −28.69), triglycerides (rats: MD = −70.17; mice: MD = −24.57), total cholesterol (rats: MD = −35.77; mice: MD = −52.61), and LDL cholesterol (rats: MD = −69.34; mice: MD = −42.93). HDL cholesterol increased significantly in rats but not in mice. Inflammatory cytokines were markedly reduced, while oxidative stress improved via decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) and catalase (CAT) levels. Heterogeneity was moderate to high, primarily due to variations in curcumin dosage (ranging from 10 to 500 mg/kg) and treatment duration (2 to 16 weeks) across studies. Conclusions: This preclinical evidence supports Curcuma longa as a promising functional food component for preventing and managing MetS. Its multi-faceted effects warrant further clinical studies to validate its translational potential. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 3rd Edition)

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