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Article ; Online: Immunomodulatory activity of dipeptidyl peptidase-4 inhibitors in immune-related diseases.

Drakul, Marija / Čolić, Miodrag

2023 Volume 53, Issue 12, Page(s) e2250302

Abstract: Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is a 110-kDa cell surface glycoprotein with enzymatic and signal transducing activity. DPP-4/CD26 is expressed by various cells, including CD4+ and CD8+ T cells, B cells, dendritic cells, macrophages, ... ...

Abstract	Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is a 110-kDa cell surface glycoprotein with enzymatic and signal transducing activity. DPP-4/CD26 is expressed by various cells, including CD4+ and CD8+ T cells, B cells, dendritic cells, macrophages, and NK cells. DPP-4 inhibitors (DPP-4i) were introduced to clinics in 2006 as new oral antihyperglycemic drugs approved for type 2 diabetes mellitus treatment. In addition to glucose-lowering effects, emerging data, from clinical studies and their animal models, suggest that DPP-4i could display anti-inflammatory and immunomodulatory effects as well, but the molecular and immunological mechanisms of these actions are insufficiently investigated. This review focuses on the modulatory activity of DPP-4i in the immune system and the possible application of DPP-4i in other immune-related diseases in patients with or without diabetes.
MeSH term(s)	Animals ; Humans ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy ; Dipeptidyl Peptidase 4/metabolism
Chemical Substances	Dipeptidyl-Peptidase IV Inhibitors ; Dipeptidyl Peptidase 4 (EC 3.4.14.5)
Language	English
Publishing date	2023-09-28
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202250302
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Article ; Online: Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response.

Milanović, Marijana / Bekić, Marina / Đokić, Jelena / Vučević, Dragana / Čolić, Miodrag / Tomić, Sergej

International journal of biological sciences

2024 Volume 20, Issue 3, Page(s) 1064–1087

Abstract: Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key ...

Abstract	Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs' capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.
MeSH term(s)	Humans ; Ketoglutaric Acids/metabolism ; Dendritic Cells/metabolism ; Th1 Cells ; Th2 Cells ; Cell Differentiation ; Monocytes ; Oxidation-Reduction ; Cells, Cultured
Chemical Substances	Ketoglutaric Acids
Language	English
Publishing date	2024-01-20
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2179208-2
ISSN	1449-2288 ; 1449-2288
ISSN (online)	1449-2288
ISSN	1449-2288
DOI	10.7150/ijbs.91109
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Article: The 2012 Nobel Prize Laureates in Physiology or Medicine.

Colić, Miodrag

Vojnosanitetski pregled

2012 Volume 69, Issue 11, Page(s) 938–939

MeSH term(s)	Cell Biology/history ; History, 20th Century ; History, 21st Century ; Japan ; Nobel Prize ; Pluripotent Stem Cells ; United Kingdom
Language	English
Publishing date	2012-11
Publishing country	Serbia
Document type	Biography ; Editorial ; Historical Article ; Portraits
ZDB-ID	123795-0
ISSN	0042-8450
ISSN	0042-8450
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Article ; Online: Immunological aspects of nanocellulose.

Čolić, Miodrag / Tomić, Sergej / Bekić, Marina

Immunology letters

2020 Volume 222, Page(s) 80–89

Abstract: Cellulose is the most abundant natural polymer in the world. Nanoscale forms of cellulose, including cellulose nanofibers (CNF), cellulose nanocrystals (CNC) and bacterial nanocellulose (BC), are very attractive in industry, medicine and pharmacy. ... ...

Abstract	Cellulose is the most abundant natural polymer in the world. Nanoscale forms of cellulose, including cellulose nanofibers (CNF), cellulose nanocrystals (CNC) and bacterial nanocellulose (BC), are very attractive in industry, medicine and pharmacy. Biomedical applications of nanocellulose in tissue engineering, regenerative medicine, and controlled drug delivery are the most promising. Nanocellulose is considered a biocompatible nanomaterial and relatively safe for biomedical applications. However, more studies are needed to prove this hypothesis, especially those related to chronic exposure to nanocellulose. Besides toxicity, the response of the immune system is of particular importance in this sense. This paper provides a comprehensive and critical review of the current-state knowledge of the impact of nanocellulose on the immune system, especially on macrophages and dendritic cells (DC), as the central immunoregulatory cells, which has not been addressed in the literature sufficiently. Nanocellulose, especially CNC, can induce the inflammatory response upon the internalization by macrophages, but this reaction may be significantly modulated by introducing different functional groups on their surface. Our original results showed that nanocellulose has a potent immunotolerogenic potential. Native CNF potentiated the capacity of DC to induce conventional Tregs. When carboxyl groups were introduced on the CNF surface, the tolerogenic potential of DC was shifted towards the induction of regulatory CD8
MeSH term(s)	Animals ; Biocompatible Materials ; Cellulose/immunology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Humans ; Immune Tolerance ; Immunomodulation ; Macrophages/immunology ; Macrophages/metabolism ; Monocytes/immunology ; Monocytes/metabolism ; Nanofibers ; Nanoparticles ; Nanostructures
Chemical Substances	Biocompatible Materials ; Cellulose (9004-34-6)
Language	English
Publishing date	2020-04-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2020.04.004
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Article: The 2011 Nobel Prize Laureates in Physiology or Medicine.

Colić, Miodrag

Vojnosanitetski pregled

2011 Volume 68, Issue 11, Page(s) 907–908

MeSH term(s)	Allergy and Immunology/history ; Germany ; History, 20th Century ; History, 21st Century ; Luxembourg ; Nobel Prize ; United States
Language	English
Publishing date	2011-11
Publishing country	Serbia
Document type	Biography ; Editorial ; Historical Article ; Portraits
ZDB-ID	123795-0
ISSN	0042-8450
ISSN	0042-8450
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Article ; Online: Ex vivo study of IL-6 expression and function in immune cell subsets from human periapical lesions.

Džopalić, Tanja / Tomić, Sergej / Bekić, Marina / Vučević, Dragana / Mihajlović, Dušan / Eraković, Mile / Čolić, Miodrag

International endodontic journal

2022 Volume 55, Issue 5, Page(s) 480–494

Abstract: Aim: Even though IL-6 is a key inflammatory cytokine in periapical lesions (PLs), its function in stable periapical disease is unknown. Therefore, the aim of this study was to investigate the following: first, the ex vivo production of IL-6 by ... ...

Abstract	Aim: Even though IL-6 is a key inflammatory cytokine in periapical lesions (PLs), its function in stable periapical disease is unknown. Therefore, the aim of this study was to investigate the following: first, the ex vivo production of IL-6 by clinically different PLs; next, subsets of immune cells expressing IL-6 in PLs according to their inflammatory status and finally, modulatory effect of IL-6 on T-cell cytokine production in cell cultures. Methodology: Inflammatory cells were isolated from a total of 95 human PLs. Detection of IL-6 Results: The levels of IL-6 in PL MNC culture supernatants were significantly higher compared with total PL cells and PL granulocytes (p < .001). MNC from Sy PLs produced significantly higher levels of IL-6 than MNC from Asy PLs (p < .001). Flow cytometry analysis showed that NKT cells, CD8 Conclusions: Most immune cells from Sy PLs expressed higher levels of IL-6 compared with Asy PLs, which correlated with IL-6 production in culture. Analysis of cytokines suggested a dominant pro-inflammatory T-cell response and osteodestructive function of IL-6 in PLs judging by Th17/Tfh cell activation, Tregs inhibition and increased RANKL/OPG ratio. Excessive IL-6 production decreased Th1/Th2 responses.
MeSH term(s)	CD8-Positive T-Lymphocytes ; Cytokines ; Humans ; Interleukin-10 ; Interleukin-4 ; Interleukin-6 ; Transforming Growth Factor beta
Chemical Substances	Cytokines ; IL6 protein, human ; Interleukin-6 ; Transforming Growth Factor beta ; Interleukin-10 (130068-27-8) ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2022-02-25
Publishing country	England
Document type	Journal Article
ZDB-ID	603734-3
ISSN	1365-2591 ; 0143-2885
ISSN (online)	1365-2591
ISSN	0143-2885
DOI	10.1111/iej.13704
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Article ; Online: Long-term antibody-response monitoring following primary exposure to SARS-COV-2 and afterward mRNA COVID-19 vaccination

Balint Bela / Todorović Milena / Andrić Zorana / Jovičić Milica / Blagojević Glorija / Čolić Miodrag

Vojnosanitetski Pregled, Vol 78, Iss 3, Pp 379-

A case report

2021 Volume 381

Abstract: ... ...

Abstract	nema
Keywords	antibodies ; covid-19 ; covid-19 serotherapy ; infections ; vaccination ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Military Health Department, Ministry of Defance, Serbia
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anti-inflammatory effect of amalgam on periapical lesion cells in culture

Eraković Mile / Duka Miloš / Bekić Marina / Milanović Marijana / Tomić Sergej / Vučević Dragana / Čolić Miodrag

Vojnosanitetski Pregled, Vol 78, Iss 3, Pp 289-

2021 Volume 295

Abstract: Background/Aim. Amalgam has been used for years in dentistry, but the controversy on its adverse effects, both on local oral/dental tissues and systemic health, still exists. When used for retrograde filling in apical surgery, amalgam comes in close ... ...

Abstract	Background/Aim. Amalgam has been used for years in dentistry, but the controversy on its adverse effects, both on local oral/dental tissues and systemic health, still exists. When used for retrograde filling in apical surgery, amalgam comes in close contact with the periapical tissue, and it is sometimes responsible for the induction of periapical lesion (PL) or its exacerbation. Therefore, the aim of the study was to examine the effect of amalgam on cytotoxicity and production of pro-inflammatory cytokine by cells isolated from PL. Methods. Conditioned medium from freshly prepared amalgam (ACM) was performed according to the ISO 10993-12 by incubating the alloy in RPMI medium (0.2 g/mL) for 3 days at 37°C. Cells were isolated from 20 human PLs after apicoectomy by collagenase/DNA-ase digestion and cultured with different dilutions of ACM. Cytotoxicity was determined by MTT assay (n = 7 cultures) and apoptosis/necrosis assays (n = 8 cultures), whereas cytokine production was measured by a Flow Cytomix Microbeads Assay (n = 8 cultures). Results. Undiluted (100%) and 75% ACM was cytotoxic due to induction of apoptosis of PL cells. Non-cytotoxic concentrations of ACM (50% and 25%) inhibited the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), concentration-dependently. Conclusion. For the first time, our results showed an unexpected anti-inflammatory property of amalgam on PL cells, which could be beneficial for PL healing after apicoectomy.
Keywords	dental amalgam ; periapical tissue ; cytokines ; cytotoxicity ; immunologic ; inflammation ; apicoectomy ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Military Health Department, Ministry of Defance, Serbia
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sitagliptin Induces Tolerogenic Human Dendritic Cells.

Drakul, Marija / Tomić, Sergej / Bekić, Marina / Mihajlović, Dušan / Vasiljević, Miloš / Rakočević, Sara / Đokić, Jelena / Popović, Nikola / Bokonjić, Dejan / Čolić, Miodrag

International journal of molecular sciences

2023 Volume 24, Issue 23

Abstract: Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and ...

Abstract	Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection.
MeSH term(s)	Humans ; Interleukin-10/metabolism ; Dipeptidyl Peptidase 4/metabolism ; Sitagliptin Phosphate/pharmacology ; Cells, Cultured ; Cell Differentiation ; Monocytes/metabolism ; Transforming Growth Factor beta/metabolism ; Dendritic Cells ; Forkhead Transcription Factors/metabolism
Chemical Substances	Interleukin-10 (130068-27-8) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5) ; Sitagliptin Phosphate (TS63EW8X6F) ; Transforming Growth Factor beta ; Forkhead Transcription Factors
Language	English
Publishing date	2023-11-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242316829
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Article: Periodontal Disease in Young Adults as a Risk Factor for Subclinical Atherosclerosis: A Clinical, Biochemical and Immunological Study.

Cicmil, Smiljka / Cicmil, Ana / Pavlic, Verica / Krunić, Jelena / Sladoje Puhalo, Dragana / Bokonjić, Dejan / Čolić, Miodrag

Journal of clinical medicine

2023 Volume 12, Issue 6

Abstract: Although a strong relationship between periodontal disease (PD) and atherosclerosis was shown in adults, little data are published in younger PD patients. Therefore, this study aimed to investigate and correlate clinical parameters of PD, pro- and ... ...

Abstract	Although a strong relationship between periodontal disease (PD) and atherosclerosis was shown in adults, little data are published in younger PD patients. Therefore, this study aimed to investigate and correlate clinical parameters of PD, pro- and immunoregulatory cytokines in gingival crevicular fluid (GCF) and serum, biochemical and hematological parameters associated with atherosclerosis risk, and carotid intima-media thickness (IMT) in our younger study participants (n = 78) (mean age 35.92 ± 3.36 years) who were divided into two equal groups: subjects with and without PD. PD patients had higher values of IMT, hs-CRP, triglycerides, total cholesterol, and LDL; most proinflammatory and Th1/Th17-associated cytokines in GCF; and IL-8, IL-12, IL-18, and IL-17A in serum compared to subjects without PD. These cytokines in GCF positively correlated with most clinical periodontal parameters. Clinical periodontal parameters, TNF-α and IL-8 in GCF and IL-17A, hs-CRP, and LDL in serum, had more significant predictive roles in developing subclinical atherosclerosis (IMT ≥ 0.75 mm) in comparison with other cytokines, fibrinogen, and other lipid status parameters. Hs-CRP correlated better with the proinflammatory cytokines than the parameters of lipid status. Except for serum IL-17A, there was no significant association of clinical and immunological PD parameters with lipid status. Overall, these results suggest that dyslipidemia and PD status seem to be independent risk factors for subclinical atherosclerosis in our younger PD population.
Language	English
Publishing date	2023-03-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12062197
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