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Dry eye disease (DED) is a chronic inflammatory disease of the lacrimal system and ocular surface. Considering the important role of inflammation in DED development, the main treatment strategy has shifted from hydration and lubrication of dry ocular surface to the immunomodulation and immunoregulationapproach that should address the main pathologic processes responsible for disease progression. Due to their capacity for production of immunosuppressive factors, mesenchymal stem cells (MSCs) and their secretome have been considered as potentially new agents in DED therapy. We recently developed an immunomodulatory ophthalmic solution “derived- Multiple Allogeneic Proteins Paracrine Signaling (d-MAPPS)” which activity is relied on immunosuppressive capacity of MSC-derived secretome. d-MAPPS contains MSC-derived exosomes, growth factors and immunosuppressive cytokines that are able to efficiently suppress generation of inflammatory phenotype in T cells and macrophages. Herewith, we demonstrated that d-MAPPS protected human corneal epithelial cells from chemical injury and efficiently alleviated ocular discomfort and pain in 131 DED patients during the 12-month follow-up, indicating d-MAPPS eye drops as potentially new remedy for the treatment of DED patients.

Background/Aim. Chronic microbial infections of the root canal are a common issue. This process very often causes an immune reaction in the root canal system that results in forming of chronic periapical lesions (PLs). The aim of this study was to determine the quantitative expression of the bacterial heat shock protein (HSP), chaperonin 60 (cpn60), and the pro-inflammatory and anti-inflammatory cytokines in periapical tissue obtained from individuals with chronic PLs and to determine if there is a correlation between the expression of the bacterial HSP and the expression of these cytokines. Methods. The study was performed on 18 PLs and 6 control samples of healthy periapical tissue, taken at the Department of Dentistry, Faculty of Medicine, University of Pristina/Kosovska Mitrovica. The levels of messenger ribonucleic acid (mRNA) expression of pro- and anti-inflammatory cytokines and bacterial HSP were determined by quantitative real-time polymerase chain reaction (RT-PCR) and quantified by comparing to the internal control gene for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Results. Analysis revealed significantly higher mRNA levels of tumor necrosis factor-alpha (TNF-a) and cpn60 in the tissue of PLs compared with normal periapical tissue (p < 0.05). Contrary to these results, the mRNA expression of anti-inflammatory interleukin-10 (IL-10) was significantly higher in the samples of normal periapical tissue compared with the mRNA levels of this cytokine in the tissue of PLs (p < 0.001). Expression of cpn60 is in strong correlation with TNF-a expression in PLs. Conclusion. cpn60 released from bacteria in periapical tissue could be a strong stimulator of inflammatory response and one of the important players in the pathogenesis of PLs.

Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental, and microbial factors drives chronic intestinal inflammation. Gastrointestinal symptoms are predominant including pathological manifestations in the oral cavity, as well as extra-intestinal complications. Lingua plicata (LP) is a condition characterized by an increased number of fissures and grooves at the central and lateral aspects of the dorsal surface of the tongue. LP is usually asymptomatic and discovered incidentally, but the accumulation of food in the fissures and grooves can lead to focal glossitis and halitosis. In this study, we analyzed the level of proinflammatory cytokines in gingival crevicular fluid (GCF) and demonstrated that proinflammatory cytokines IFN-γ, IL-12, and IL-1β were significantly increased in the group of UC patients when compared with healthy controls. Obtained results have shown that 35% of UC patients have lingua plicata. The GCF levels of IFN-γ and IL-12 were higher in UC patients with LP compared with UC patients without lingua plicata. In conclusion, increased GCF values of IFN-γ and IL-12, in UC patients with LP may be considered as a sign of the disease progression and, consequently, of a poor prognosis for patients.

Background/Aim. In the spirit of personalized medicine, determining caries biomarkers in the saliva and gingival crevicular fluid (GCF) attracts great attention in the current dental re-search. The concentration of GCF cytokines is illustrative in depicting the processes in tooth structures. Their relevance must be inspected with aspects of tooth position and caries lesion level. Different impacts of dental restoration materials on GCF IL-1? and TNF-? could be used as a parameter for estimating local inflammation. This paper aimed to estimate the concentrations of the proinflammatory cytokines (IL-1? and TNF-?) in the GCF and to correlate them with caries extension, tooth position, and different restorative biomaterials. Methods. GCF samples were collected from 90 periodontally healthy patients demonstrating at least one tooth with proximal caries and one intact tooth, at the baseline, 7 and 30-days post-treatment. The biomarkers? profile was investigated in relation to different levels of caries extension (superficial, pulpitis, gangrenous, root affection), defect size, and restorative biomaterial. Results. Before therapy, caries level was significantly associated with GCF IL-1? concentration, demonstrating the lowest level in gangrenous (C4) and superficial caries (C2). Thirty days after therapy, root affection (C5) was characterized by the highest IL-1? concentration. Different dental fillings showed various GCF cytokine changes. CPC induced a significant IL-1? increase in more than 70% of treated patients. Caries lesion size was insignificantly associated with GCF levels of these proinflammatory cytokines, where larger defects were followed by an average cytokine increase. Considering the tooth position be-fore therapy, IL-1? had the highest level in GCF samples from caries-affected canines and second molars, while TNF-? showed the highest levels from canines GCF. Dental restoration induced cytokine increase in canines (IL-1? and TNF-?), 1st and 2nd molars GCF (IL-1?). Conclusion. Inflammation intensity of tooth structures was directly reflected in IL-1? and TNF-? concentrations. Dental restoration significantly affects IL-1? and TNF-? levels, depending on the used dental filling-type material. The profile of these cytokines varied in GCF samples of the tooth with different anatomical positions, where canines and molars demonstrated the highest level. An increase of these proinflammatory cytokines in the absence of any symptomatic manifestation of the inflammatory response can be considered as a possible tooth reparation parameter.

There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24 h after melanoma induction (B16F10+MSC1d-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-α and IFN-γ), remarkably lower plasma levels of immunosuppressive cytokines (TGF-β and IL-10), and a significantly higher number of tumor-infiltrating, IFN-γ-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-γ- and TNF-α-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC1d-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC14d-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-β and IL-10, remarkably lower plasma levels of TNF-α and IFN-γ, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-γ- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC14d-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion.

One of the therapeutic options for the treatment of fulminant hepatitis is repopulation of intrahepatic regulatory cells because their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of regulatory T cells (Tregs) and regulatory B cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of interleukin (IL) 10-producing CD4+ CD25+ forkhead box P3+ Tregs and IL10- and transforming growth factor β-producing marginal zone-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, whereas depletion of Tregs completely abrogated hepatoprotective effects of MSCs and inhibited their capacity to attenuate hepatotoxicity of liver natural killer T cells (NKTs), indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in a paracrine, indoleamine 2,3-dioxygenase-dependent manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and to suppress hepatotoxicity of liver NKTs. Accordingly, adoptive transfer of MSC-primed Tregs resulted in the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicated the significance of MSC-mediated priming of Tregs as a new therapeutic approach in Treg-based therapy of acute liver injury. Liver Transplantation 24 687-702 2018 AASLD.

The aim of this study is to describe the morphological characteristics, the number of roots and number of root canals of mandibular central incisors, lateral incisors and canines, and the relationship of these characteristics with the sex and the jaw side where the tooth is located, in the Serbian population using cone-beam computed tomography (CBCT). CBCT images of a total of 902 mandible front teeth, including 296 central incisors, 294 lateral incisors and 312 canines were analyzed in the database. For assessing the morphology of the root canal, Vertucci method of classification was used. Central incisors had two canals in 27%, similar as lateral incisor which had two canals in 26.5%. Mandibular canines had two canals in 7.1% and there was a significant difference between genders. The most prevalent root canal configuration type in all mandibular anterior teeth was type I. In the groups of mandibular incisors with two root canals the most common was type III. In the group of mandibular canines with two root canals, type V had the greatest occurrence. Most mandibular anterior teeth had one root canal. Two root canals were found in 27% of the mandibular incisors. There is a significant difference in root morphology between genders. It is important for dental practitioner to expect different morphological variations when performing endodontic treatment. More studies are needed to further define morphological characteristics of roots of mandibular anterior teeth in Serbian population.

Introduction. The aim of this study was to establish the number of roots and present the root canal configuration in the maxillary and mandibular premolar teeth, and evaluate the relations among these characteristics with gender and teeth position in the Serbian population using cone-beam computed tomography. Material and Methods. Cone-beam computed tomography images of 570 teeth of 150 patients were evaluated. Teeth were classified into the following groups: maxillary first premolars, maxillary second premolars, mandibular first premolars and mandibular second premolars, and the number of roots and root canals per tooth, whereas root canal configurations were examined along with the tooth position and patients? gender. The root canal configuration was classified using Vertucci?s classification. Statistical significance was obtained using Chi square test. Results. In maxillary first premolars, two roots (53.5%) and two root canals (84.5%) were the most prevalent, as well as type IV configuration (58.9%). In maxillary second premolars, most teeth had one root (88.1%) and one root canal (59.6%). In regard to gender, complex configurations with multiple canals were more prevalent in males. Higher incidence of type IV configuration in maxillary first premolars was present on the right side of the jaw (70.2%). Most mandibular first premolars had one root (98.5%). In mandibular second premolar, all teeth had one root and most had type I configuration (96.2%). Males showed higher incidence of two canals in mandibular first premolars. Conclusion. Cone-beam computed tomography is a useful tool for obtaining valuable information on root canal morphology of premolar teeth. Patient?s gender should be considered when performing the preoperative assessment of endodontic treatment.

Introduction: Accessory mental foramen (AMF) is defined as any additional opening on the anterior surface of the mandible body that is connected to the mandibular canal. The presence of AMF is an important anatomical parameter when planning the therapy to avoid neurovascular bundle injury and other complications. Cone-beam computed tomography (CBCT) provides an accurate, three-dimensional determining of the position, its dimensions and the relation of AMF to the mental foramen (MF), as well as the distinction from nutritive openings. Material and Methods: The research was carried out at the Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, as a retrospective study where 148 CBCT images were analyzed. The analysis of the position of AMF, the relation to and the distance from the MF were made on cross-sectional and axial images. Only those openings that have had a clear connection with the mandibular canal were counted as AMF. Results: AMF was present in 12 (8.11%) patients. In most cases, AMF was positioned superior to MF, in 27% of patients. There was no significant statistical difference between sex and the jaw side. The average distance of AMF from MF was 4.52 ± 2.21 mm. In most cases, AMF is round shaped (60%). The average value of the surface area is 1.62 ± 1.14 mm2. Discussion and Conclusion: Timely detection of AMF using CBCT contributes to the diagnosis and planning of appropriate dentures, surgical technique, preventing possible damage to adjacent anatomical structures, or some other therapy.

Background: Dendritic cell (DC)-derived indolamine 2,3-dioxygenase (IDO) degrades tryptophan to kynurenine, which promotes conversion of inflammatory T cells in immunosuppressive regulatory T cells (Tregs). We analyzed the significance of the IDO:Treg axis for inducing and maintaining mucosal healing in ulcerative colitis (UC). Methods: Dextran sodium sulphate (DSS)-induced colitis in BALB/c mice (model for mucosal healing) and C57BL/6 mice (model for persistent disease) was used. Serum, fecal samples and colon-infiltrating immune cells of 65 patients with UC with mucosal healing or persistent colitis were analyzed. Results: Significantly higher serum levels of kynurenine and downregulated inflammatory cytokines were noticed in DSS-treated BALB/c mice compared with C57BL/6 mice. Increased IDO activity and attenuated capacity for antigen presentation and production of inflammatory cytokines, observed in BALB/c DCs, was followed by a significantly lower number of inflammatory T helper 1 (Th1) and Th17 cells and a notably increased number of Tregs in the colons of DSS-treated BALB/c mice. DCs and Tregs were crucially important for the maintenance of mucosal healing since their depletion aggravated colitis. Mucosal healing, followed by an increase in kynurenine and intestinal Tregs, was re-established when BALB/c DCs were transferred into DC-depleted or Treg-depleted DSS-treated BALB/c mice. This phenomenon was completely abrogated by the IDO inhibitor. Significantly higher serum and fecal levels of kynurenine, accompanied by an increased presence of intestinal Tregs, were noticed in patients with UC with mucosal healing and negatively correlated with disease severity, fecal calprotectin, colon-infiltrating interferon γ and interleukin-17-producing cells, serum and fecal levels of inflammatory cytokines. Conclusion: IDO-dependent expansion of endogenous Tregs should be further explored as a new approach for the induction and maintenance of mucosal healing in patients with UC.

Indoleamine 2,3-dioxygenase (IDO) has the most important role in modulation of tryptophan-dependent effects in the gastrointestinal tract, including modulation of intestinal immune response. An increased IDO activity maintains immune tolerance and attenuates ongoing inflammation but allows immune escape and uncontrolled growth of gastrointestinal tumors. Accordingly, IDO represents a novel therapeutic target for the treatment of inflammatory and malignant diseases of the gastrointestinal tract. In this review article, we summarize current knowledge about molecular and cellular mechanisms that are involved in IDO-dependent effects. We provide a brief outline of experimental and clinical studies that increased our understanding of how enhanced IDO activity: controls host–microbiota interactions in the gut; regulates detrimental immune response in inflammatory disorders of the gastrointestinal system; and allows immune escape and uncontrolled growth of gastrointestinal tumors. Additionally, we present future perspectives regarding modulation of IDO activity in the gut as possible new therapeutic approaches for the treatment of inflammatory and malignant diseases of the gastrointestinal system.