Медицински факултет [Научни радови] / Faculty of Medicine [Scientific papers]
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- СтавкаSitagliptin Induces Tolerogenic Human Dendritic Cells(MDPI, 2023) Drakul, Marija; Tomić, Sergej; Bekić, Marina; Mihajlović, Dušan; Vasiljević, Miloš; Rakočević, Sara; Ðokić, Jelena; Popović, Nikola; Bokonjić, Dejan; Čolić, MiodragSitagliptin, 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-y treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 g/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- , 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- ) 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- + 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.
- СтавкаEssential Oil of Satureja montana L. from Herzegovina: Assessment of Composition, Antispasmodic, and Antidiarrheal Effects(ACG Publications, 2023) Kulić, Milan; Drakul, Dragana; Sokolović, Dragana; Kordić-Bojinović, Jelena; Milovanović, Slobodan; Blagojević, DuškoSatureja montana L. (SM) has a long traditional use as a spice and a medicine for various gastrointestinal disorders, including painful spasms and diarrhea. Contrary to conventional drugs, administration of SM and its extracts are considered safe. Previous studies have shown that the essential oils (EOs) of SM from different areas are rich in monoterpenes, sesquiterpenes, diterpens, and phenolic compounds, including flavonoids, tannins, and acids with great composition variability. Determination of composition of EO from Herzegovinian SM done by gas chromatographyflame ionization detection and gas chromatography mass spectrometry (GC-FID and GC/MS, respectively) revealed carvacrol as a primary substance followed by γ-terpinene, p-cymene, and β-caryophyllene. Ex vivo spasmolitic activity caused by EO was evident in different types of isolated rat ileum function with the most potent effect on spontaneous activity followed by electrical field stimulation and KCl- and CaCl2-induced activity. SMEO produced in vivo antidiarreal activity on castor oil-induced diarrhea in young rats and showed the potential to cause a decrese water content in the feces of adult Wistar rats.This study indicates that effects of SM on the intestinum could be mediated through combination of Kv channel activation and Ca channel blockade, but additional mechanisms might be involved. The results of this study corroborate the traditional use of SM as antispasmodic, antidiarrheal, and antisecretory agents.
- СтавкаRenal Manifestations of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome: A Systematic Review of 71 Cases(MDPI, 2023) Dagnon da Silva, Marilia; Domingues, Sidney Marcel; Oluic, Stevan; Radovanovic, Milan; Kodela, Pratyusha; Nordin, Terri; Paulson, Margaret R.; Joksimović, Bojan; Adetimehin, Omobolanle; Singh, Devender; Madrid, Cristian; Cardozo, Milena; Baralic, Marko; Dumic, IgorUnlike other adverse drug reactions, visceral organ involvement is a prominent feature of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and correlates with mortality. The aim of this study was to systematically review cases published in PubMed-indexed, peer-reviewed journals in which patients had renal injury during the episode of DRESS syndrome (DS).We found 71 cases, of which 67 were adults and 56% were males. Female sex was associated with higher mortality. Chronic kidney disease (CKD) was present in 14% of patients who developed acute kidney injury (AKI) during DS. In 21% of cases, the kidneys were the only visceral organ involved, while 54% of patients had both liver and kidney involvement. Eosinophilia was absent in 24% of patients. The most common classes of medication associated with renal injury in DS were antibiotics in 34%, xanthine oxidase inhibitors in 15%, and anticonvulsants in 11%. Among antibiotics, vancomycin was the most common culprit in 68% of patients. AKI was the most common renal manifestation reported in 96% of cases, while isolated proteinuria or hematuria was present in only 4% of cases. In cases with AKI, 88% had isolated increase in creatinine and decrease in glomerular filtration (GFR), 27% had AKI concomitantly with proteinuria, 18% had oliguria, and 13% had concomitant AKI with hematuria. Anuria was the rarest manifestation, occurring in only 4% of patients with DS. Temporary renal replacement therapy was needed in 30% of cases, and all but one patient fully recovered renal function. Mortality of DS in this cohort was 13%, which is higher than previously reported. Medication class, latency period, or pre-existing CKD were not found to be associated with higher mortality. More research, particularly prospective studies, is needed to better recognize the risks associated with renal injury in patients with DS. The development of disease-specific biomarkers would also be useful so DS with renal involvement can be easier distinguished from other eosinophilic diseases that might affect the kidney.
- СтавкаPeriodontal Disease in Young Adults as a Risk Factor for Subclinical Atherosclerosis: A Clinical, Biochemical and Immunological Study(MDPI, 2023) Cicmil, Smiljka; Cicmil, Ana; Pavlic, Verica; Krunić, Jelena; Sladoje Puhalo, Dragana; Bokonjić, Dejan; Čolić, MiodragAlthough 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- 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.
- СтавкаNew in vitro findings about halogenated boroxine cytotoxicity and deregulation of cell death-related genes in GR-M melanoma cells(Institute for Medical Research and Occupational Health, 2023) Elez-Burnjaković, Nikolina; Pojskić, Lejla; Haverić, Anja; Lojo-Kadrić, Naida; Hadžić Omanović, Maida; Ramić, Jasmin; Smajlović, Ajla; Maksimović, Milka; Haverić, SaninAnti-proliferative effects of halogenated boroxine – K2(B3O3F4OH) (HB) – have been confirmed in multiple cancer cell lines, including melanoma, but the exact mechanism of action is still unknown. This study aimed to determine its cytotoxic effects on human Caucasian melanoma (GR-M) cell growth in vitro as well as on the expression of cell death-related genes BCL-2, BECN1, DRAM1, and SQSTM1. GR-M and peripheral blood mononuclear (PBM) cells were treated with different HB concentrations and their growth inhibition and relative gene expression profiles were determined using the Alamar blue assay and real-time PCR. HB significantly inhibited cell growth of both GR-M and PBM cells but was even more effective in GR-M melanoma cells, as significant inhibition occurred at a lower HB concentration of 0.2 mg/mL. GR-M BCL-2 expression was significantly downregulated (P=0.001) at HB concentration of 0.4 mg/mL, which suggests that HB is a potent tumour growth inhibitor. At the same time, it upregulated BCL-2 expression in normal (PBM) cells, probably by activating protective mechanisms against induced cytotoxicity. In addition, all but the lowest HB concentrations significantly upregulated SQSTM1 (P=0.001) in GR-M cells. Upregulated BECN1 expression suggests early activation of autophagy at the lowest HB concentration in SQSTM1 cells and at all HB concentrations in PBM cells. Our findings clearly show HB-associated cell death and, along with previous cytotoxicity studies, reveal its promising anti-tumour potential