Publications by authors named "Zeljka Stanojevic"

10 Publications

  • Page 1 of 1

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts.

Immunity 2021 May 23;54(5):1002-1021.e10. Epub 2021 Mar 23.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum fuer Immuntherapie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2021.03.003DOI Listing
May 2021

Role of AMPK/mTOR-independent autophagy in clear cell renal cell carcinoma.

J Investig Med 2020 12 21;68(8):1386-1393. Epub 2020 Oct 21.

Institute of Microbiology and Immunology, University of Belgrade Faculty of Medicine, Belgrade, Serbia

We examined the status and role of autophagy, a process of lysosomal recycling of cellular material, in clear cell renal cell carcinoma (ccRCC). Paired samples of tumor and adjacent non-malignant tissue were collected from 20 patients with ccRCC after radical nephrectomy. The mRNA levels of apoptosis (, , , , ) and autophagy (, , , , ) regulators were measured by RT-qPCR. The protein levels of autophagosome-associated LC3-II, autophagy receptor p62, apoptotic marker PARP, as well as phosphorylation of autophagy initiator Unc 51-like kinase 1 (ULK1), its activator AMP-activated protein kinase (AMPK) and 4EBP1, the substrate of ULK1 inhibitor mechanistic target of rapamycin (mTOR), were analyzed by immunoblotting. The mRNA levels of pro-apoptotic , anti-apoptotic and pro-autophagic , and were higher in ccRCC tumors. Autophagy induction was confirmed by an increase in phospho-ULK1 and degradation of the autophagic target p62, while apoptotic PARP cleavage was unaltered. AMPK phosphorylation was reduced and 4EBP1 phosphorylation was increased in ccRCC tissue. The expression of apoptosis regulators did not correlate with clinicopathological features of ccRCC. Conversely, high mRNA levels of and were associated with lower tumor stage, as well as with smaller tumor size and better disease-specific 5-year survival ( and ). Accordingly, low p62 protein levels, corresponding to increased autophagic flux, were associated with lower tumor stage, reduced metastasis and improved 5-year survival. These data demonstrate that transcriptional induction of autophagy in ccRCC is accompanied by AMPK/mTOR-independent increase in ULK1 activation and autophagic flux, which might slow tumor progression and metastasis independently of apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jim-2020-001524DOI Listing
December 2020

Influence of preoperative statins and aspirin administration on biological and magnetic resonance imaging properties in patients with abdominal aortic aneurysm.

Vasa 2021 Feb 16;50(2):116-124. Epub 2020 Jul 16.

School of Medicine, University of Belgrade, Serbia.

: Main objective of this study was to evaluate the influence of statins and/or acetylsalicylic acid on biochemical characteristics of abdominal aortic aneurysm (AAA) wall and intraluminal thrombus (ILT). : Fifty patients with asymptomatic infrarenal AAA were analyzed using magnetic resonance imaging on T1w sequence. Relative ILT signal intensity (SI) was determined as a ratio between ILT and psoas muscle SI. Samples containing the full ILT thickness and aneurysm wall were harvested from the anterior surface at the level of the maximal diameter. The concentration of enzymes such as matrix metalloproteinase (MMP) 9, MMP2 and neutrophil elastase (NE/ELA) were analyzed in ILT and AAA wall; while collagen type III, elastin and proteoglycan 4 were analyzed in harvested AAA wall. Oxidative stress in the AAA wall was assessed by catalase and malondialdehyde activity in tissue samples. : Relative ILT signal intensity (1.09 ± 0.41 vs 0.89 ± 0.21, p = 0.013) were higher in non-statin than in statin group. Patients who were taking aspirin had lower relative ILT area (0.89 ± 0.19 vs 1.13. ± 0.44, p = 0.016), and lower relative ILT signal intensity (0.85 [0.73-1.07] vs 1.01 [0.84-1.19], p = 0.021) compared to non-aspirin group. There were higher concentrations of elastin in AAA wall among patients taking both of aspirin and statins (1.21 [0.77-3.02] vs 0.78 (0.49-1.05) ng/ml, p = 0.044) than in patients who did not take both of these drugs. : Relative ILT SI was lower in patients taking statin and aspirin. Combination of antiplatelet therapy and statins was associated with higher elastin concentrations in AAA wall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/0301-1526/a000895DOI Listing
February 2021

Magnetic resonance imaging assessment of proteolytic enzyme concentrations and biologic properties of intraluminal thrombus in abdominal aortic aneurysms.

J Vasc Surg 2020 09 14;72(3):1025-1034. Epub 2020 Feb 14.

School of Medicine, University of Belgrade, Belgrade, Serbia; Clinic for Vascular and Endovascular Surgery, Clinical Center of Serbia, Belgrade, Serbia.

Objective: The aim of the study was to determine whether magnetic resonance imaging (MRI) can be used in assessment of biologic activity of intraluminal thrombus (ILT) and proteolytic processes of the abdominal aortic aneurysm wall.

Methods: Using MRI, 50 patients with asymptomatic infrarenal abdominal aortic aneurysm were analyzed at the maximum aneurysm diameter on T1-weighted images in the arterial phase after administration of contrast material. Relative ILT signal intensity (SI) was determined as the ratio between ILT SI and psoas muscle SI. During surgery, the full thickness of the ILT and the adjacent part of the aneurysm wall were harvested at the maximal diameter for biochemical analysis. The concentrations of matrix metalloproteinase 9 and neutrophil elastase (NE/ELA) were analyzed in harvested thrombi, and the concentrations of collagen type III, elastin, and proteoglycans were analyzed in harvested aneurysm walls.

Results: A significant positive correlation was found between the NE/ELA concentration of the ILT and the relative SI (ρ = 0.309; P = .029). Furthermore, a negative correlation was observed between the elastin content of the aneurysm wall and the relative SI (ρ = -0.300; P = .034). No correlations were found between relative SI and concentration of matrix metalloproteinase 9, NE/ELA, collagen type III, or proteoglycan 4 in the aneurysm wall.

Conclusions: These findings indicate a potential novel use of MRI in prediction of thrombus proteolytic enzyme concentrations and the extracellular matrix content of the aneurysm wall, thus providing additional information for the risk of potential aneurysm rupture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2019.11.032DOI Listing
September 2020

Effects of Sideritis scardica Extract on Glucose Tolerance, Triglyceride Levels and Markers of Oxidative Stress in Ovariectomized Rats.

Planta Med 2019 Apr 28;85(6):465-472. Epub 2019 Jan 28.

Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.

Menopause is characterized by deep metabolic disturbances, including decreased insulin sensitivity, adiposity, and changes in lipid profiles. Estrogen replacement therapy can partially reverse these changes, and while it is safe in most healthy postmenopausal women, there are still existing concerns regarding an increased risk for breast and endometrial cancer as well as a risk for cardiovascular and thromboembolic disease. Therefore, certain natural compounds with positive metabolic effects may be considered as a possible alternative or adjunctive treatment in patients not willing to take estrogens or patients with contraindications for estrogens. The aim of this study was to investigate the influence of (mountain tea) extract on metabolic disturbances induced by ovariectomy in rats. The study included 24 rats divided into three groups: ovariectomized rats treated with 200 mg/kg extract for 24 weeks (n = 8), ovariectomized non-treated (n = 8), and Sham-operated (n = 8) rats. Food intake, weight gain, body composition, fasting glucose levels, response to oral glucose challenge, liver glycogen content, catalase activity, thiol groups, and malondialdehyde concentrations as well as AMP-activated protein kinase activity in liver cells were studied. Ovariectomized rats treated with extract had lower blood triglycerides, reduced fasting glucose levels, as well lower glucose peaks after oral glucose challenge, increased liver glycogen content, and significantly higher catalase activity and thiol group concentration than non-treated ovariectomized rats. The ability of extract to attenuate metabolic disturbances associated with ovariectomy was associated with the activation of AMP-activated protein kinase in liver cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0835-6622DOI Listing
April 2019

Standardized L. leaf extract exhibits protective activity in carbon tetrachloride-induced acute liver injury in rats: the insight into potential mechanisms.

Arch Physiol Biochem 2020 Dec 11;126(5):399-407. Epub 2019 Jan 11.

Biomedical Research, R&D Institute, Galenika a.d., Belgrade, Serbia.

The protective activity of dry olive leaf extract (DOLE) in carbon tetrachloride (CCl)-induced liver damage and possible mechanisms involved in this protection were investigated in rats. Acute CCl intoxication resulted in a massive hepatic necrosis, in increased serum transaminases, and in a perturbation of oxidative stress parameters in liver tissue [malondyaldehide, glutathione (GSH), catalase]. CCl did not affect the expression of caspase-3 and cytochrome c as markers of apoptosis; however, CCl increased the AMP-activated protein kinase (AMPK) activity and the expression of autophagy-related protein LC3II and decreased the expression of p62 protein. The pre-treatment with DOLE significantly improved serum markers of liver damage, liver catalase activity, and GSH concentration, suggesting that antioxidative mechanism is responsible for hepatoprotection. Oral administration of DOLE did not influence LC3II conversion and p62 degradation in liver, but AMPK activity was significantly decreased, suggesting the energy balance perturbation as an additional potential mechanism of DOLE hepatoprotective effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13813455.2018.1550095DOI Listing
December 2020

Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats.

Neuropharmacology 2019 03 22;146:95-108. Epub 2018 Nov 22.

Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 1, 11000, Belgrade, Serbia. Electronic address:

We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0-32), while the protection was less pronounced if the treatment was limited to the induction (day 0-7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-γ-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.11.030DOI Listing
March 2019

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats.

J Neurochem 2015 Oct 15;135(1):125-38. Epub 2015 Jul 15.

Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.

Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2 /5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, TH 1 cytokine IFN-γ, TH 17 cytokine IL-17, as well as the signature transcription factors of TH 1 (T-bet) and TH 17 (RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.13198DOI Listing
October 2015

CXCL12 expression within the CNS contributes to the resistance against experimental autoimmune encephalomyelitis in Albino Oxford rats.

Immunobiology 2011 Sep 7;216(9):979-87. Epub 2011 Apr 7.

Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Serbia.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis, a chronic inflammatory and demyelinating disease of the CNS. Albino Oxford (AO) rats are resistant to the induction of EAE, while the disease can be readily induced in Dark Agouti (DA) rats. Here we investigated a potential contribution of the CNS milieu in the limitation of the encephalitogenic autoimmune response. EAE was induced by immunization of the respective rat strains with spinal cord homogenate emulsified in complete Freund's adjuvant. AO rats did not exhibit clinical signs after immunization while DA rats developed severe neurologic deficits. Infiltration of immune cells into spinal cords (SC) was evident in both strains 12-14 days after the immunization. EAE lesions of AO rats contained substantially lower numbers of CD4+ T cells and CD11b+ cells compared to those in DA rats. This went together with lower levels of interferon (IFN)-γ and interleukin (IL)-17 in the cells isolated from SC. We found a dramatic increase of CXCL12 expression in SC tissue and microvessels of AO rats, whereas DA rats markedly decreased the expression of this chemokine within their CNS. Administration of the CXCL12 antagonist AMD3100 to a substrain of AO rats that developed a weak EAE led to earlier onset and exacerbation of the disease. These results suggest a role of CXCL12 in down-regulating autoimmune processes in AO rats during EAE. Therapeutic modulation of CXCL12 could be a promising strategy for the treatment of CNS autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imbio.2011.03.013DOI Listing
September 2011

It is still not for the old iron: adjuvant effects of carbonyl iron in experimental autoimmune encephalomyelitis induction.

J Neurochem 2011 Jul;118(2):205-14

Department of Immunology, Institute for Biological Research Siniša Stanković, University of Belgrade, Belgrade, Serbia.

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis. Dark Agouti rats immunized with spinal cord homogenate (SCH) and carbonyl iron (CI), as an adjuvant, develop severe hyperacute form of EAE. They succumb to EAE earlier and have higher clinical scores and lethality rate in comparison to counterparts immunized with SCH + complete Freund's adjuvant. There is no difference in the number of cells or in histological presentation of the CNS infiltrates of rats immunized with the two adjuvants. However, there are more granulocytes, NK and NKT cells, and less CD4(+) T cells in the spinal cord infiltrates of SCH + CI-immunized animals. Nitric oxide (NO)-generating enzyme inducible NO synthase have higher expression in spinal cord of SCH + CI-immunized rats, and this corresponds to more intensive nitrotyrosine formation in the CNS tissue of these rats. Abundant infiltration of granulocytes and NK cells into the CNS and excessive generation of peroxynitrite within the CNS of SCH + CI-immunized rats might account for the severe neurological deficits induced by immunization with CI. These factors should be closely examined in the fulminant forms of multiple sclerosis and acute disseminated encephalomyelitis, as they could represent a promising targets for therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2011.07303.xDOI Listing
July 2011
-->