Cytotoxic effects of selected gold(III) complexes on the murine BCL-1 B lineage leukaemia cell line

In recent years, gold(III) complexes have attracted great interest because of their cytotoxicity to cancer cells. We investigated the cytotoxic effects of three newly synthesised gold(III) complexes, [Au(en)Cl 2] + (dichloride (ethylendiamine) aurate(III)-ion), [Au(dach)Cl 2] (dichloride (1,2- diaminocyclohexane) aurate(III)-ion) and [Au(bipy)Cl 2] + (dichloride (2,2'-bipyridyl) aurate(III)-ion), on the murine BCL-1 B lineage leukaemia cell line. The cytotoxicity of these gold(III) complexes was evaluated by cytotoxic assay (MTT test). The results showed that all of the tested gold(III) complexes displayed a cytotoxic effect on BCL-1 cells. The concentration decrease was followed by a marked increase in BCL-1 cell viability. At a concentration of 125 μM, which we suppose could be used in vivo, the [Au(bipy)Cl 2] + complex showed the greatest cytotoxic effects among the tested gold(III) complexes and similar cytotoxicity asto the cisplatinum that we used as control. Among the tested gold(III) complexes, [Au(en)Cl 2] +was the least cytotoxic to BCL-1 cells. In line with the obtained results, we suggest that the [Au(bipy)Cl 2] + complex should be tested in vivo in experimental models of B cell leukaemia

Possible role of TGF-B pathways in schizophrenia

© 2016, University of Kragujevac, Faculty of Science. All Rights Reserved. The phenomenological uniqueness of each patient with schizophrenia is determined by complex symptomatology, particularly the overlapping of symptoms and their prominence in certain phases of this mental disorder. Establishing biological markers is an important step in the further objectivisation and quantification of schizophrenia. Identifying the cytokine profiles that precede a psychotic episode could direct the strategies for relapse prevention and be useful in predicting disease progression and treatment response. In the context of inflammation, TGF-β exerts potent anti-inflammatory and immunosuppressive functions by inhibiting pro-inflammatory cytokine synthesis, but it can also have pro-inflammatory functions through its stimulatory effects on inflammatory 17 cells. It has been shown that the T helper cell type-1 and type-17 responses are reduced and type-2 response is increased in patients with schizophrenia. Both data from the literature and our results also indicate the presence of an anti-inflammatory response through production of the TGF-β regulatory cytokine. A meta-analysis of plasma cytokine alterations suggested that TGF-β is the state marker for acute exacerbation of schizophrenia, and we showed that TGF-β can also be a valuable marker for psychosis. Hyperactivity of TGF-β signalling pathways in schizophrenia may be both a neuroprotective mechanism and a possible therapeutic target

IL-33/ST2 axis in innate and acquired immunity to tumors

Interleukin-33, a ligand for ST2/T1, has an important role in allergy, autoimmunity and inflammation. The role of IL-33/ST2 axis in cancer is not elucidated. Using metastatic breast cancer model we provide evidence that lack of ST2 signaling led to reduced tumor growth and metastasis and enhanced anti-tumor immunity

Mesenchymal stem cells attenuate acute liver failure by promoting expansion of regulatory T cells in an indoleamine 2,3-dioxygenase-dependent manner

© 2020, University of Kragujevac, Faculty of Science. All rights reserved. The influence of mesenchymal stem cells (MSCs) on the phenotype and function of CD4+CD49b+FoxP3-regulatory cells has not been elucidated. We used Concanavalin A (ConA)-and α-galactosylceramide (α-GalCer)-induced acute liver injury to estimate the effects of MSCs on liver-infiltrating CD4+CD49b+FoxP3-regulatory cells. MSCs significantly reduced ConA-and α-GalCer-mediated liver injury in C57BL/6 mice, as demonstrated by biochemical tests, reduced influx of inflammatory CD4+ T cells, and increased presence of CD4+CD49b+FoxP3-regulatory cells in the injured livers. The number of CD4+CD49b+FoxP3-regulatory cells was also significantly increased in α-GalCer-treated mice that received MSC-derived condi-tioned medium (MSC-CM). The presence of 1-methyltryp-tophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), in MSC-CM completely abrogated the hepatopro-tective effect of MSCs and significantly decreased the total number of liver-infiltrated CD4+CD49b+FoxP3-regulatory cells, indicating the crucial importance of MSC-derived IDO for the expansion of CD4+CD49b+FoxP3-regulatory cells and the consequent MSC-dependent attenuation of acute liver injury

Galectin-3 Deficiency Facilitates TNF-α-Dependent Hepatocyte Death and Liver Inflammation in MCMV Infection

Galectin-3 (Gal-3) has a role in multiple inflammatory pathways. Various, opposite roles of Gal-3 in liver diseases have been described but there are no data about the role of Gal-3 in development of hepatitis induced with cytomegalovirus infection. In this study we aimed to clarify the role of Gal-3 in murine cytomegalovirus (MCMV)-induced hepatitis by using Gal-3-deficient (Gal-3 KO) mice. Here we provide the evidence that Gal-3 has the protective role in MCMV-induced hepatitis. Enhanced hepatitis manifested by more inflammatory and necrotic foci and serum level of ALT, enhanced apoptosis and necroptosis of hepatocytes and enhanced viral replication were detected in MCMV-infected Gal-3 deficient mice. NK cells does not contribute to more severe liver damage in MCMV-infected Gal-3 KO mice. Enhanced expression of TNF-α in the hepatocytes of Gal-3 KO mice after MCMV infection, abrogated hepatocyte death, and attenuated inflammation in the livers of Gal-3 KO mice after TNF-α blockade suggest that TNF-α plays the role in enhanced disease in Gal-3 deficient animals. Treatment with recombinant Gal-3 reduces inflammation and especially necrosis of hepatocytes in the livers of MCMV-infected Gal-3 KO mice. Our data highlight the protective role of Gal-3 in MCMV-induced hepatitis by attenuation of TNF-α-mediated death of hepatocytes

IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis

Schizophrenia and treatment of this disorder are often accompanied with metabolic syndrome and cardiovascular issues. Alterations in the serum level of innate immune mediators, such as interleukin-33 (IL-33) and its receptor IL-33R (ST2) and Galectin-3 (Gal-3) were observed in these conditions. Moreover, these parameters are potential prognostic and therapeutic markers. There is also accumulating evidence that these molecules play a role in neuroinflammation. Therefore, in this study we have investigated the serum level of Gal-3, IL-33 and soluble ST2 (sST2) in different stages of schizophrenia. Gal-3 levels were elevated in remission and lower in schizophrenia exacerbation in comparison with controls. Levels of IL-33 and sST2 are higher in schizophrenia exacerbation in comparison with controls and patients in remission. This initial analysis of new markers of neuroinflammation suggested their involvement in schizophrenia pathophysiology and/or cardiometabolic comorbidity

IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice

Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Prevention of type 1 diabetes requires early intervention in the autoimmune process against beta-cells of the pancreatic islets of Langerhans, which is believed to result from disordered immunoregulation. CD4+Foxp3+ regulatory T cells (Tregs) participate as one of the most important cell types in limiting the autoimmune process. The aim of this study was to investigate the effect of exogenous IL-33 in multiple low dose streptozotocin (MLD-STZ) induced diabetes and to delineate its role in the induction of protective Tregs in an autoimmune attack. C57BL/6 mice were treated i. p. with five doses of 40 mg/kg STZ and 0.4 μg rIL-33 four times, starting from day 0, 6, or 12 every second day from the day of disease induction. 16 weeks old NOD mice were treated with 6 injections of 0.4 μg/mouse IL-33 (every second day). Glycemia and glycosuria were measured and histological parameters in pancreatic islets were evaluated at the end of experiments. Cellular make up of the pancreatic lymph nodes and islets were evaluated by flow cytometry. IL-33 given simultaneously with the application of STZ completely prevented the development of hyperglycemia, glycosuria and profoundly attenuated mononuclear cell infiltration. IL-33 treatment was accompanied by higher number of IL-13 and IL-5 producing CD4+ T cells and increased presence of ST2+Foxp3+ regulatory T cells in pancreatic lymph nodes and islets. Elimination of Tregs abrogated protective effect of IL-33. We provide evidence that exogenous IL-33 completely prevents the development of T cell mediated inflammation in pancreatic islets and consecutive development of diabetes in C57BL/6 mice by facilitating the induction Treg cells. To extend this finding for possible relevance in spontaneous diabetes, we showed that IL-33 attenuate insulitis in prediabetic NOD mice

Gal-3 plays an important pro-inflammatory role in the induction phase of acute colitis by promoting activation of NLRP3 inflammasome and production of IL-β in macrophages

BACKGROUND AND AIMS: Galectin-3 [Gal-3] is an endogenous lectin with a broad spectrum of immunoregulatory effects: it plays an important role in autoimmune/inflammatory and malignant diseases, but the precise role of Gal-3 in pathogenesis of ulcerative colitis is still unknown. METHODS: We used a model of dextran sulphate sodium [DSS]-induced acute colitis. The role of Gal-3 in pathogenesis of this disease was tested by evaluating disease development in Gal-3 deficient mice and administration of Gal-3 inhibitor. Disease was monitored by clinical, histological, histochemical, and immunophenotypic investigations. Adoptive transfer was used to detect cellular events in pathogenesis. RESULTS: Genetic deletion or pharmacological inhibition of Gal-3 significantly attenuate DSS-induced colitis. Gal-3 deletion suppresses production of pro-inflammatory cytokines in colonic macrophages and favours their alternative activation, as well as significantly reducing activation of NOD-like receptor family, pyrin domain containing 3 [NLRP3] inflammasome in macrophages. Peritoneal macrophages isolated from untreated Gal-3(-/-) mice and treated in vitro with bacterial lipopolysaccharide or DSS produce lower amounts of tumour necrosis factor alpha [TNF-α] and interleukin beta [IL-1β] when compared with wild type [WT] cells. Genetic deletion of Gal-3 did not directly affect total neutrophils, inflammatory dendritic cells [DCs] or natural killer [NK] T cells. However, the total number of CD11c+ CD80+ DCs which produce pro-inflammatory cytokines, as well as TNF-α and IL-1β producing CD45+ CD11c- Ly6G+ neutrophils were significantly lower in colons of Gal-3(-/-) DSS-treated mice. Adoptive transfer of WT macrophages significantly enhanced the severity of disease in Gal-3(-/-) mice. CONCLUSIONS: Gal-3 expression promotes acute DSS-induced colitis and plays an important pro-inflammatory role in the induction phase of colitis by promoting the activation of NLRP3 inflammasome and production of IL-1β in macrophages

A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma

Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR-/low, CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) lt 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI

Galectin-3 in inflammasome activation and primary biliary cholangitis development

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development