Docking studies, cytotoxicity evaluation and interactions of binuclear copper(ii) complexes with s-isoalkyl derivatives of thiosalicylic acid with some relevant biomolecules

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5′-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver

Cytotoxicity of glass ionomer cement on human exfoliated deciduous teeth stem cells correlates with released fluoride, strontium and aluminum ion concentrations

Stem cells from human exfoliated deciduous teeth (SHED) can be used as a cell-based therapy in regenerative medicine and in immunomodulation. Pulp from human deciduous teeth can be stored as a source of SHED. Glass ionomer cements (GICs) are commonly used in restorative dentistry and in cavity lining. GICs have lower biocompatibility and are cytotoxic for dental pulp cells. In this study, seven commonly used GICs were tested for their cytotoxic effects on SHED, for their potential to arrest mitosis in cells and induce chromosome aberrations, and were compared with the effects of composite. Fuji II, Fuji VIII, Fuji IX, Fuji plus and Vitrebond had significantly higher cytotoxic effects on SHED than composite. Only SHEDs that have been treated with Fuji I, Fuji IX, Fuji plus and composite recovered the potential for proliferation, but no chromosome aberrations were found after treatment with GICs. The cytotoxic effects of GICs on SHEDs were in strong correlation with combined concentrations of released fluoride, aluminum and strontium ions. Fuji I exhibited the lowest activity towards SHEDs; it did not interrupt mitosis and did not induce chromosome aberrations, and was accompanied by the lowest levels of released F, Al and Sr ions. Projekat Ministarstva nauke Republike Srbije, br. ON175069, br. ON175071 i br. ON175103

Phytochemical screening and biological activity of extracts of plant species Halacsya sendtneri (Boiss.) Dörfl.

This study is aimed at examining total polyphenol, flavonoid, gallotannin and condensed tannins content in acetone, chloroform, ethyl acetate and petroleum ether extracts of Halacsya sendtneri (Boiss.) Dörfl., their antimicrobial and antioxidant activities, as well as identifying and quantifying the phenolic components. The antioxidant activity is consistent with the results of total quantity of phenolic compound. The results showed that the acetone extract of plant species Halascya sendtneri (Boiss.) Dörfl. possessed the highest antioxidant activity. IC50 values were determined: 9.45��1.55 μg/mL for DPPH free radical scavenging activity, 13.46±1.68 μg/mL for inhibitory activity against lipid peroxidation, 59.11±0.83 μg/mL for hydroxyl radical scavenging activity and 27.91±0.88 μg/mL for ferrous ion chelating ability. The antimicrobial activity was tested using broth dilution procedure for determination of the minimum inhibitory concentration (MIC). The MICs were determined for 8 selected indicator strains. All of the extracts showed strong to moderate strong antimicrobial activity. The phenolic composition of Halacsya sendtneri extracts was determined by the HPLC method. The dominant phenolic compound in acetone, chloroform and ethyl acetate extract is rosmarinic acid. Ethyl acetate extract was also abundant in p-hydroxybenzoic acid and ferulic acid. The main compounds in petrol ether extract were chlorogenic acid and quercetin

Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy

Abstract Background The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated. Patients and methods This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position − 675 of the PAI-1 gene was detected by PCR-RFLP analysis. Results Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, − 675 4G/5G and − 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (− 675 4G/4G). Conclusion Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy

Galectin-3 Deficiency Accelerates High-Fat Diet-Induced Obesity and Amplifies Inflammation in Adipose Tissue and Pancreatic Islets

Obesity-induced diabetes is associated with low-grade inflammation in adipose tissue and macrophage infiltration of islets. We show that ablation of galectin-3 (Gal-3), a galactoside-binding lectin, accelerates high-fat diet-induced obesity and diabetes. Obese LGALS3(-/-) mice have increased body weight, amount of total visceral adipose tissue (VAT), fasting blood glucose and insulin levels, homeostasis model assessment of insulin resistance, and markers of systemic inflammation compared with diet-matched wild-type (WT) animals. VAT of obese LGALS3(-/-) mice exhibited increased incidence of type 1 T and NKT lymphocytes and proinflammatory CD11c(+)CD11b(+) macrophages and decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells and M2 macrophages. Pronounced mononuclear cell infiltrate, increased expression of NLRP3 inflammasome and interleukin-1 beta (IL-1 beta) in macrophages, and increased accumulation of advanced glycation end products (AGEs) and receptor for AGE (RAGE) expression were present in pancreatic islets of obese LGALS3(-/-) animals accompanied with elevated phosphorylated nuclear factor-kappa B (NF-kappa B) p65 and mature caspase-1 protein expression in pancreatic tissue and VAT. In vitro stimulation of LGALS3(-/-) peritoneal macrophages with lipopolysaccharide (LPS) and saturated fatty acid palmitate caused increased caspase-l-dependent IL-1 beta production and increased phosphorylation of NF-kappa B p65 compared with WT cells. Transfection of LGALS3(-/-) macrophages with NLRP3 small interfering RNA attenuated production in response to palmitate and LPS plus palmitate. Obtained results suggest important protective roles for Gal-3 in obesity-induced inflammation and diabetes.Serbian Ministry of Science and Technological Development [175071, 175069

Metformin Effects on Malignant Cells and Healthy PBMC; The Influence of Metformin on the Phenotype of Breast Cancer Cells

The aim of research was to determine the effects of maximally therapeutically achievable concentrations of metformin on malignant cells and healthy peripheral blood mononuclear cells (PBMC). Eight patients with T2D or hyperglycemia and nine healthy volunteers were included in the study. For determination of the influence of metformin on the phenotype of breast carcinoma, 1,410 patients with surgically removed tumors were included. From this group 37 breast cancer patients had DM type 2 or hyperglycemia and were pretreated with metformin alone or sometimes in combination with other antidiabetic drugs. Our results proved that metformin at low concentrations induced mild decrease in survival of malignant cells and PBMC stimulated for proliferation, but it didn't affect survival of resting PBMC. The effects of plasma of hyperglycemic patients who were under metformin therapy on autologous PBMC-induced decrease in survival of MDA-MB-361 cells, was noticeable in some patients. Metformin pretreatment for 24 h of HER2+ MDA-MB-361 cells, which were subsequently treated for 48 h with Herceptin, induced additional decline in cell survival. The analysis of influence of metformin on phenotype of breast cancer cells revealed significantly lower number of diabetic cancer patients treated with metformin with overexpressed HER2+ tumors (p lt 0.013), while the number of patients with ER+PR+ tumors was not significantly changed (p lt 0.832). In conclusion, therapeutically used concentrations of metformin exhibit mild cytotoxic action on malignant and dividing normal cells pointing to its preferred role in malignant and autoimmune diseases. The use of metformin was associated with pronounced decrease in HER2 overexpressing tumors

Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure

The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}(2)(-1,5-nphe)](ClO4)(2) (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (+/-)-1,2-propylenediamine (Pt3), trans-(+/-)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes