Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives

Derivatives of 2-amino-5-benzylthiazole are heterocyclic pharmacophores that exhibit different pharmacological activities including anticancer action. The mechanisms of such action of these compounds are not clear. The aim of the present study was to investigate apoptosis induction, particularly DNA damage in human leukemia cells, by the novel synthesized thiazole derivatives ‒ 2,8-dimethyl-7-(3-trifluoromethyl-benzyl)pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 1) and 7-benzyl-8-methyl-2-propylpyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 2). Western-blot analysis, DNA comet assay in alkaline conditions, diphenylamine DNA fragmentation assay, agarose gel retardation, and methyl green DNA intercalation assays were used to study the effects of the studied compounds in human leukemia cells. These compounds induced PARP1 and caspase 3 cleavage in the leukemia cells, also increased the level of pro-apoptotic Bim protein and the mitochondrion-specific EndoG nuclease, and decreased the level of the anti-apoptotic Bcl-2 protein. They caused DNA single-strand breaks and DNA fragmentation in the leukemia cells without direct DNA binding or DNA intercalation. Thus, novel 2-amino-5-benzylthiazole derivatives may be promising agents for apoptosis induction in the targeted human leukemia cells

Processes of lipopero­xidation and respiration of mitochondria in rat liver under the action of thiazoles derivatives in vitro

One of the main problems of chemotherapy is development of negative side effects, when anti-tumor drugs damage healthy cells, in particular hepatocytes. Liver is the main detoxifying organ in human and animals. This organ plays an important role in the excretion of drugs from the body. Changes in free radical oxidation processes and respiratory function of mitochondria in liver cells following the effects of newly synthesized antitumor agents may indicate adverse side effects that often occur after taking such substances. It was shown that thiazole derivatives passess anti-neoplastic activity against cancer cells in vitro. The influence in vitro of newly synthesized derivatives of thiazoles (N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide and 8-methyl-2-Me-7-[tri­fluoro­methyl-phenylmethyl]-pyrazolo-[4,3-e]-[1,3]-thiazolo-[3,2-a]-pyrimidin-4(2H)-one) in concentarion of 1, 10 and 50 mM on lipid peroxidation processes in hepatocyte membranes, respiration and oxidative phosphorylation in rat liver mitochondria was studied. The effects of these substances did not reveal changes in the products of the primary peroxide lipid oxidation, and the content of secondary products was significantly reduced. Such results may indicate that the studied substances might to interact with the active forms of Oxygen, while the antioxidant defense system was not changed. These results may also indirectly indicate that the thiazole derivatives not only do not activate, but also decrease the formation of peroxide oxidation products. The processes of respiration and oxidative phosphorylation in liver mitochondria practically did not change due to the influence of the studied thiazole derivatives. The only exceptions when energy changes were observed at using high doses (50 mM) of substances with nonselective effects. Since the studied thiazole derivatives, as shown earlier, exhibit high cytotoxicity to cancer cells, these substances can be applied as antitumor drugs with minimal negative side effects

Activity of antioxidant enzymes in hepatocytes of mice with lymphoma under the action of thiazole derivative in complex with polymeric nanocarrier

Many chemotherapeutics drugs have low water solubility, which potentially can decrease their anticancer potential. The use of drug delivery systems has proven to be highly effective in addressing the challenges associated with delivering hydrophobic chemotherapy drugs to tumor tissues. However, two major issues that arise in the clinical nanoparticle-based treatment of cancer are hepatotoxicity and suppression of the hematopoietic system, which can limit their medical applicability. As previously established, thiazole derivative N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide in complex with polymeric nanocarriers (nanomicelles) based on polyethylene glycol exhibited a greater level of cytotoxicity towards specific tumor cell lines melanoma, glioblastoma, hepatocarcinoma, leukemia, etc. This compound and its complexes with polymeric nanomicelle significantly changed the activity of antioxidant enzymes in lymphoma cells. Therefore, the purpose of this study was to examine the impact of a thiazole derivative with polymeric nanomicelles based on polyethylene glycol on the hepatocytes (liver cells) of mice that had been implanted with Nemet-Kelner lymphoma. The investigated compounds thiazole derivative, polymeric nanomicelle, and combination of thiazole derivative with nanomicelle at a final concentration of 10 μM were added to the liver samples and incubated for 10 min. The activity of antioxidant defense system enzymes such as superoxiddismutase, catalase, glutathionperoxidase was determined in liver homogenate under the action of studied compounds in vitro. It was reported that neither thiazole derivative, nanomicelle, nor their complex changed the activity of antioxidant enzymes in hepatocytes from mice with lymphoma. Thiazole derivative and it complex with nanomicelle had limited negative side effects in the mice with lymphoma. The investigated compounds were not hepatotoxic toward murine liver cells

Prooxidant and antioxidant processes in lymphoma cells under the action of pyrazolopyrimidine derivative

Background. The influence in vitro of thiazole derivative 8-methyl-2-Me-7-[trifluoro­methyl-phenylmethyl]-pyrazolo-[4,3-e]-[1,3]-thiazolo-[3,2-a]-pyrimidin-4(2H)-one (PP2) on the level of lipid peroxidation products, superoxide anion radical and antioxidant system activity in lymphoma cells was studied. A pronounced cytotoxic action of the thiazole derivative on the tumor cells in vitro was reported earlier, however, no cytotoxicity of this substance was detected toward non-cancerous cells. In addition, it was shown that the sca­vengers of active forms of Oxygen significantly reduced the cytotoxic effect of the studied compound. The purpose of this work was to investigate the effect of 8-methyl-2-Me-7-[trifluoromethyl-phenylmethyl]-pyrazolo-[4,3-e]-[1,3]-thiazolo-[3,2-a]-pyrimidin-4(2H)-one on the content of lipid peroxidation products, superoxide radical and the activity of enzymes of antioxidant defense in the lymphoma cells. Materials and Methods. Experiments were conducted on white wild-type male mice with grafted NK/Ly lymphoma. Ascites tumor cells were passaged by the intreperitoneal inoculation to mice. Abdominal drainage with ascites was performed with a sterile syringe under ether anesthesia. PP2 was dissolved in dimethylsulfoxide. The product content and enzymatic activity were determined spectrophotometrically. Statistical analysis of obtained results was carried out using MS Excel-2013 program. Results. The influence of the pyrazolopyrimidine derivative on the content of lipid peroxidation products and superoxide radical in lymphoma cells was investigated. It was found that the studied compound did not change the amount of the primary lipid peroxidation products, but reduced the amount of secondary products. A decrease in the MDA content under the action of the studied derivative indicates probable interaction of the substance with the reactive Oxygen species. Pyrazolopyrimidine derivative did not change the level of the superoxide radical. The effect of the thiazole derivative on the activity of key enzymes of the antioxidant system in lymphoma cells was investigated. The studied compound at the concentration of 10 µM activated superoxide dismutase. Pyrazolopyrimidine derivative decreased the activity of catalase and glutathione peroxidase. Such changes in the activity of enzymes can cause the growth of hydrogen peroxide in the cell, which is toxic in large quantities. Conclusions. The obtained results may indicate that the studied pyrazolopyrimidine derivative can realize its cytotoxic effect on lymphoma cells though the action on the pro­ducts of lipid peroxidation and antioxidant system activity. These data can be used to understand the mechanism of action of the studied compounds and for further improvement of their antitumor effect

Comprehensive gene expression profiling reveals synergistic functional networks in cerebral vessels after hypertension or hypercholesterolemia.

Atherosclerotic stenosis of cerebral arteries or intracranial large artery disease (ICLAD) is a major cause of stroke especially in Asians, Hispanics and Africans, but relatively little is known about gene expression changes in vessels at risk. This study compares comprehensive gene expression profiles in the middle cerebral artery (MCA) of New Zealand White rabbits exposed to two stroke risk factors i.e. hypertension and/or hypercholesterolemia, by the 2-Kidney-1-Clip method, or dietary supplementation with cholesterol. Microarray and Ingenuity Pathway Analyses of the MCA of the hypertensive rabbits showed up-regulated genes in networks containing the node molecules: UBC (ubiquitin), P38 MAPK, ERK, NFkB, SERPINB2, MMP1 and APP (amyloid precursor protein); and down-regulated genes related to MAPK, ERK 1/2, Akt, 26 s proteasome, histone H3 and UBC. The MCA of hypercholesterolemic rabbits showed differentially expressed genes that are surprisingly, linked to almost the same node molecules as the hypertensive rabbits, despite a relatively low percentage of 'common genes' (21 and 7%) between the two conditions. Up-regulated common genes were related to: UBC, SERPINB2, TNF, HNF4A (hepatocyte nuclear factor 4A) and APP, and down-regulated genes, related to UBC. Increased HNF4A message and protein were verified in the aorta. Together, these findings reveal similar nodal molecules and gene pathways in cerebral vessels affected by hypertension or hypercholesterolemia, which could be a basis for synergistic action of risk factors in the pathogenesis of ICLAD

Evaluation of antiproliferative activity of pyrazolothiazolopyrimidine derivatives

The research aim was to test cytotoxic effects in vitro of seven novel pyrazolothiazolopyrimidine derivatives in targeting several lines of tumor and pseudo-normal mammalian cells. We demonstrated that cytotoxic effects of these derivatives depended on the tissue origin of targeted cells. Leukemia cells were found to be the most sensitive to the action of compounds 2 and 7. Compound 2 demonstrated approximately two times higher toxicity towards the multidrug-resistant sub-line of HL-60/ADR cells compared to the Doxorubicin effect. Antiproliferative action of compounds 2 and 7 dropped in the order: leukemia > melanoma > hepatocarcinoma > glioblastoma > colon carcinoma > breast and ovarian carcinoma cells. These compounds were less toxic than Doxorubicin towards the non-tumor cells. The novel pyrazolothiazolopyrimidine, compound 2, demonstrated high toxicity towards human leukemia and, of special importance, towards multidrug-resistant leukemia cells, and low toxicity towards pseudo-normal cells

Foreign Trade Statistical Bulletin Imports December 2009

The data presented in this publication comprises import by HS type of good, SITC good classification, commodity (HS), country of origin, port of import, five main good classification 3 digit SITC, some commodity and main country of origin. It also presents Import of Connected Area by 2 digit good classification, SITC good classification, country of origin, province and port of import

Mean arterial pressure and serum cholesterol levels in rabbits.

<p>(A) Mean arterial pressure in hypertension only rabbits. (B) Serum cholesterol levels in hypertension only rabbits. (C) Mean arterial pressure in hypercholesterolemia plus sham- and hypertension plus hypercholesterolemia rabbits. (D) Serum cholesterol levels in hypercholesterolemia plus sham- and hypertension plus hypercholesterolemia rabbits. H: Hypertension only. HC: Hypercholesterolesterolemia plus sham operation. HTHC: Hypertension plus hypercholesterolemia. MAP: mean arterial pressure. Data are expressed as mean ± SEM. *<i>p</i><0.05, **<i>p</i><0.01 vs. control (Student’s t-test in A,B; repeated measure ANOVA followed by Tukey test in C,D).</p

IPA network showing the network with the largest number of up-regulated focus genes in the hypercholesterolemia plus sham group, compared with sham operated controls.

<p>IPA network showing the network with the largest number of up-regulated focus genes in the hypercholesterolemia plus sham group, compared with sham operated controls.</p

IPA network showing the network with the second largest number of up-regulated focus genes in the hypertension plus hypercholesterolemia group, compared with sham operated controls.

<p>IPA network showing the network with the second largest number of up-regulated focus genes in the hypertension plus hypercholesterolemia group, compared with sham operated controls.</p