Current Issue : October - December Volume : 2018 Issue Number : 4 Articles : 5 Articles
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous\nsystem (CNS). The immune response in MS patients leads to the infiltration of immune cells in\nthe CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis.\nDuring glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced. MGO is a glycating\nagent that can rapidly form advanced glycation endproducts (AGEs). In turn, AGEs are able to\ninduce inflammatory responses. The glyoxalase system is the endogenous defense system of the body\nto reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1\nand glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels\nare induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of\nMS. Twenty seven days post EAE induction, MGO and AGE (N�µ-(carboxymethyl)lysine (CML),\nN�µ-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly\nincreased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1\noverexpression were unable to counteract AGE production during EAE and did not influence\nthe clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord,\nbut AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect\ndisease progression....
The Bruton�s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as\nan antileukemic agent, but applications in solid cancer have been found recently. The compound promotes\napoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs.\nWe decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal\ntransduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by\nEpo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial\nmembrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein\nBCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated\nwith Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo\nand LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in\nxenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed\nby the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells\nwith externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo\nand LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid\ntumors such as colon cancer....
Although oncolytic viruses provide attractive vehicles for cancer treatment, their adverse\neffects are largely ignored. In this work, rat C6 glioblastoma cells were subcutaneously xenografted into\nmice, and a thymidine kinase-deficient oncolytic vaccinia virus (oncoVV) induced severe toxicity in this\nmodel. However, oncoVV-HddSBL, in which a gene encoding Haliotis discus discus sialic acid-binding\nlectin (HddSBL) was inserted into oncoVV, significantly prolonged the survival of mice as compared\nto the control virus. HddSBL reduced the tumor secreted serum rat IL-2 level upregulated by oncoVV,\npromoted viral replication, as well as inhibited the expression of antiviral factors in C6 glioblastoma cell\nline. Furthermore, HddSBL downregulated the expression levels of histone H3 and H4, and upregulated\nhistone H3R8 and H4R3 asymmetric dimethylation, confirming the effect of HddSBL on chromatin\nstructure suggested by the transcriptome data. Our results might provide insights into the utilization of\nHddSBL in counteracting the adverse effects of oncolytic vaccinia virus....
One of the primary effector functions of immune cells is the killing of virus-infected or\nmalignant cells in the body. Natural killer (NK) and CD8 effector T cells are specialized for this\nfunction. The gold standard for measuring such cell-mediated cytolysis has been the chromium\nrelease assay, in which the leakage of the radioactive isotope from damaged target cells is being\ndetected. Flow cytometry-based single cell analysis of target cells has recently been established\nas a non-radioactive alternative. Here we introduce a target cell visualization assay (TVA) that\napplies similar target cell staining approaches as used in flow cytometry but based on single cell\ncomputer image analysis. Two versions of TVA are described here. In one, the decrease in numbers\nof calcein-stained, i.e., viable, target cells is assessed. In the other, the CFSE/PI TVA, the increase\nin numbers of dead target cells is established in addition. TVA assays are shown to operate with\nthe same sensitivity as standard chromium release assays, and, leaving data audit trails in form of\nscanned (raw), analyzed, and quality-controlled images, thus meeting requirements for measuring\ncell-mediated cytolysis in a regulated environment....
In the current study, we investigated the inhibitory activity of pyridoxine, pyridoxal,\nand pyridoxamine, against various digestive enzymes such as �±-glucosidases, sucrase, maltase,\nand glucoamylase. Inhibition of these enzymes involved in the absorption of disaccharide can\nimprove post-prandial hyperglycemia due to a carbohydrate-based diet. Pyridoxal (4.14 mg/mL\nof IC50) had the highest rat intestinal �±-glucosidase inhibitory activity, followed by pyridoxamine\nand pyridoxine (4.85 and 5.02 mg/mL of IC50, respectively). Pyridoxal demonstrated superior\ninhibition against maltase (0.38 mg/mL IC50) and glucoamylase (0.27 mg/mLIC50). In addition,\npyridoxal showed significant higher �±-amylase inhibitory activity (10.87 mg/mL of IC50) than that of\npyridoxine (23.18 mg/mL of IC50). This indicates that pyridoxal can also inhibit starch hydrolyzing by\npancreatic �±-amylase in small intestine. Based on these in vitro results, the deeper evaluation of the\nanti-hyperglycemic potential of pyridoxine and its derivatives using Sprague-Dawley (SD) rat models,\nwas initiated. The post-prandial blood glucose levels were tested two hours after sucrose/starch\nadministration, with and without pyridoxine and its derivatives. In the animal trial, pyridoxal\n(p < 0.05) had a significantly reduction to the postprandial glucose levels, when compared to the\ncontrol. The maximum blood glucose levels (Cmax) of pyridoxal administration group were decreased\nby about 18% (from 199.52 �± 22.93 to 164.10 �± 10.27, p < 0.05) and 19% (from 216.92 �± 12.46 to\n175.36 �± 10.84, p < 0.05) in sucrose and starch loading tests, respectively, when compared to the control\nin pharmacodynamics study. The pyridoxal administration significantly decreased the minimum,\nmaximum, and mean level of post-prandial blood glucose at 0.5 h after meals. These results indicate\nthat water-soluble vitamin pyridoxine and its derivatives can decrease blood glucose level via the\ninhibition of carbohydrate-hydrolyzing and absorption-linked enzymes. Therefore, pyridoxal may\nhave the potential to be used as a food ingredient for the prevention of prediabetes progression to\ntype 2 diabetes....
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