Thiosemicarbazones reprogram pancreatic cancer bidirectional oncogenic signaling between cancer cells and stellate cells to suppress desmoplasia.

Standard treatments have shown dismal activity against pancreatic cancer (PC), due in part to the development of a dense stroma (desmoplasia). This perspective discusses the development of the di-2-pyridylketone thiosemicarbazones that overcomes bidirectional oncogenic signaling between PC cells and pancreatic stellate cells (PSCs), which is critical for desmoplasia development. This activity is induced by the up-regulation of the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which inhibits oncogenic signaling via HGF, IGF-1 and Sonic Hedgehog pathway. More recent studies have deciphered additional pathways including those mediated by Wnt and tenascin C that are secreted by PSCs to activate ß-catenin and YAP/TAZ signaling in PC cells. Suppression of bidirectional signaling between cell types presents a unique therapeutic opportunity.

Ascorbate-and iron-driven redox activity of Dp44mT and Emodin facilitates peroxidation of micelles and bicelles.

BACKGROUND: Iron (Fe)-induced oxidative stress leads to reactive oxygen species that damage biomembranes, with this mechanism being involved in the activity of some anti-cancer chemotherapeutics. METHODS: Herein, we compared the effect of the ligand, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), or the potential ligand, Emodin, on Fe-catalyzed lipid peroxidation in cell membrane models (micelles and bicelles). These studies were performed in the presence of hydrogen peroxide (H2O2) and the absence or presence of ascorbate. RESULTS: In the absence of ascorbate, Fe(II)/Emodin mixtures incubated with H2O2 demonstrated slight pro-oxidant properties on micelles versus Fe(II) alone, while the Fe(III)-Dp44mT complex exhibited marked antioxidant properties. Examining more physiologically relevant phospholipid-containing bicelles, the Fe(II)- and Fe(III)-Dp44mT complexes demonstrated antioxidant activity without ascorbate. Upon adding ascorbate, there was a significant increase in the peroxidation of micelles and bicelles in the presence of unchelated Fe(II) and H2O2. The addition of ascorbate to Fe(III)-Dp44mT substantially increased the peroxidation of micelles and bicelles, with the Fe(III)-Dp44mT complex being reduced by ascorbate to the Fe(II) state, explaining the increased reactivity. Electron paramagnetic resonance spectroscopy demonstrated ascorbyl radical anion generation after mixing ascorbate and Emodin, with signal intensity being enhanced by H2O2. This finding suggested Emodin semiquinone radical formation that could play a role in its reactivity via ascorbate-driven redox cycling. Examining cultured melanoma cells in vitro, ascorbate at pharmacological levels enhanced the anti-proliferative activity of Dp44mT and Emodin. CONCLUSIONS AND GENERAL SIGNIFICANCE: Ascorbate-driven redox cycling of Dp44mT and Emodin promotes their anti-proliferative activity.

Prevalence of Cervical Intraepithelial Neoplasia in four Upazila of Dhaka Division.

This cross-sectional and population based study was carried out in four randomly selected Upazila of four districts of Dhaka division by the department of Obstetrics and Gynaecology of Dhaka Medical College Hospital (DMCH) and Bangabandhu Sheikh Mujib University (BSMMU), Dhaka, Bangladesh from October 2014 to March 2015 to detect the prevalence of Cervical Intraepithelial Neoplasia (CIN) among women in four Upazila of Dhaka division of Bangladesh. Married women ages between 25-55 years, mentally able to provide informed consent were recruited. Women with chronic illness, pregnancy and women with previous treatment for CIN were excluded from the study. During 6 months of study period, a total 1165 cases were examined. Most of the attendants were between 30-35 years. Muslim participants were more than Hindus (95.27% vs. 4.37%) and 0.34% attendants were from Christian religion. Among the participants majority (42.37%) of them were up to primary level. Most (98.45%) of the women were house wife and most (54.5%) of them had monthly family income between Tk. 5001-10000. It was observed that 6.5% of their husband had 2 wives and 1.2% had 3 wives. Regarding their living status, 90.6% were living together, 8.6% of their husband was living at their work place & 0.7% was living abroad. About 30.4% of their husbands were farmer others were businessman, unemployed, driver and other service holder. It was found that 67(5.8%) out of 1165 cases were diagnosed as VIA +ve cases. Among 1165 cases 94.2% were normal, 4.7% were diagnosed as CIN I, 1% were CIN II and none of them was CIN III. Colposcopy guided punch biopsy were taken from all CIN cases and found that among 67 cases of colposcopically diagnosed CIN, histopathologically 28(2.4%) cases were diagnosed as normal, 32(2.7%) cases were CIN I, 4(0.3%) cases were CIN II & 3 (0.3%) cases were CIN III. In this study, crude prevalence of CIN I, CIN II and CIN III were 2.7%, 0.3% and 0.3% respectively. This study provides the first population-based prevalence of CIN in Bangladesh which will guide the Government of Bangladesh to upgrade the activities of already existing cervical cancer screening programme.

A model of chlorpyrifos distribution and its biochemical effects on the liver and kidneys of rats.

This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, adipose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in adipose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals.

Localization of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocampal neurons.

Fragile X syndrome is caused by the absence of the fragile X mental-retardation protein (FMRP), an mRNA-binding protein, which may play important roles in the regulation of dendritic mRNA localization and/or synaptic protein synthesis. We have recently applied high-resolution fluorescence imaging methods to document the presence, motility and activity-dependent regulation of FMRP granule trafficking in dendrites and spines of cultured hippocampal neurons. In this study, we show that FMRP granules distribute to F-actin-rich compartments, including filopodia, spines and growth cones during the staged development of hippocampal neurons in culture. Fragile X mental-retardation protein granules were shown to colocalize with ribosomes, ribosomal RNA and MAP1B mRNA, a known FMRP target, which encodes a protein important for microtubule and actin stabilization. The levels of FMRP within dendrites were reduced by disruption of microtubule dynamics, but not by disruption of F-actin. Direct measurements of FMRP transport kinetics using fluorescence recovery after photobleaching in living neurons showed that microtubules were required to induce the mGluR-dependent translocation into dendrites. This study provides further characterization of the composition and regulated trafficking of FMRP granules in dendrites of hippocampal neurons.