Metformin Attenuates Palmitate-Induced Endoplasmic Reticulum Stress, Serine Phosphorylation of IRS-1 and Apoptosis in Rat Insulinoma Cells

Lipotoxicity refers to cellular dysfunctions caused by elevated free fatty acid levels playing a central role in the development and progression of obesity related diseases. Saturated fatty acids cause insulin resistance and reduce insulin production in the pancreatic islets, thereby generating a vicious cycle, which potentially culminates in type 2 diabetes. The underlying endoplasmic reticulum (ER) stress response can lead to even β-cell death (lipoapoptosis). Since improvement of β-cell viability is a promising anti-diabetic strategy, the protective effect of metformin, a known insulin sensitizer was studied in rat insulinoma cells. Assessment of palmitate-induced lipoapoptosis by fluorescent microscopy and by detection of caspase-3 showed a significant decrease in metformin treated cells. Attenuation of β-cell lipotoxicity was also revealed by lower induction/activation of various ER stress markers, e.g. phosphorylation of eukaryotic initiation factor 2α (eIF2α), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1) and induction of CCAAT/enhancer binding protein homologous protein (CHOP). Our results indicate that the β-cell protective activity of metformin in lipotoxicity can be at least partly attributed to suppression of ER stress

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

YesTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes

DUSP6 regulates drug sensitivity by modulating DNA damage response

Background: Dual specificity phosphatase 6 (DUSP6) is a member of a family of mitogen-activated protein kinase phosphatases that dephosphorylates and inhibits activated ERK1/2. Dual specificity phosphatase 6 is dynamically regulated in developmental and pathological conditions such as cancer. Methods: Cancer cell lines were made deficient in DUSP6 by siRNA and shRNA silencing. Sensitivity to anti-EGFR and chemotherapeutic agents was determined in viability and apoptosis assays, and in xenografts established in SCID mice. Cellular effects of DUSP6 inactivation were analysed by proteomic methods, followed by analysis of markers of DNA damage response (DDR) and cell cycle. Results: We determined that depletion of DUSP6 reduced the viability of cancer cell lines and increased the cytotoxicity of EGFR and other targeted inhibitors, and cytotoxic agents, in vitro and in vivo. Subsequent phosphoproteomic analysis indicated DUSP6 depletion significantly activated CHEK2 and p38, which function in the DDR pathway, and elevated levels of phosphorylated H2AX, ATM, and CHEK2, for the first time identifying a role for DUSP6 in regulating DDR. Conclusion: Our results provide a novel insight into the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer.Lewis Katz School of MedicineCancer and Cellular Biolog

Assessment of the microbiological quality of popular food items on sale in secondary school canteens of Mauritius

This study was carried out to assess the microbiological status of three hot meals served in eight selected school canteens of Mauritius, with two schools randomly selected from each of the four school zones of the island. Three individual samples of farata, panini, or fried noodles were collected at each school during two independent visits. The three individual samples of each food type collected during each visit were then pooled before being subjected to microbiological analyses. A total of 48 composite samples were analyzed. The parameters tested were Total Viable Count (TVC), Escherichia coli, Salmonella spp., Clostridium perfringens, Staphylococcus aureus, and Listeria spp. The microbiological analyses revealed that paninis were deemed as generally acceptable with TVC falling in the range of 3.0-5.7 Log CFU/g and undetectable levels of S. aureus and E. coli. In contrast, fried noodles and faratas harboured a moderately high level of TVC (4.4-6.7 Log CFU/g) and objectionably high levels S. aureus (3.1 to 5.0 Log CFU/g) and E. coli (3.1-5.1 Log CFU/g) for seven out of the eight schools

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Dose Dependent Effects on Cell Cycle Checkpoints and DNA Repair by Bendamustine

Bendamustine (BDM) is an active chemotherapeutic agent approved in the U. S. for treating chronic lymphocytic leukemia and non-Hodgkin lymphoma. Its chemical structure suggests it may have alkylator and anti-metabolite activities; however the precise mechanism of action is not well understood. Here we report the concentration-dependent effects of BDM on cell cycle, DNA damage, checkpoint response and cell death in HeLa cells. Low concentrations of BDM transiently arrested cells in G2, while a 4-fold higher concentration arrested cells in S phase. DNA damage at 50, but not 200 µM, was efficiently repaired after 48 h treatment, suggesting a difference in DNA repair efficiency at the two concentrations. Indeed, perturbing base-excision repair sensitized cells to lower concentrations of BDM. Timelapse studies of the checkpoint response to BDM showed that inhibiting Chk1 caused both the S- and G2-arrested cells to prematurely enter mitosis. However, whereas the cells arrested in G2 (low dose BDM) entered mitosis, segregated their chromosomes and divided normally, the S-phase arrested cells (high dose BDM) exhibited a highly aberrant mitosis, whereby EM images showed highly fragmented chromosomes. The vast majority of these cells died without ever exiting mitosis. Inhibiting the Chk1-dependent DNA damage checkpoint accelerated the time of killing by BDM. Our studies suggest that BDM may affect different biological processes depending on drug concentration. Sensitizing cells to killing by BDM can be achieved by inhibiting base-excision repair or disrupting the DNA damage checkpoint pathway

Comunidades de insectos fitófagos en árboles y lianas en el dosel y sotobosque del Parque Natural Metropolitano

The food and nutrient intake of Paleolithic hunter-gatherers (Homo erectus) and of Western populations (Homo economicus) show marked variations. With increase in wealth and affluence there is a decrease in the intake of omega-3 fatty acids, vitamins, antioxidants and amino acids and a significant increase in the intake of refined carbohydrates, fats (saturated & trans fats, omega-6 fatty acids) and salt in comparison with those of the Paleolithic period. The protein or amino acid intake was 2.5 fold greater (33 vs. 13%) in the Paleolithic diet of Homo erectus compared to that of the modern Western diet. Prior to the Agricultural Revolution, man's diet was based on an enormous variety of wild plants, eggs, fish and seeds. In comparison, today about 17% of plant species provide 90% of the world's food supply which is mainly contributed by grains produced from fertilizer-based rapidly grown crops potentially lower in nutrient density and higher in energy. Grains are high in omega-6 fatty acids and carbohydrates and low in omega-3 fatty acids and antioxidants compared to leafy green vegetables. The appropriate diet for Homo sapiens is characterized by high levels of protective essential nutrients; amino acids, minerals, vitamins, flavonoids, omega-6/3 fatty acids. Whereas the average diet of Homo erectus did comply with this evolutionary pattern, the modern Western dietary pattern of Homo economicus has excess of energy-rich refined carbohydrates, omega-6, trans and saturated fats. The consumption of such foods in wealthy countries in conjunction with sedentary behavior are associated with increased risk of deaths due to cardiovascular (CVDs) and other non-communicable diseases (NCDs). © Nova Science Publishers, Inc