N-myc downstream-regulated gene 1 (NDRG1) is defined as metastasis suppressor and can be downregulated in many types of cancers, and reported to be an indication of tumor progression in hepatocellular carcinomas. Several in-vivo and in-vitro studies have demonstrated that iron chelators such as Desferrioxamine (DFO) and 1-10 Phenanthroline (PHEN) are effective antitumor agents. It is suggested that these chelators deliver their antitumor activity by acting on the NDRG1 gene expression. It remains unclear why NDRG1 gene expression affects the tumors differently, or becomes affected differently. We consider that this different effect might be caused by variants. Based on this information, we developed specific primers and probes for NDRG1 mRNA variants using bioinformatics analysis, and investigated how DFO and PHEN affected the dynamics of NDRG1 variant on the cell lines of Human Breast Adenocarcinoma (MCF-7) and Hepatocellular Carcinoma (HepG2) that demonstrate opposite action for the relationship NDRG1-metastasis. We administrated various doses of DFO and PHEN into the cells to monitor cell vitality and proliferation with Real time Cell Analyzer. We analyzed the gene expression levels of study groups with Quantitative RT-PCR as well as relative gene expression. Variants of NDRG1 mRNA were transcriptionally regulated after HepG2 and MCF-7 cells were treated by iron chelators, resulting in domination of NDRG1 mRNA Variant 1 (V1) in the HepG2 calls and domination of NDRG1 mRNA Variant 2 (V2) in the MCF-7 cells. Anti-proliferative and cytotoxic effects were observed in the MCF-7 cells whereas an increased proliferation was present in the HepG2 cells.
Ouabain is a cardiotonic steroid and specific inhibitor of the Na + /K + -ATPase. The relationship between ouabain treatment and the unfolded protein response (UPR) in cells is not precisely understood. Therefore, we studied the possible effects of ouabain on proliferation, apoptosis, and the UPR. HepG2 cells were cultured overnight and then treated with various concentrations of ouabain (0.75 to 750 nM) in the absence or presence of 10 mM 2-deoxyglucose (2-DG) for 48 hours. We also used real-time polymerase chain reaction to obtain quantitative measurements of expression levels of Grp78, Grp94, CHOP, MTJ-1, HKII, MDR-1, MRP-1, HO-1, and Par-4. Cell number, viability, and proliferation of HepG2 cells were monitored with a real-time cell analyzer system (xCELLigence). We show that ouabain modulates the UPR transcription program and induces cell death in glucose-deprived tumor cells. Ouabain at all concentrations showed no cytotoxicity whereas all concentrations were very effective under 2-DG stress conditions. Our findings show that disruption of the UPR during glucose deprivation could be an attractive approach for selective cancer cell killing and could provide a chemical basis for developing UPR-targeting drugs against solid tumors. Ouabain use as an adjunct to conventional cancer therapy also warrants vigorous investigation.
Aim In this study it was aimed to evaluate the prognostic factors for the geriatric patients with confirmed COVID-19 in a tertiary-care hospital at Kastamonu region of Turkey. Method Patients (≥65-year-old) who had PCR positivity for COVID-19 between March 2020 and April 2020 in our center were recorded retrospectively. A p value less than 0.05 was considered significant. Ethical committee approval was given from the Bolu University with decision number 2020/176. Results There were a total of 100 patients (44% female). In-hospital mortality was recorded as 7%. In univariate analysis for 1 month mortality, diabetes mellitus (p = 0.038), leucocyte count (p = 0.005), neutrophile count (p = 0.02), neutrophile-to-lymphocyte ratio (NLR) (p < 0.001), thrombocyte-to-lymphocyte ratio (TLR) (p = 0.001), C-reactive protein (CRP) (p = 0.002), lactate dehydrogenase (LDH) (p = 0.001), sequential organ failure assessment (SOFA) score (p = 0.001) and qSOFA score (p = 0.002) were found as independent risk factors. On admission, one point increase of NLR (p = 0.014, odds ratio (OR) = 1.371, 95% CI = 1.067–1.761) and one point increase of LDH (p = 0.047, OR = 1.011, 95% CI = 1.001–1.023) were associated with mortality on day 30 according to logistic regression analysis. The cut-off values were found as > 7.8 for NLR (83.33% sensitivity, 97.7% specificity) and > 300 U/L for LDH (100% sensitivity, 79.31% specificity) regarding the prediction of 30-day mortality. Conclusion In order to improve clinical management and identify the geriatric patients with COVID-19 who have high risk for mortality, NLR and LDH levels on admission might be useful prognostic tools.
Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA), and iron chelators, including deferoxamine (DFO) and phenanthroline (PHEN), appear to have anticancer effects. We hypothesized that the HDAC inhibitors and iron chelators would be synergistic with their effect on breast cancer cell line MCF7, because the HDAC inhibitors increase glucose-regulated protein 78 (Grp78) and the iron chelators reduce its expression. Although the administration of TSA alone resulted in a dose-related decrease in the cell index, it did not have an antiproliferative effect except the 62.5 and 500 nM of TSA. However, all doses of TSA produced a cytotoxic effect from the initial hours when combined with 150 μM of DFO and 25 μM of PHEN. DFO and PHEN downregulated Grp78, Grp94, and MRP1 expressions and upregulated CHOP and HO-1 expressions. TSA upregulated all the genes in various rates when used alone but resulted in decreased expression levels when combined with DFO and PHEN. Increased HDAC-1 levels in the Grp78 promoter region indicated that DFO and PHEN either promoted binding of HDAC-1 to this region or inhibited its detachment. We determined that the reduction of increased Grp78, Grp94, HO-1, and MRP1 expressions, which appears to inhibit the chemotherapeutic effect of TSA, through the combination with DFO or PHEN will contribute to the anticancer effect.
Fluvastatin (FLU) prevents the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic acid by inhibiting HMG-CoA reductase and decreases cholesterol level. Although the effects of FLU treatment on several cancer types through many mechanisms have been identified, its relationship with unfolded protein response and apoptosis has not been clearly understood. In this recent study, we aimed to investigate the cytotoxic effect of Fluvastatin on MCF-7 cells and define the transcriptional regulation of specific genes during the occurrence of this cytotoxic effect. We administered 0.62, 2.5, 5, and 40 μM FLU on MCF-7 cells singly and in combination with 2-deoxyglucose (2-DG), and we monitored cell viability and proliferation for 48 hours using real-time cell analyzer system (xCELLigence). At the same time, we measured the mRNA expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein, homologous protein (CHOP), caveolin-1 (CAV1), NDRG1 Variant 1 and Variant 2, HMOX1, SGK1, and prostate apoptosis response-4 (PAR4) genes using quantitative real-time polymerase chain reaction (LightCycler 480 II). We accepted GAPDH gene and control groups as the reference gene and calibrator, respectively. We performed relative gene expression analyses of the study groups using the QIAGEN 2009 Relative Expression Software Tool (REST). FLU revealed an antiproliferative and cytotoxic effect on MCF-7 cells, while causing the transcriptional regulation of many genes. Of these genes, the mRNA expressions of CHOP, heme oxygenase 1 (HMOX1), N-myc downstream-regulated gene 1 (NDRG1) V1, and NDRG1 V2 increased. On the other hand, the mRNA expression levels of SGK1 and CAV1 decreased. The antiproliferative effects of FLU may be related to the decreased expression levels of SGK1 and CAV1.
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