Association of 45-bp ins/del polymorphism of uncoupling protein 2 (UCP2) and susceptibility to nonalcoholic fatty liver and type 2 diabetes mellitus in North-west of Iran.

OBJECTIVE: Uncoupling protein 2 (UCP2) plays a crucial role in energy homeostasis via insulin secretion regulation, free fatty acid concentrations, and lipid metabolism. This study aimed to investigate the association of 45-bp ins/del polymorphism of UCP2 with susceptibility to NAFLD (Non-Alcoholic Fatty Liver Disease) and T2DM (Type 2 Diabetes Mellitus). DNA was extracted from the white blood cells of the subjects, and the gene polymorphism was determined using polymerase chain reaction (PCR). In this study, 72 patients with NAFLD, 71 healthy individuals as control, 80 patients with T2DM, and 77 healthy controls were enrolled in the study. RESULTS: A higher prevalence of insertion/insertion genotype was observed in T2DM patients compared to the controls (p- value˂ 0.05). There was no difference in genotype distribution between NAFLD patients and controls (p-value > 0.05). NAFLD patients with D/D, D/I genotype had higher triglyceride, ALT, and AST levels; however, their HDL levels were lower than healthy controls. Patients with T2DM with D/D or D/I genotype also had significantly higher fasting serum glucose (FSG). While we found an association between the 45 bp I/D polymorphism in 3'UTR of UCP2 and T2DM, no correlation between this polymorphism and NAFLD was identified.

Quercetin Promotes Cell Cycle Arrest and Apoptosis and Attenuates the Proliferation of Human Chronic Myeloid Leukemia Cell Line-K562 Through Interaction with HSPs (70 and 90), MAT2A and FOXM1.

BACKGROUND: Chronic Myeloid Leukaemia (CML) starts in certain blood-forming cells of the bone marrow when cells acquire Philadelphia chromosome. Nowadays, scientists attempt to find novel and safe therapeutic agents and approaches for CML therapy using Tyrosine Kinase Inhibitors (TKIs), CML conventional treatment agents, has some restrictions and also adverse effects. Recently, it has been proposed that phytochemicals, such as flavonoids due to their low side effects and notable safety have the potential to be used for CML therapy. MATERIALS AND METHODS: K-562 cells were exposed with three concentrations of the querectin (10, 40 and 80µM) for 12, 24 and 48 hours. After that, these cells apoptosis rate was estimated using Annexin-V/PI staining and flowcytometry analysis, and their proliferation rate was evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT). Finally, the expression of the 70 and 90 kilodalton heat shock proteins (HSP70 and 90), methionine adenosyltransferase 2A (MAT2A), Forkhead box protein M1 (FOXM1), caspase-3 and -8, Bcl-X(L) and Bax involved in leukemic cells survival and proliferation was assessed using Real-Time PCR within 12, 24 and 48 hours after exposure with quercetin 40 and 80µM. RESULTS: Considering consequences, querecetin induced apoptosis in K-562 cells, and also abrogated these cells proliferation. On the other hand, RT-PCR results showed a reduction in some of the candidate genes expression, especially HSP70, Bcl-X(L) and FOXM1, when cells were treated with quercetin 40 and 80µM. Also, Bax, caspase-3 and caspase-8 expression was significantly improved in K-562 cells upon quercetin exposure. CONCLUSION: We concluded that CML therapy by querecetin due to its anti-proliferative and anti-survival potentials could lead to the promising therapeutic outcome through targeting major survival and proliferation involved genes expression.

Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms.

Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.

Deregulated expression of HDAC3 in colorectal cancer and its clinical significance.

BACKGROUND: To date, 4 classes of histone deacetylases (HDACs) have been identified in humans. Class I HDACs are zinc-dependent and NAD+-independent enzymes, and include 4 isoforms closely related to yeast RPD3: HDAC1, 2, 3, and 8. OBJECTIVES: The aims of the study were to quantitatively evaluate the expression of HDAC3 in colorectal cancer (CRC) and to correlate its expression levels with clinicopathological parameters. MATERIAL AND METHODS: We characterized expression patterns of HDAC3 as class I HDAC isoforms in a cohort of 48 CRC patients by quantitative (real-time) reverse transcription polymerase chain reaction (RT-PCR). In addition, the potential relationship between HDAC3 expression levels and clinicopathological parameters in patients suffering from CRC was explored. RESULTS: We found that HDAC3 was highly expressed in colorectal tumors compared to normal colorectal tissues (p < 0.05). Furthermore, we found significant correlations between HDAC3 expression levels and tumor differentiation grades (p < 0.05). CONCLUSIONS: In this prospective study we identified a pronounced HDAC3 expression pattern in CRC. Our findings support an important role of HDAC3 as a complementary molecular marker for existing histopathological diagnostic elements; it might also have applications in prognostic and targeted therapy. Furthermore, HDAC3 can be used as a biomarker to differentiate between tumor borders and margins, and it may also be useful for characterizing field cancerization in CRC.

STC1 and NF-κB p65 (Rel A) is Constitutively Activated in Colorectal Cancer.

BACKGROUND: Stanniocalcin-1 (STC1) and nuclear factor (NF)-κB subunit p65 transcription factor are involved in various types of human malignancies. The roles of STC1 and NFκB-p65 in colorectal cancer (CRC) are still not fully understood. We investigated expression levels of NF-κB p65 and STC1 and also correlations between STC1 and NF-κB p65 expression and clinicopathological features in CRC. METHODS: Tumor tissue samples were collected from 48 patients with CRC. RT-PCR and Real-time PCR analysis was performed to examine mRNA levels of STC1 and NF-κB p65. RESULTS: The relative mRNA levels of STC1 and NF-κB p65 were significantly higher in tumor tissues than in adjacent mucosa (p = 0.025 and p = 0.044, respectively). The data also showed that STC1 and NF-κB p65 mRNA levels were not significantly associated with clinicopathological characteristics. In addition, there was no association between expression levels of STC1 and NF-κB p65 in tumor samples. CONCLUSIONS: Our data indicate that STC1 and NF-κBp65 is activated constitutively in colorectal carcinoma tissues, suggesting that activation of these factors might play an important role in colorectal tumorigenesis. Future studies should examine STC1 and NF-κBp65 as a molecular target for the treatment of CRC.