Synergistic Anti-Cancer Activity of the Combination of 1,25-Dihydroxyvitamin D3 and Retinoic Acid in U937 Cell Line.

Background: MicroRNA is a form of non-coding RNAs that able to regulate gene expression. miR-424 is one of the members of the regulatory family, which plays an important role in the proliferation and differentiation of myeloid cells. Epigenetic changes can change the level of miR-424 under environmental factors. Therefore, the level of expression of miR-424 in U937 cells of the myeloid line was evaluated in this research under the influence of vitamin D3 (VitD3) and retinoic acid (RA). Methods: In this study, U937 cells were cultured in the presence of VitD3, and RA to evaluate cell proliferation, viability via the trypan blue exclusion test, and expression level of miR-424 by real-time PCR at specific times. Results: Cell proliferation has shown a significant decrease in the RA group versus other groups during incubation times (P < 0.05). In VitD3 group, there was a significant increase in cell proliferation after 24- and 48-hours incubation periods versus other groups. In the VitD3 and RA groups, the increase of cell proliferation caused the downregulation of miR-424. In addition, the upregulation of VitD3 group and downregulation of the RA group were significant versus the control group (P < 0.05). Discussion: We concluded that the expression level of miR-424 was critically affected in the dose- and time-dependent of RA and VitD3 treatment in the U937 cell line. Treatment with VitD3 decreased the expression of miR-424 and RA treatment increase miR-424 expression level in physiological doses.

Molecular Docking Studies of Methamphetamine and Amphetamine- Related Derivatives as an Inhibitor against Dopamine Receptor.

BACKGROUND: The catecholamines such as dopamine, norepinephrine, and epinephrine are neurotransmitters that regulate different physiological functions of the central nervous system. Some evidence suggests that the degeneration of dopamine neurons in the substantia nigra contributes to Parkinson's Disease (PD), which is a neurodegenerative disorder and it is responsible for the major symptoms of PD. It is suggested that replenishment of striatal dopamine through the oral administration of the dopamine precursor, levodopa, can compensate for the lack of endogenously produced dopamine. Some studies have shown competitive inhibition of dopamine receptor such as methamphetamine, and other amphetamine-related derivatives, which block dopamine receptor activity to uptake dopamine. METHODS: In this study, 3D structures of amphetamine, methamphetamine, cocaine, methylphenidate, cathinone, MDMA, and mephedrone were obtained from the PubChem database, which has reported some evidence about their inhibitory effect with dopamine receptor. Then, these structures were provided for molecular docking analysis by Autodock Vina software. Eventually, the binding energies between docked dopamine receptor and them were calculated and their interactions were prognosticated. RESULTS: Our results indicated that all chemicals can interact with dopamine receptor molecule in the active site of dopamine and the minimum binding energies belong to Cocaine and Methylphenidate with -7.9 Kcal/mol and -7.2 Kcal/mol, respectively. CONCLUSION: It might be concluded that amphetamine, methamphetamine, cocaine, methylphenidate, cathinone, MDMA, and mephedrone could act as potential inhibitors of DA receptor for dopamine uptake, which could cause degenerative disorders.

Apelin-13 Protects PC12 Cells Against Methamphetamine-Induced Oxidative Stress, Autophagy and Apoptosis.

Methamphetamine (METH) is a potent psychomotor stimulant that has a high potential for abuse in humans. In addition, it is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson's disease. Apelin-13 is a novel endogenous ligand which studies have shown that may have a neuroprotective effect. Therefore, we hypothesized that Apelin-13 might adequately prevent METH-induced neurotoxicity via the inhibition of apoptotic, autophagy, and ROS responses. In this study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, 6 mmol/L) and Apelin-13 (0.5, 1.0, 2.0, 4.0, 8.0 µmol/L) in vitro for 24 h to measure determined dose, and then downstream pathways were measured to investigate apoptosis, autophagy, and ROS responses. The results have indicated that Apelin-13 decreased the apoptotic response post-METH exposure in PC12 cells by increasing cell viability, reducing apoptotic rates. In addition, the study has revealed Apelin-13 decreased gene expression of Beclin-1 by Real-Time PCR and LC3-II by western blotting in METH-induced PC12 cells, which demonstrated autophagy is reduced. In addition, this study has shown that Apelin-13 reduces intracellular ROS of METH-induced PC12 cells. These results support Apelin-13 to be investigated as a potential drug for treatment of neurodegenerative diseases. It is suggested that Apelin-13 is beneficial in reducing oxidative stress, which may also play an important role in the regulation of METH-triggered apoptotic response. Hence, these data indicate that Apelin-13 could potentially alleviate METH-induced neurotoxicity via the reduction of oxidative damages, apoptotic, and autophagy cell death.

GHSR DNA hypermethylation is a new epigenetic biomarker for gastric adenocarcinoma and beyond.

Aberrations of DNA methylation are early events in the development of tumors. In this study, we investigated the DNA methylation status of growth hormone secretagogue receptor (GHSR), a promising pan-cancer biomarker, in gastric cancer (GC). Initially, data sets from DNA methylation and gene expression studies available at Gene Expression Omnibus (GEO) were analyzed. Confirmation was done on primary tumor specimens and adjacent normal stomach tissue samples. Both analyses showed significant hypermethylation of GHSR. For further validation, The Cancer Genome Atlas data on stomach cancer was used. A receiver operating characteristic curve analysis yielded an area under the curve value of 0.85, corroborating its usefulness as a diagnostic marker. A genome-wide comethylation analysis revealed several correlated genes. CREB1 was found to act as an upstream regulator of this gene network. Furthermore, GHSR methylation was found to be a biomarker in several other tumor entities, namely cancers of the bladder, endometrium, esophagus, head and neck, liver, thyroid, kidney, and ovary. Our findings along with previous reports on other types of cancer suggest a high potential of GHSR gene methylation as a pan-cancer biomarker, which could be considered for liquid biopsy applications.

Tissue-Specific Down-Regulation of the Long Non-Coding RNAs PCAT18 and LINC01133 in Gastric Cancer Development.

Gastric cancer (GC) is the fifth most common cancer and the third most frequent cause of cancer deaths worldwide. The high death rate associated with GC, and lack of appropriate biomarkers for diagnosis, prognosis, and treatment emphasize the need for identification of novel molecules. Given the emerging roles for long non-coding RNAs (lncRNAs) in cancer development, we studied novel lncRNA candidates involved in gastric carcinogenesis. LncRNA candidate discovery was performed using analyses of available datasets and literature. Validation was done using an internal sample set of GC/normal tissues, and external independent datasets. Network analysis and functional annotation of co-expressed protein coding genes were performed using the weighted gene correlation network analysis (WGCNA) and ingenuity pathway analysis. Two novel lncRNAs, PCAT18 and LINC01133, associated with GC development were identified by analysis of the discovery Gene Expression Omnibus (GEO) datasets. The down-regulation of these genes in GC tissues was successfully validated internally and externally. The results showed a tissue-specific down-regulation of PCAT18 and LINC01133 in gastrointestinal tissues. WGCNA and ingenuity pathway analyses revealed that the genes co-expressed with the two lncRNAs were mostly involved in metabolic pathways and networks of gastrointestinal disease and function. Our findings of a tissue-specific down-regulation of PCAT18 and LINC01133 in gastric and other gastrointestinal cancers imply that these lncRNAs may have a tumor suppressive function in the development of these tumor entities. The two lncRNA biomarkers may contribute to a better understanding of the complex mechanisms of gastric carcinogenesis.