ABCC6P1 pseudogene induces ABCC6 upregulation and multidrug resistance in breast cancer.

BACKGROUND: The elevated drug efflux by ABC transports has been considered the primary mechanism of drug resistance in cancer. Recently, non-coding RNAs, such as pseudogenes, have been proposed to be involved in transporter-mediated drug resistance in cancer. The human genome has 22 ABC transporter pseudogenes. Among these pseudogenes, ABCC6P1 has co-expression with its ancestral gene in various human tissues. In the present study, we assessed the effect of ABCC6P1 pseudogene overexpression on ABCC6 expression and drug resistance. METHODS AND RESULTS: The ABCC6P1 was transfected into the MCF-7 and MDA-MB-231 cells. In ABCC6P1-overexpressing cells, the ABCC6 level significantly increased. The results of cell treatment with doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel showed that the survival of ABCC6P1-overexpressing cells was higher than normal cells. Furthermore, uptake of doxorubicin was lower in ABCC6P1-overexpressing cells. CONCLUSIONS: In conclusion, our results show that overexpression of ABCC6P1 pseudogene induces the drug resistance phenotype, possibly through activation of the ancestral gene.

Curcumin loaded on graphene nanosheets induced cell death in mammospheres from MCF-7 and primary breast tumor cells.

Elimination of tumor cells is still a therapeutic challenge for breast cancer (BC) in men and women. Mammospheres serve as valuablein vitrotools for evaluating tumor behavior and sensitivity to anticancer treatments. Graphene nanosheets with unique physicochemical properties have been considered as potential biomedical approaches for drug delivery, bioimaging, and therapy. Graphene oxide (GO) and graphene quantum dots (GQDs) are suitable nanocarriers for hydrophobic and low bioaccessible anti-tumor materials like curcumin. Despite extensive studies on the potential application of graphene nanosheets in medicine, our knowledge of how different cells function and respond to these nanoparticles remains limited. Here, we evaluated cell death in mammospheres from MCF-7 and primary tumor cells in response to curcumin loaded on graphene nanosheets. Mammospheres were exposed to graphene oxide-curcumin (GO-Cur) and graphene quantum dots-curcumin (GQDs-Cur), and the incidence of cell death was evaluated by Hoechst 33342/propidium iodide double staining and flow cytometry. Besides, the expression of miR-21, miR-29a, Bax, and Bcl-2 genes were assessed using RT-qPCR. We observed, GO, and GQDs had no cytotoxic effect on Kerman male breast cancer/71 (KMBC/71) and MCF-7 tumor cells, while curcumin induced death in more than 50% of tumor cells. GO-Cur and GQDs-Cur synergistically enhanced anti-tumor activity of curcumin. Moreover, GQDs-Cur induced cell death in almost all cells of KMBC/71 mammospheres (99%;p< 0.0001). In contrast, GO-Cur induced cell death in only 21% of MCF-7 mammosphere cells (p< 0.0001). Also, the expression pattern of miR-21, miR-29a, and Bax/Bcl-2 ratio in KMBC/71 and MCF-7 mammospheres was different in response to GO-Cur and GQDs-Cur. Although KMBC/71 and MCF-7 tumor cells had similar clinical features and displayed similar responses to curcumin, more investigations are needed to clarify the detailed molecular mechanisms underlying observed differences in response to GO-Cur and GQDs-Cur.

Altered IFN-γ Levels after Treatment of Epileptic Patients with Omega-3 Fatty Acids.

Epilepsy is a frequent chronic disorder of the brain characterized by intermittent epileptic seizures caused by hypersynchronous discharge of neurons in the brain. Studies have reported the role of cytokines in the pathogenesis of epilepsy, and a number of investigations have shown decreased levels of omega-3 fatty acids in epileptic patients. We investigated differences in serum levels of two cytokines, transforming growth factor (TGF)-ß and interferon (IFN)-γ, in 40 epileptic cases prior to and after treatment with omega-3 fatty acids. IFN-γ levels were significantly increased after the 16-week treatment period (P < 0.001). However, TGF-ß levels remained unchanged (P = 0.14). Omega-3 fatty acid treatment may alter the immune response in epileptic patients. This should be considered in prescription of omega-3 fatty acid supplements in these patients. Future studies with larger sample sizes should verify the results of the current study.

Secondary toxic effect of graphene oxide and graphene quantum dots alters the expression of miR-21 and miR-29a in human cell lines.

For in vitro studies, non-toxic doses of nanomaterials are routinely selected by quantification of live cells after exposing to different concentrations of nanoparticles but considering only morphological changes or viability of cells is not sufficient to conclude that these nanomaterials are non-cytotoxic. Here we investigated if secondary toxicity is active in the cells exposed to non-toxic doses of graphene oxide (GO) and graphene quantum dots (GQDs). Non-cytotoxic dose of 15 µg mL-1 of GO (100 nm) and GQDs (50 nm) was selected according to MTT and Hoechst 33342/PI double staining assays. In order to investigate the secondary toxicity, the expression of miR-21, miR-29a and three genes at both mRNA and protein level were evaluated in MCF-7, HUVEC, KMBC/71 cells 4 and 24 h post exposure. Mitochondrial membrane potential (MMP) was assessed by Rhodamine 123 staining. According to our results, there was no significant decrease in viability of cells after exposure to the non-cytotoxic dose of GO and GQDs, but we observed significant alterations in the expression level of miR-21, miR-29a, Bax, Bcl2 and PTEN genes after treatment in all three cells. In addition to molecular changes, we observed alteration in mitochondrial activity at cellular level. However, we also observed that GO influenced the basal level of genes and MMP more compare to GQDs. Considering that all these genes are involved in breast tumor development and metastasis, the observed changes in miRNA expression and protein synthesis may alter cell fate and susceptibility and cause deviation in the desired outcome of GO and GQDs application in medical research.

Fabrication and biocompatibility assessment of polypyrrole/cobalt(II) metal-organic frameworks nanocomposites.

Nowadays, metal-organic frameworks (MOFs) have emerged as promising tools for different biological applications and therefore, efforts are ongoing to develop more biocompatible MOFs-based nanocomposites. We aimed to fabricate some new conductive nanocomposites of polypyrrole and cobalt-MOF with different weight percentages (PPy/x%Co-MOF) using the solution mixing method and characterize them through FT-IR (Fourier-transform infrared), PXRD (powder X-ray diffraction), SEM (scanning electron microscope), and TEM (transmission electron microscope) techniques. The biocompatibility of nanocomposites was assessed by haemolytic, cytotoxic, and quantitative reverse transcription PCR (qRT-PCR) assays. FT-IR and PXRD results revealed that nanocomposites consisted of pure MOFs and PPy. Moreover, SEM results indicated their spherical morphology along with an average diameter of 190 nm. (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed a concentration, and percentagedependent cytotoxic effect of the nanocomposites on some cell lines including 3T3 fibroblasts, MCF-7, and J774.A1 macrophages. Haematological toxicity of PPy/x%Co-MOF composites was less than 7% in most concentrations. Furthermore, PPy/x%Co-MOF composites did not show any significant effect on the expression of cyclooxygenase-2( COX-2) and inducible nitric oxide synthase( iNOS) genes. In sum, regarding the haemolytic, proinflammatory, and cytotoxic tests, prepared nanocomposite demonstrated the reasonable in vitro biocompatibility which may be considered as a hopeful platform for further investigations including clinical applications.

Distributed robust adaptive control of high order nonlinear multi agent systems.

In this paper, a robust adaptive neural network based controller is presented for multi agent high order nonlinear systems with unknown nonlinear functions, unknown control gains and unknown actuator failures. At first, Neural Network (NN) is used to approximate the nonlinear uncertainty terms derived from the controller design procedure for the followers. Then, a novel distributed robust adaptive controller is developed by combining the backstepping method and the Dynamic Surface Control (DSC) approach. The proposed controllers are distributed in the sense that the designed controller for each follower agent only requires relative state information between itself and its neighbors. By using the Young's inequality, only few parameters need to be tuned regardless of NN nodes number. Accordingly, the problems of dimensionality curse and explosion of complexity are counteracted, simultaneously. New adaptive laws are designed by choosing the appropriate Lyapunov-Krasovskii functionals. The proposed approach proves the boundedness of all the closed-loop signals in addition to the convergence of the distributed tracking errors to a small neighborhood of the origin. Simulation results indicate that the proposed controller is effective and robust.

Adaptive control for a class of MIMO nonlinear time delay systems against time varying actuator failures.

This paper investigates an adaptive controller for a class of Multi Input Multi Output (MIMO) nonlinear systems with unknown parameters, bounded time delays and in the presence of unknown time varying actuator failures. The type of considered actuator failure is one in which some inputs may be stuck at some time varying values where the values, times and patterns of the failures are unknown. The proposed approach is constructed based on a backstepping design method. The boundedness of all the closed-loop signals is guaranteed and the tracking errors are proved to converge to a small neighborhood of the origin. The proposed approach is employed for a double inverted pendulums benchmark and a chemical reactor system. The simulation results show the effectiveness of the proposed method.