Targeting Myc-driven stress addiction in colorectal cancer.

MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of various types of cancer cells. MYC rearrangement and amplification is a common cause of hematologic malignancies. In epithelial cancers such as colorectal cancer, genetic alterations in MYC are rare. Activation of Wnt, ERK/MAPK, and PI3K/mTOR pathways dramatically increases Myc levels through enhanced transcription, translation, and protein stability. Elevated Myc promotes stress adaptation, metabolic reprogramming, and immune evasion to drive cancer development and therapeutic resistance through broad changes in transcriptional and translational landscapes. Despite intense interest and effort, Myc remains a difficult drug target. Deregulation of Myc and its targets has profound effects that vary depending on the type of cancer and the context. Here, we summarize recent advances in the mechanistic understanding of Myc-driven oncogenesis centered around mRNA translation and proteostress. Promising strategies and agents under development to target Myc are also discussed with a focus on colorectal cancer.

Role of biologically important imidazole moiety on the antimicrobial and anticancer activity of Fe(III) and Mn(II) complexes.

Currently, most pathogens influencing a number of epidemics outline a notable warning to human health. It has pushed researchers to design new antimicrobial drugs using transition metals that are studied in proceeding fewer years for their antimicrobial properties. Henceforth, in this work, two mononuclear complexes [Imz-H][Fe(pda)2]⋅1⋅3H2O (1) and [Mn(Imz)6]⋅2Cl-⋅2H2O (2) [Imz = imidazole and H2pda = 2,6 pyridine dicarboxylic acid] are isolated and characterized systematically by various spectral and single-crystal XRD studies. The antimicrobial activity of the present hexadentate complexes of Fe(III) and Mn(II) against Gram-positive as well as Gram-negative bacteria is also assessed. Augmented activity against standard isolates of Staphylococcus aureus with a minimum inhibitory concentration (MIC) is observed. Similar activity was also observed toward Escherichia coli, Klebsiella pneumoniae and Listeria monocytogenes. 1 and 2 have excellent bactericidal activity, and no resistant mutant for S. aureus was seen. The compound also unveiled antibiofilm activity and was capable to disrupt significantly the pre-formed biofilms and this property was confirmed by XTT assay experiment. The MTT assay data indicate that 1 and 2 can be used as anticancer agents toward the RAW 64.7 (human macrophage/monocyte) cell line. Further, the molecular docking study reveals that the role of imidazole is very important in the biological activity of these complexes. Moreover, our results suggest that 1 and 2 with its effective anti-microbial, anti-biofilm and cytotoxicity activity can be used to treat bacterial and fungal infections and could be appraised clinically for further applications.Communicated by Ramaswamy H. Sarma.

Corrigendum: Olax scandens Mediated Biogenic Synthesis of Ag-Cu Nanocomposites: Potential Against Inhibition of Drug-Resistant Microbes.

[This corrects the article DOI: 10.3389/fchem.2020.00103.].

Bio-Mediated Synthesis of Reduced Graphene Oxide Nanoparticles from Chenopodium album: Their Antimicrobial and Anticancer Activities.

A novel method of preparing reduced graphene oxide (RGOX) from graphene oxide (GOX) was developed employing vegetable extract, Chenopodium album, as a reducing and stabilizing agent. Chenopodium album is a green leafy vegetable with a low shelf life, fresh leaves of this vegetable are encouraged to be used due to high water content. The previously modified 'Hummers method' has been in practice for the preparation of GOX by using precursor graphite powder. In this study, green synthesis of RGOX was functionally verified by employing FTIR and UV-visible spectroscopy, along with SEM and TEM. Our results demonstrated typical morphology of RGOX stacked in layers that appeared as silky, transparent, and rippled. The antibacterial activity was shown by analyzing minimal inhibitory concentration values, agar diffusion assay, fluorescence techniques. It showed enhanced antibacterial activity against Gram-positive and Gram-negative bacteria in comparison to GOX. It has also been shown that the synthesized compound exhibited enhanced antibiofilm activity as compared to its parent compound. The efficacy of RGOX and GOX has been demonstrated on a human breast cancer cell line, which suggested RGOX as a potential anticancer agent.

Olax scandens Mediated Biogenic Synthesis of Ag-Cu Nanocomposites: Potential Against Inhibition of Drug-Resistant Microbes.

In the present study, we have synthesized silver-copper nanocomposites (Ag-Cu NCs) using an Olax scandens leaf extract (green synthesis method) and evaluated their antimicrobial potential against less susceptible pathogens. The kinetics of Ag-Cu NCs synthesis was followed by UV-VIS and fluorescence spectroscopy. The physicochemical characterization of as-synthesized Ag-Cu NCs was executed using electron microscopy, Energy Dispersive X-Ray, Fourier Transform Infrared Spectroscopy, and a Differential Light Scattering method. As-synthesized Ag-Cu NCs induced the formation of Reactive Oxygen Species (ROS), thereby causing alteration and decrementation of cellular proteins, DNA, lipids, etc., and eventually leading to cell death, as determined by a Live/Dead assay. Next, we assessed the anti-biofilm potential of as-synthesized Ag-Cu NCs against biofilm forming bacteria. The as-synthesized Ag-Cu NCs, when compared to monometallic silver nanoparticles, exhibited significantly higher anti-microbial activity against both sensitive as well as drug resistant microbial isolates.

Cardiac glycoside digoxin ameliorates pro-inflammatory cytokines in PBMCs of rheumatoid arthritis patients in vitro.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by hyperplasia of the synovial membrane along with persistent inflammation of joints. Earlier studies suggest the crucial role of Th1 and Th17 subsets of T-helper cells in the pathogenesis of RA. Digoxin, a cardiac glycoside, is widely used in the treatment of heart failure. Keeping into consideration the potential of digoxin to regulate inflammatory responses in the host, we assessed its effect on the peripheral blood mononuclear cells (PBMCs) of RA patients. The PBMCs were incubated with a varying amount (10-500 nM) of digoxin for 24 h at 37 °C. There was a significant reduction in the population of Th17 cells upon treatment with digoxin. On the other hand, the digoxin treatment failed to modify the expression of T-bet and IFN-γ at both proteins as well as mRNA level in the treated PBMCs. The cardiac glycoside also inhibited transcription factor ROR-γt in the Th17 cells. We also found a decrease in the levels of IL-1ß, IL-6, IL-17, and IL-23 cytokines in the culture supernatant of digoxin treated PBMCs isolated from RA patients. The data of the present study suggest the preferential role of digoxin in suppressing the differentiation of Th17 cells in RA patients.

A quinoline-based fluorescent probe for selective detection and real-time monitoring of copper ions - a differential colorimetric approach.

A quinoline moiety was used as a building block for designing a probe for the selective detection of copper ions in a partially aqueous medium. We have developed a molecular sensing system which gives insight into the complex physiological and redox aspects of labile copper. The probe provides a colorimetric approach for distinguishing cuprous and cupric ions along with their simultaneous discrimination from other metal ions in the visible range of the spectrum. The chemosensor showed a remarkable fluorescence enhancement along with a significant bathochromic shift of about 35 nm. The detection limit of the probe was found to be 1.03 µM which is optimally favorable to be applied in real-time monitoring. Fabrication of paper strips with the probe was done to detect the presence of cuprous ions in the real sample. The value of the binding constant (1.37 × 104 M-1) suggests stable complex formation between the metal ion and the sensing probe. The photoluminescence and structural aspects of the chemosensor were characterized by using fluorescence, absorption, ESI-MS, and 1H NMR spectroscopy. Furthermore, the cytotoxic nature and bioimaging properties of the probe were interpreted in vitro on RAW 264.7 macrophage cell lines and peripheral blood mononuclear cells (PBMCs) respectively.

T helper cell subpopulations repertoire in peripheral blood and its correlation with sex of newly diagnosed arthritis patients: A gender based study.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder. Autoreactive T cells play a very significant role in the pathogenesis of RA. However, the exact mechanisms of disease severity and pathogenesis are poorly understood. We attempted to correlate T-helper cell activities with sexes of newly diagnosed patients with RA. The patients were divided based on their sex and disease severity. Examination of the expression of various factors using quantitative real-time PCR and FACS analysis of peripheral blood mononuclear cells revealed that T-bet, ROR-γt, Foxp3, and the level of cytokines associated with Th1 cells were almost identical among male and female patients with RA. Interestingly, there was a high correlation between Th17 expression and disease severity in female patients with RA. In general, there was no significant correlation between Th1 cell population and the disease severity in newly diagnosed patients with RA. In contrast, the frequency of both Th17 and Treg cells was higher in patients with more severe disease. The results suggested that, in patients with RA, the T-helper cell balance within peripheral blood was skewed towards the Th17 and Treg phenotypes. Besides Th17- and Treg-associated cytokines, elevated expression of IL-27/IL-23 cytokines might also be responsible for increased disease severity in female patients with RA.