Role of ascorbate in lung cellular toxicity mediated by light-exposed parenteral nutrition solution

Neonatal lung injury has been induced experimentally by infusion of multivitamin-containing light-exposed parenteral nutrition (PN) solutions. The objective was to explore the role of ascorbate in toxic effects of light-exposed PN on primary cultured foetal rat lung epithelial cells. Hydroperoxides were measured in 3% amino acid solutions at baseline, immediately after addition of either multivitamins or ascorbate alone (400 μg/mL) and again after a 24-h period of exposure to (or protection from) ambient light. Cellular toxicity was assessed by [C(14)]adenine release. Multivitamins or ascorbate alone increased hydroperoxides in PN, which was attenuated by light protection. Light-exposed PN containing multivitamins was more toxic to cells than baseline or light-protected PN. Exposure to ascorbate at concentrations both lower (< 5 μg/mL) and higher (> 1000 μg/mL) than normally contained in PN-induced oxidant-mediated cell death, as indicated by protective effects of hydroperoxide and hydroxyl radical scavengers. This study concludes that ascorbate generates toxic amounts of peroxide in PN solutions. The types and physiological importance of hydroperoxides induced by pro-oxidant effects of ascorbate require further evaluation in vivo.     

Enhanced Vesicular Stomatitis Virus Targeting of Head and Neck Cancer in Combination with Radiation Therapy or ZD6126 Vascular Disrupting Agent

ABSTRACT: BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 5th most common cancer worldwide. Locally advanced HNSCC are treated with either radiation or chemo-radiotherapy, but still associated with high mortality rate, underscoring the need to develop novel therapies. Oncolytic viruses have been garnering increasing interest as anti-cancer agents due to their preferential killing of transformed cells. In this study, we evaluated the therapeutic potential of mutant vesicular stomatitis virus (VSVdelta51) against the human hypopharyngeal FaDu tumour model in vitro and in vivo. METHODS: MTS assay was utilized to assess cell viability. Flow cytometry and Caspase 3/7 activation was utilized to assess apoptosis. In vivo studies were conducted using CD-1 nude mice. Fluorescence microscopy was utilized to assess viral replication in vitro and in vivo. RESULTS: Our data demonstrated high toxicity of the virus against FaDu cells in vitro, which was associated with induction of apoptosis. In vivo, systemic injection of 1x109 pfu had minimal effect on tumour growth; however, when combined with two doses of ionizing radiation (IR; 5 Gy each) or a single injection of the vascular disrupting agent (ZD6216), the virus exhibited profound suppression of tumour growth, which translated to a prolonged survival in the treated mice. Concordantly, VSVdelta51 combined with ZD6216 led to a significant increase in viral replication in these tumours. CONCLUSIONS: Our data suggest that the combinations of VSVdelta51 with either IR or ZD6216 are potentially novel therapeutic opportunities for HNSCC.     

Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer,synthesized from oxygen heterocyclic natural compounds

Two new series of furochromone and benzofuran derivatives were designed, synthesized and evaluated for their in vitro anticancer activity against MCF-7 and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16, 17a and 18 exhibited the best antiproliferative activities with IC₅₀ values ranging from 1.19 to 2.78?µM against MCF-7 superior to lapatinib as reference standard (IC₅₀; 4.69?µM). Compounds 15a and 18 revealed significant cytotoxic activity against MCF-7 and MDA231, therefore their inhibitory potencies against p38α MAP kinase were evaluated. Remarkably they exhibited significant IC₅₀ of 0.04?µM comparable to SB203580 (IC₅₀; 0.50?µM) as a reference standard. These promising results of cytotoxic activity and significant inhibition of p38α MAP kinase, were confirmed by exploring the effect of benzofuran derivative (18) on the apoptotic induction and cell cycle progression of MCF-7 cell line. Compound 18 induced preG1 apoptosis and cell growth arrest at G2/M phase preventing the mitotic cycle. Moreover it activated the caspase-7 which executes apoptosis. Molecular docking study was carried out using GOLD program to predict the mode of binding interaction of the synthesized compounds into the target p38α MAPK. Additionally, the physicochemical properties and ADME parameters of compound 18 were examined in silico to investigate its drug-likeness.     

Attempts at improving citric acid fermentation by Aspergillus niger in beet-molasses medium

Natural oils with high unsaturated fatty acids content when added at concentrations of 2% and 4% (v/v) to beet molasses (BM) medium caused a considerable increase in citric acid yield from Aspergillus niger. The fermentation capacities were also examined for production of citric acid using BM-oil media under different fermentation conditions. Maximum citric acid yield was achieved in surface culture in the presence of 4% olive oil after 12 days incubation.     

Structural,photoluminescence, and optical characteristics of a Sm3+-doped lead borate–strontium–tungsten glass system: Evaluation of Judd–Ofelt intensity parameters and radiative properties

In this study, the melt quenching approach is used to synthesize a lead borate–strontium-based glass system doped with samarium ions. Modifications in the glass network structure arising from the addition of various concentrations of Sm³⁺ ions were investigated via Fourier transform infrared (FTIR) spectroscopy. FTIR analysis revealed B–O–B bridges, BO₃, and BO₄ units are present. UV–vis–NIR spectroscopic measurement was performed to study the optical absorption spectra. Optical constants such as optical bandgap energies, refractive indices, and other related parameters were evaluated. The lifetime fluorescence decay was measured and ranged between 1.04 and 1.88 ns. The photoluminescence spectra in the range 500–750 nm revealed four transitions from the ground state ⁶G_5/2 to the excited states ⁶H_5/2, ⁶H_7/2, ⁶H_9/2 and ⁶H_11/2 and J–O theory was utilized to study these optical transitions for Sm³⁺ ions. Calculations of the oscillator strengths and J–O intensity parameters were performed and the obtained J–O parameters followed the sequence Ω₄ > Ω₆ > Ω₂. The ratio O/R indicated a high lattice asymmetry around the samarium ions. The values of lifetimes and branching ratios for the fabricated samples emphasized their suitability to be used in laser applications. The current glass samples are good candidates for orange and red emission devices.     

Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells

Background

Molecular profiling of colorectal cancer (CRC) based on global gene expression has revealed multiple dysregulated signalling pathways associated with drug resistance and poor prognosis. However, the role of BMP2 signaling in CRC is not fully characterised.

Methods

Bioinformatics data analysis were conducted on the GSE21510 dataset. Leniviral technology was utilized to stably express BMP2 in the HCT116 CRC model. Gene expression profiling was conducted using Agilent microarray platform while data normalization and bioinformatics were conducted using GeneSpring software. Changes in gene expression were assessed using qRT-PCR. AlamarBlue assay was used to assess cell viability in vitro. In vivo experiments were conducted using SCID mice.

Results

Our data revealed frequent downregulation of BMP2 in primary CRC tissues. Additionally, interrogation of publically available gene expression datasets revealed significant downregulation of BMP2 in metastatic recurrent compared to non-metastatic cancer (p = 0.02). Global gene expression analysis in CRC cells over-expressing BMP2 revealed multiple dysregulated pathways mostly affecting cell cycle and DNA damage response. Concordantly, lentiviral-mediated re-expression of BMP2 inhibited HCT116 CRC growth, sphere formation, clonogenic potential, cell migration, and sensitized CRC cells to 5-fluorouracil (5-FU) in vitro. Additionally, BMP2 inhibited CRC tumor formation in SCID mice.

Conclusions

Our data revealed an inhibitory role for BMP2 in CRC, suggesting that restoration of BMP2 expression could be a potential therapeutic strategy for CRC.

     

Olive Phenolics as c-Met Inhibitors: (-)-Oleocanthal Attenuates Cell Proliferation,Invasiveness, and Tumor Growth in Breast Cancer Models

Dysregulation of the Hepatocyte growth factor (HGF)/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis. (-)-Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (-)-oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (-)-oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (-)-oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (-)-oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (-)-oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.     

Whale Sharks,Rhincodon typus,Aggregate around Offshore Platforms in Qatari Waters of the Arabian Gulf to Feed on Fish Spawn

Whale sharks, Rhincodon typus, are known to aggregate to feed in a small number of locations in tropical and subtropical waters. Here we document a newly discovered major aggregation site for whale sharks within the Al Shaheen oil field, 90 km off the coast of Qatar in the Arabian Gulf. Whale sharks were observed between April and September, with peak numbers observed between May and August. Density estimates of up to 100 sharks within an area of 1 km² were recorded. Sharks ranged between four and eight metres’ estimated total length (mean 6.92±1.53 m). Most animals observed were actively feeding on surface zooplankton, consisting primarily of mackerel tuna, Euthynnus affinis, eggs.     

The Proapoptotic Protein tBid Forms Both Superficially Bound and Membrane-Inserted Oligomers

Bid is a proapopotic activator protein of the Bcl-2 family that plays a pivotal role in controlling mitochondrial outer membrane permeabilization during apoptosis. Here, we characterized the interaction of fluorescently labeled truncated Bid (tBid) with a mitochondria-like supported lipid bilayer at the single-molecule level. The proteins observed at the membrane exhibited a very wide range of mobility. Confocal images of the membrane displayed both diffraction-limited Gaussian spots and horizontal streaks, corresponding to immobile and mobile tBid species, respectively. We observed 1), fast-diffusing proteins corresponding to a loosely, probably electrostatically bound state; 2), slowly diffusing proteins, likely corresponding to a superficially inserted state; and 3), fully immobilized proteins, suggesting a fully inserted state. The stoichiometry of these proteins was determined by normalizing their fluorescence intensity by the brightness of a tBid monomer, measured separately using fluorescence fluctuation techniques. Strikingly, the immobile species were found to be mainly tetramers and higher, whereas the mobile species had on average a significantly lower stoichiometry. Taken together, these results show that as soluble Bid progresses toward a membrane-inserted state, it undergoes an oligomerization process similar to that observed for Bax.