Tissue Distribution, Pharmacokinetics, and Effect of Hematological and Biochemical Parameters of Acute Intravenous Administration of Silver Nanoparticles in Rats.

The widespread biomedical and commercial applications of silver nanoparticles (AgNPs) have increased their potential for human and environmental exposure and toxicity to human health. The bio-distribution and toxicity of AgNPs in rodents following inhalation, intratracheal instillation, and oral ingestion are well documented; however, little is known about the bio-distribution of intravenously (IV)-administered AgNPs and their organ-specific pathophysiological effects. Here, we investigate the pharmacokinetic pattern and tissue distribution of AgNPs in male rats following IV administration. The animals were humanely sacrificed after 10 min, 1 h, 6 h, 12 h, 24 h, and 168 h of AgNP administration, and the silver (Ag) content was measured from blood samples and various tissues following acid digestion. The AgNPs were readily absorbed and subsequently distributed into most organs predominantly in the colon, small intestine, kidney, and heart after 6 h; however, they were the highest in the spinal cord after 168 h. White blood cells (WBCs) were significantly increased (42-60%) in AgNP-administered animals at all time points except 10 min. Regarding platelets, all AgNP-administered animals showed counts 7.8-39.2% lower, with the lowest count at 168 h post-administration. In the case of lymphocytes (LYMs), the AgNP-treated animals exhibited a count 19.5-41% lower at 10 min and 1 h post-administration; however, the animals at 168 h post-administration showed a count 30.5% more. The mean corpuscular hemoglobin (MCH) counts from the AgNP-treated animals were decreased by 50-62%. The concentrations of aspartate transaminase (AST), urea, and creatinine were increased in the AgNP-treated animals. Taken together, the results suggest that the acute IV administration of AgNPs alters metabolic and hematological parameters in animals and may pose a health risk to humans.

Effects of Dietary Doum Palm Fruit Powder on Growth, Antioxidant Capacity, Immune Response, and Disease Resistance of African Catfish, Clarias gariepinus (B.).

Application of herbal immune-stimulants for modulation of fish growth and immune response has received great interest during the past decades. With several pharmacological properties, Doum palm, Hyphaene thebaica (Mart.) is known to be a beneficial medicinal plant. The objective of this study was to investigate the effects of the dietary addition of doum palm fruit powder (DPFP) on growth performance, non-specific immune response, and antioxidant parameters of African catfish, Clarias gariepinus (B.). A total of 120 fish (average initial weight 60.50 ± 0.04 g) were randomly allocated to four groups (three replicates/group, 10 fish/aquarium); a basal diet without DPFP supplementation was used as a control, and three other diets were prepared by supplementing 5, 10, or 15 g kg-1 DPFP for a ten-week feeding period. Following ten weeks of feeding, the fish were challenged with Aeromonas hydrophila (as an immune challenge test), and mortalities were recorded. In comparison to the control diet, dietary DPFP significantly improved growth parameters, including final body weight, body weight gain (WG), specific growth rate (SGR), feed conversion ratio (FCR), and protein efficiency ratio (PER), along with an increase in the content of dry matter of the whole body, in a concentration-dependent manner. Moreover, the heights of intestinal villi, numbers of goblet cells, and intraepithelial lymphocytes (IEL) exhibited marked escalation in all parts of the intestine by increasing the level of DPFP, except for numbers of IEL in the proximal part. The decline in serum glucose, cholesterol, and triglyceride levels was prominent in DPFP10 and DPFP15 groups respective to the DPFP0 group. Furthermore, DPFP boosted the hepatic level of catalase (CAT) in the fish, in a dose-dependent manner; meanwhile, the activity of superoxide dismutase (SOD) and reduced glutathione (GSH) content were also augmented in DPFP10 and DPFP15 groups respective to the DPFP0 group. Dietary DPFP (DPFP15 followed by DPFP10 then DPFP5) led to a pronounced enhancement in the innate immune response (phagocytic percent and index, lysozyme activity, nitric oxide (NO) production, and sialoglycans, namely α 2,3-sialyltransferase and α 2,6-sialyltransferase content); however, the myeloperoxidase (MPO) activity was reduced. Significantly higher relative percentage survival (RPS, 88.56%) of the fish, following the A. hydrophila challenge, was observed for the DPFP15 group. We can suggest that DPFP can beneficially influence fish growth, intestinal histomorphology, hepatic levels of catalase (CAT), superoxide dismutase (SOD) activity and glutathione (GSH) content, immune response, and disease resistance against A. hydrophila challenge.

Cancer cell death induced by nanomagnetolectin.

Magnetic nanoparticles represent a new paradigm for molecular targeting therapy in cancer. However, the transformative targeting potential of magnetic nanoparticles has been stymied by a key obstacle-safe delivery to specified target cells in vivo. As cancer cells grow under nutrient deprivation and hypoxic conditions and decorate cell surface with excessive sialoglycans, sialic acid binding lectins might be suitable for targeting cancer cells in vivo. Here we explore the potential of magnetic nanoparticles functionalized with wheat germ lectin (WGA) conjugate, so-called nanomagnetolectin, as apoptotic targetable agents for prostate cancer. In the presence of magnetic field (magnetofection) for 15min, 2.46nM nanomagnetolectin significantly promoted apoptosis (∼12-fold, p value <0.01) of prostate cancer cells (LNCaP, PC-3, DU-145) compared to normal prostate epithelial cells (PrEC, PNT2, PZ-HPV-7), when supplemented with 10mM sialic acid under nutrient deprived condition. Nanomagnetolectin targets cell-surface glycosylation, particularly sialic acid as nanomagnetolectin induced apoptosis of cancer cells largely diminished (only 2 to 2.5-fold) compared to normal cells. The efficacy of magnetofected nanomagnetolectin was demonstrated in orthotopically xenografted (DU-145) mice, where tumor was not only completely arrested, but also reduced significantly (p value <0.001). This was further corroborated in subcutaneous xenograft model, where nanomagnetolectin in the presence of magnetic field and photothermal heating at ∼42°C induced apoptosis of tumor by ∼4-fold compared to tumor section heated at ∼42°C, but without magnetic field. Taken all together, the study demonstrates, for the first time, the utility of nanomagnetolectin as a potential cancer therapeutic.

Harnessing cancer cell metabolism for theranostic applications using metabolic glycoengineering of sialic acid in breast cancer as a pioneering example.

Abnormal cell surface display of sialic acids - a family of unusual 9-carbon sugars - is widely recognized as distinguishing feature of many types of cancer. Sialoglycans, however, typically cannot be identified with sufficiently high reproducibility and sensitivity to serve as clinically accepted biomarkers and similarly, almost all efforts to exploit cancer-specific differences in sialylation signatures for therapy remain in early stage development. In this report we provide an overview of important facets of glycosylation that contribute to cancer in general with a focus on breast cancer as an example of malignant disease characterized by aberrant sialylation. We then describe how cancer cells experience nutrient deprivation during oncogenesis and discuss how the resulting metabolic reprogramming, which endows breast cancer cells with the ability to obtain nutrients during scarcity, constitutes an "Achilles' heel" that we believe can be exploited by metabolic glycoengineering (MGE) strategies to develop new diagnostic methods and therapeutic approaches. In particular, we hypothesize that adaptations made by breast cancer cells that allow them to efficiently scavenge sialic acid during times of nutrient deprivation renders them vulnerable to MGE, which refers to the use of exogenously-supplied, non-natural monosaccharide analogues to modulate targeted aspects of glycosylation in living cells and animals. In specific, once non-natural sialosides are incorporated into the cancer "sialome" they can be exploited as epitopes for immunotherapy or as chemical tags for targeted delivery of imaging or therapeutic agents selectively to tumors.

Lectin staining and Western blot data showing differential sialylation of nutrient-deprived cancer cells to sialic acid supplementation.

This report provides data that are specifically related to the differential sialylation of nutrient deprived breast cancer cells to sialic acid supplementation in support of the research article entitled, "Nutrient-deprived cancer cells preferentially use sialic acid to maintain cell surface glycosylation" [1]. Particularly, breast cancer cells, when supplemented with sialic acid under nutrient deprivation, display sialylated glycans at the cell surface, but non-malignant mammary cells show sialylated glycans intracellularly. The impact of sialic acid supplementation under nutrient deprivation was demonstrated by measuring levels of expression and sialylation of two markers, EGFR1 and MUC1. This Data in Brief article complements the main manuscript by providing detailed instructions and representative results for cell-level imaging and Western blot analyses of changes in sialylation during nutrient deprivation and sialic acid supplementation. These methods can be readily generalized for the study of many types of glycosylation and various glycoprotein markers through the appropriate selection of fluorescently-labeled lectins.

Nutrient-deprived cancer cells preferentially use sialic acid to maintain cell surface glycosylation.

Cancer is characterized by abnormal energy metabolism shaped by nutrient deprivation that malignant cells experience during various stages of tumor development. This study investigated the response of nutrient-deprived cancer cells and their non-malignant counterparts to sialic acid supplementation and found that cells utilize negligible amounts of this sugar for energy. Instead cells use sialic acid to maintain cell surface glycosylation through complementary mechanisms. First, levels of key metabolites (e.g., UDP-GlcNAc and CMP-Neu5Ac) required for glycan biosynthesis are maintained or enhanced upon Neu5Ac supplementation. In concert, sialyltransferase expression increased at both the mRNA and protein levels, which facilitated increased sialylation in biochemical assays that measure sialyltransferase activity as well as at the whole cell level. In the course of these experiments, several important differences emerged that differentiated the cancer cells from their normal counterparts including resistant to sialic acid-mediated energy depletion, consistently more robust sialic acid-mediated glycan display, and distinctive cell surface vs. internal vesicle display of newly-produced sialoglycans. Finally, the impact of sialic acid supplementation on specific markers implicated in cancer progression was demonstrated by measuring levels of expression and sialylation of EGFR1 and MUC1 as well as the corresponding function of sialic acid-supplemented cells in migration assays. These findings both provide fundamental insight into the biological basis of sialic acid supplementation of nutrient-deprived cancer cells and open the door to the development of diagnostic and prognostic tools.

Live cell integrated surface plasmon resonance biosensing approach to mimic the regulation of angiogenic switch upon anti-cancer drug exposure.

In this work, we report a novel surface plasmon resonance (SPR) based live-cell biosensing platform to measure and compare the binding affinity of vascular endothelial growth factor (VEGF) to vascular endothelial growth factor receptor (VEGFR) and VEGF to bevacizumab. Results have shown that bevacizumab binds VEGF with a higher association rate and affinity compared to VEGFR. Further, this platform has been employed to mimic the in vivo condition of the VEGF-VEGFR angiogenic switch. Competitive binding to VEGF between VEGFR and bevacizumab was monitored in real-time using this platform. Results demonstrated a significant blockage of VEGF-VEGFR binding by bevacizumab. From the results, it is evident that the proposed strategy is simple and highly sensitive for the direct and real-time measurements of bevacizumab drug efficacy to the VEGF-VEGFR angiogenic switch in living SKOV-3 cells.

Infants of diabetic mothers. A cohort study.

OBJECTIVE: To determine the outcome of infants born to diabetic mothers at Security Forces Hospital, Riyadh, Saudi Arabia, and compare the complications seen in these infants with infants of non-diabetic mothers. METHODS: This is a concurrent prospective cohort study of a population of newborn infants delivered at Security Forces Hospital, Riyadh, Saudi Arabia for diabetic mothers between January 2011 and November 2011. RESULTS: A total of 601 infants were enrolled in the study consisting of 319 infants of non-diabetic mothers, and 282 infants of diabetic mothers. Infants of diabetic mothers showed significantly higher rates of associated complications and prolonged hospital stay reflected in their admission to the neonatal intensive care when compared with infants of non-diabetic mothers. There was no difference in rate of complications between infants of gestational diabetics and pre-gestational diabetics. CONCLUSION: Our study showed that diabetic pregnancies are associated with an increased incidence of neonatal complications. These seem to be related to the degree of maternal glycemic control. The higher rates of complications among our infants of diabetic mothers, particularly major congenital malformations call for those involved in the care of diabetic mothers to consolidate their efforts to facilitate early booking in specialist clinics.

Lectin approaches for glycoproteomics in FDA-approved cancer biomarkers.

The nine FDA-approved protein biomarkers for the diagnosis and management of cancer are approaching maturity, but their different glycosylation compositions relevant to early diagnosis still remain practically unexplored at the sub-glycoproteome scale. Lectins generally exhibit strong binding to specific sub-glycoproteome components and this property has been quite poorly addressed as the basis for the early diagnosis methods. Here, we discuss some glycoproteome issues that make tackling the glycoproteome particularly challenging in the cancer biomarkers field and include a brief view for next generation technologies.

Preferential lectin binding of cancer cells upon sialic acid treatment under nutrient deprivation.

The terminal monosaccharide of glycoconjugates on a eukaryotic cell surface is typically a sialic acid (Neu5Ac). Increased sialylation usually indicates progression and poor prognosis of most carcinomas. Here, we utilize two human mammary epithelial cell lines, HB4A (breast normal cells) and T47D (breast cancer cells), as a model system to demonstrate differential surface glycans when treated with sialic acid under nutrient deprivation. Under a starved condition, sialic acid treatment of both cells resulted in increased activities of α2→3/6 sialyltransferases as demonstrated by solid phase assay using lectin binding. However, a very strong Maackia amurensis agglutinin I (MAL-I) staining on the membrane of sialic acid-treated T47D cells was observed, indicating an increase of Neu5Acα2→3Gal on the cell surface. To our knowledge, this is a first report showing the utility of lectins, particularly MAL-I, as a means to discriminate between normal and cancer cells after sialic acid treatment under nutrient deprivation. This method is sensitive and allows selective detection of glycan sialylation on a cancer cell surface.