The Intestinal and Biliary Metabolites of Ibuprofen in the Rat with Experimental Hyperglycemia

Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics; furthermore, it can result in the formation of non-enzyme catalyzed oxidative metabolites. The present work aimed to investigate how experimental hyperglycemia affects the intestinal and biliary appearance of the oxidative and Phase II metabolites of ibuprofen in rats. In vivo studies were performed by luminal perfusion of 250 μM racemic ibuprofen solution in control and streptozotocin-treated (hyperglycemic) rats. Analysis of the collected intestinal perfusate and bile samples was performed by HPLC-UV and HPLC-MS. No oxidative metabolites could be detected in the perfusate samples. The biliary appearance of ibuprofen, 2-hydroxyibuprofen, ibuprofen glucuronide, hydroxylated ibuprofen glucuronide, and ibuprofen taurate was depressed in the hyperglycemic animals. However, no specific non-enzymatic (hydroxyl radical initiated) hydroxylation product could be detected. Instead, the depression of biliary excretion of ibuprofen and ibuprofen metabolites turned out to be the indicative marker of hyperglycemia. The observed changes impact the pharmacokinetics of drugs administered in hyperglycemic individuals.     

Mechanism Study on Nanoparticle Negative Surface Charge Modification by Ascorbyl Palmitate and Its Improvement of Tumor Targeting Ability

Surface charge polarity and density influence the immune clearance and cellular uptake of intravenously administered lipid nanoparticles (LNPs), thus determining the efficiency of their delivery to the target. Here, we modified the surface charge with ascorbyl palmitate (AsP) used as a negatively charged lipid. AsP-PC-LNPs were prepared by dispersion and ultrasonication of AsP and phosphatidylcholine (PC) composite films at various ratios. AsP inserted into the PC film with its polar head outward. The pK_a for AsP was 4.34, and its ion form conferred the LNPs with negative surface charge. Zeta potentials were correlated with the amount and distribution of AsP on the LNPs surface. DSC, Raman and FTIR spectra, and molecular dynamics simulations disclosed that AsP distributed homogeneously in PC at 1–8% (w/w), and there were strong hydrogen bonds between the polar heads of AsP and PC (PO²⁻), which favored LNPs’ stability. But at AsP:PC > 8% (w/w), the excessive AsP changed the interaction modes between AsP and PC. The AsP–PC composite films became inhomogeneous, and their phase transition behaviors and Raman and FTIR spectra were altered. Our results clarified the mechanism of surface charge modification by AsP and provided a rational use of AsP as a charged lipid to modify LNP surface properties in targeted drug delivery systems. Furthermore, AsP–PC composites were used as phospholipid-based biological membranes to prepare paclitaxel-loaded LNPs, which had stable surface negative charge, better tumor targeting and tumor inhibitory effects.     

Uptake of Pharmaceutical Pollutants and Their Metabolites from Soil Fertilized with Manure to Parsley Tissues

Manure is a major source of soil and plant contamination with veterinary drugs residues. The aim of this study was to evaluate the uptake of 14 veterinary pharmaceuticals by parsley from soil fertilized with manure. Pharmaceutical content was determined in roots and leaves. Liquid chromatography coupled with tandem mass spectrometry was used for targeted analysis. Screening analysis was performed to identify transformation products in the parsley tissues. A solid-liquid extraction procedure was developed combined with solid-phase extraction, providing recoveries of 61.9–97.1% for leaves and 51.7–95.6% for roots. Four analytes were detected in parsley: enrofloxacin, tylosin, sulfamethoxazole, and doxycycline. Enrofloxacin was detected at the highest concentrations (13.4–26.3 ng g⁻¹). Doxycycline accumulated mainly in the roots, tylosin in the leaves, and sulfamethoxazole was found in both tissues. 14 transformation products were identified and their distribution were determined. This study provides important data on the uptake and transformation of pharmaceuticals in plant tissues.     

Biochemical and Molecular Investigation of the Effect of Saponins and Terpenoids Derived from Leaves of Ilex aquifolium on Lipid Metabolism of Obese Zucker Rats

Ilex paraguariensis, the holly tree, is a plant with recognized biological properties, whose aqueous infusions are known as “Yerba mate”, that regulate lipid metabolism, reduce obesity, and improve brain stimulation. In the present study, the effect of standardized saponin and terpenoid fractions of a European taxon, Ilex aquifolium, on blood biochemical parameters in a rat model of metabolic disorder, (fa/fa) Zucker, are presented. The profiles of the volatile fractions of two species and six European varieties of Ilex were investigated. After selecting the best variety, the saponin and terpenoid fractions were isolated and standardized, and animals were fed 10 mg kg⁻¹ b.w. for 8 weeks. A statistically significant decrease in liver adiposity was observed, confirmed by histology and quantitative identification (gas chromatography–mass spectrometry analyses of hepatic lipids. RT-qPCR analysis of gene expression in the aorta revealed that the administration of the terpenoid fraction downregulated LOX-1, suggesting a reduction in atherosclerotic stimuli. In addition, a statistically significant reduction (p < 0.05) in PPARγ for the saponin fraction was observed in the liver. The expression of the ACAT-1 gene in the liver, responsible for the formation of cholesterol esters, increased significantly in the group receiving the terpenoid fraction compared to the control, which was also confirmed by the analysis of individual blood biochemical parameters. The opposite effect was observed for saponins. Taking the above into account, it is shown for the first time that Ilex aquifolium can be a source of compounds that positively influence lipid metabolism.     

Precise Quantification of Molybdate In Vitro by the FRET-Based Nanosensor ‘MolyProbe’

Molybdenum (Mo) is an essential trace element in all kingdoms of life. Mo is bioavailable as the oxyanion molybdate and gains biological activity in eukaryotes when bound to molybdopterin, forming the molybdenum cofactor. The imbalance of molybdate homeostasis results in growth deficiencies or toxic symptoms within plants, fungi and animals. Recently, fluorescence resonance energy transfer (FRET) methods have emerged, monitoring cellular and subcellular molybdate distribution dynamics using a genetically encoded molybdate-specific FRET nanosensor, named MolyProbe. Here, we show that the MolyProbe system is a fast and reliable in vitro assay for quantitative molybdate determination. We added a Strep-TagII affinity tag to the MolyProbe protein for quick and easy purification. This MolyProbe is highly stable, resistant to freezing and can be stored for several weeks at 4 °C. Furthermore, the molybdate sensitivity of the assay peaked at low nM levels. Additionally, The MolyProbe was applied in vitro for quantitative molybdate determination in cell extracts of the plant Arabidopsis thaliana, the fungus Neurospora crassa and the yeast Saccharomyces cerevisiae. Our results show the functionality of the Arabidopsis thaliana molybdate transporter MOT1.1 and indicate that FRET-based molybdate detection is an excellent tool for measuring bioavailable Mo.     

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.     

Promising Chemotherapy for Malignant Pediatric Brain Tumor in Recent Biological Insights

Brain tumors are the most widespread malignancies in children around the world. Chemotherapy plays a critical role in the treatment of these tumors. Although the current chemotherapy process has a remarkable outcome for a certain subtype of brain tumor, improving patient survival is still a major challenge. Further intensive treatment with conventional non-specific chemotherapy could cause additional adverse reactions without significant advancement in survival. Recently, patient derived brain tumor, xenograft, and whole genome analysis using deep sequencing technology has made a significant contribution to our understanding of cancer treatment. This realization has changed the focus to new agents, targeting the molecular pathways that are critical to tumor survival or proliferation. Thus, many novel drugs targeting epigenetic regulators or tyrosine kinase have been developed. These selective drugs may have less toxicity in normal cells and are expected to be more effective than non-specific chemotherapeutics. This review will summarize the latest novel targets and corresponding candidate drugs, which are promising chemotherapy for brain tumors according to the biological insights.     

Investigation of the Oxidation of Serum Albumin by Iodine

In studies of metabolism using serum albumin labelled with iodine (I¹³¹ and I¹²⁵) the question of the biological equivalence of the labelled material is of decisive importance. Changes of the chemical and biological characteristic of various proteins after iodination have been found by a number of workers [1–4], especially with reference to chromatographic behaviour, rate of metabolism in the organism and content of thiol. Oxidation of sulphhydryl groups can lead to interchain disulphide bridge-linkage and the formation of molecule aggregates.     

Theoretical Analysis of the Biological Thermal Effect of Millimeter Waves in Layered-Dielectric-Slabs

The theory is presented for one method of determining the biological thermal effect of millimeter waves in microwave radiometry. It has been studied theoretically that millimeter waves propagation and absorption in a human body. The model is a plane straticulate homogeneous slab of tissues under the irradiance of normal incidence plane wave. It has been discussed by obtaining the electromagnetic field, absorbent power, specific absorption rate, temperature field and their distributions in the human trunk model. Also, the principle of thermal therapeutics of millimeter waves to cancer has been discussed preliminarily.     

Tumor Hypoxia Heterogeneity Affects Radiotherapy: Inverse-Percolation Shell-Model Monte Carlo Simulations

Tumor hypoxia was discovered a century ago, and the interference of hypoxia with all radiotherapies is well known. Here, we demonstrate the potentially extreme effects of hypoxia heterogeneity on radiotherapy and combination radiochemotherapy. We observe that there is a decrease in hypoxia from tumor periphery to tumor center, due to oxygen diffusion, resulting in a gradient of radiative cell-kill probability, mathematically expressed as a probability gradient of occupied space removal. The radiotherapy-induced break-up of the tumor/TME network is modeled by the physics model of inverse percolation in a shell-like medium, using Monte Carlo simulations. The different shells now have different probabilities of space removal, spanning from higher probability in the periphery to lower probability in the center of the tumor. Mathematical results regarding the variability of the critical percolation concentration show an increase in the critical threshold with the applied increase in the probability of space removal. Such an observation will have an important medical implication: a much larger than expected radiation dose is needed for a tumor breakup enabling successful follow-up chemotherapy. Information on the TME’s hypoxia heterogeneity, as shown here with the numerical percolation model, may enable personalized precision radiation oncology therapy.