Impact of Some Ions Administration on Sex Ratio and Ovarian Structures in Rabbits.

<b>Background and Objective:</b> The sex pre-selection for offspring before conception is desirable demand especially for the breeding program of farm animals. This study aimed to evaluate the preconception treatment of monovalent and divalent ions on the primary sex ratio, ovarian structures and serum minerals levels in New Zealand white rabbit does. <b>Materials and Methods:</b> Nine New Zealand white rabbits doe<i> </i>(5.4±0.61 months of age and 2.4±0.35 kg of body weight) were used. Rabbits in the 1^st group were given drinking water only (control). While the 2^nd and 3^rd groups were given 1% of (calcium and magnesium) and (sodium and potassium) in daily drinking water, respectively for 15 days before mating. The embryos of each group were individually collected after three days of mating for primary sex detection using SRY (Sex Determining Region Y) Polymerase Chain Reaction (PCR) assay. Mineral analyses for all studied animals were weekly detected in serum before and after mating. <b>Results:</b> The primary sex ratio for embryos of rabbits does receive (Na+K) produced more males (69.7%) while (Ca+Mg) administrated rabbits does produce more females (72.2%). The mineral treatment leads to a significant increase in the number of corpus luteum, total embryos, follicles bleeding and a significant decline in the count of large follicles. Also, there was no significant change in serum Na and Ca levels in the treated groups compared to the control. <b>Conclusion:</b> The preconception administration of Ca+Mg could produce more females while Na+K could produce more males without adverse side effects on serum minerals concentration.

New therapeutic strategy: Personalization of pancreatic cancer treatment-irreversible electroporation (IRE), electrochemotherapy (ECT) and calcium electroporation (CaEP) - A pilot preclinical study.

In this study, irreversible electroporation (IRE), electrochemotherapy (ECT), and calcium electroporation (CaEP) techniques were investigated as new strategies for human pancreatic cancer. Qualification of the patients, best "therapeutic moment" for each patient, safety, and complications after procedures were examined. In this pilot study were included 13 patients in this study, which were operated on in different pancreatic cancer stages. Patients underwent IRE or ECT with intravenous admission of cisplatin or electroporation with calcium intratumoral administration. The IRE procedure was safe for the patients. Medium overall survival for IRE, IRE + CTH, and IRE + CaCl2 was respectively: 16, 29.5, and 19 months comparing to 10 months in control chemotherapy (CTH) group. Thus, IRE, ECT, and CaEP can be effective strategies for pancreatic cancer treatment.

A pH/redox-dual responsive, nanoemulsion-embedded hydrogel for efficient oral delivery and controlled intestinal release of magnesium ions.

It remains a major challenge to achieve efficient oral delivery and controlled intestinal release of ions using hydrogels. Herein, we report a novel, pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel to address this issue. The hydrogel was first synthesized by crosslinking a biocompatible, pH-responsive pseudopeptide, poly(l-lysine isophthalamide) (PLP), and redox-sensitive l-cystine dimethyl ester dihydrochloride (CDE). A suitable amount of magnesium acetate was encapsulated into oil-in-water nanoemulsions, which were then embedded into the lysine-based hydrogel. The resulting composite hydrogel collapsed into a compact structure at acidic gastric pH, but became highly swollen or degraded in the neutral and reducing intestinal environment. The ion release profiles indicated that the nanoemulsion-embedded composite hydrogel could well retain and protect magnesium ions in the simulated gastric fluid (SGF) buffer at pH 1.2, but efficiently release them in the simulated intestinal fluid (SIF) buffer at pH 6.8 in the presence of 1,4-dithiothreitol (DTT) as a reducing agent. Moreover, this composite hydrogel system displayed good biocompatibility. These results suggested that the pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel could be a promising candidate for efficient oral delivery and controlled intestinal release of magnesium and other ions.

Modulation of Properties through Covalent Bond Induced Formation of Strong Ion Pairing between Polyelectrolytes in Injectable Conetwork Hydrogels.

In situ simultaneous formation of both covalent linkages and ion pair is challenging yet necessary to control the biological properties of a hydrogel. We report that the generation of covalent linkages (+N-C) facilitates the simultaneous formation of ion pairs between polyelectrolytes (PEs) in a hydrogel network. Co-injection of tertiary amine functional macromolecules and reactive poly(ethylene glycol) (PEG) containing negatively charged PE leads to the formation of hydrogel conetworks consisting of covalent junctions and ion pairs. Our design is based on the gradual appearance of +N-C junctions followed by formation of ion pairs. This strategy provides an easy access to hydrogel networks bearing a predetermined proportion of ion pair and covalent cross-linking junction. The proportion of ion pair could be varied by introducing a precalculated proportion of mono- and difunctional reactive PEG in the hydrogel system. The topology of the prepolymer and the hydrogel could be modulated (graft) during hydrogel formation. This approach is applicable to obtain covalent/ionic, covalent bond induced purely ionic, and purely covalent hydrogels of several macromolecular entities. The effect of ion pairing in the hydrogels is strongly reflected in the modulus, strain bearing, degradation, free volume, swelling, and drug release properties. The hydrogels exhibit microscopic recovery of modulus after application of high amplitude strain depending on the prepolymer concentration (chain entanglement) and nature of hydrogel network. The hydrogels are hemocompatible, and the covalent/ionic hydrogels show a slower release of methotrexate than that of the purely covalent hydrogel. This work provides an understanding for the in situ construction and manipulation of biological properties of hydrogels through the covalent bond induced formation of a strong ion pair.

Argon Enclosed Droplet Based 3D Microfluidic Device Online Coupled with Time-Resolved ICPMS for Determination of Cadmium and Zinc in Single Cells Exposed to Cadmium Ion.

Time-resolved (TRA)-ICPMS has become a booming subfield of single-cell analysis tools in recent years, while generation of single cells remains the major challenge. Microfluidic devices reveal their great capability and potential in encapsulation of single cells into water droplets. However, current strategies to pinch off droplets require a specific oil phase, which is not compatible to conventional ICPMS and makes the signal of cells in the water phase susceptible. Herein, we built a 3D water-in-gas microfluidic device (3D W/G MFD) with commercially available components, producing single cell droplet enclosed by argon gas. By simply tuning the flow rate of gas and water, the droplets were generated to encapsulate single cells, which significantly reduced the probability of the single signal coming from multiple cells by 1 or 2 orders of magnitude compared to direct injection. The developed oil-free 3D W/G MFD was more friendly to online coupling with TRA-ICPMS than water-in-oil devices. The effect of Cd2+ on HepG2 cells was studied by single cell detecting total Zn with 3D W/G MFD-TRA-ICPMS, and the variation of labile Zn was explored by flow cytometry with an N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide probe. To the best of our knowledge, this work pioneered the exploration of variation in cellular metal content and speciation at the single-cell level, compensating for the deficiency of speciation analysis based on TRA-ICPMS and providing new insights into exploring the complexity of biology.

Encefalopatía hiperamoniémica inducida por ácido valproico en el servicio de urgencias / Valproicacid-induced hyperammonemic encephalopathy in the emergency department

No disponible

Delivery of ionic molecules to anterior chamber by iontophoretic contact lenses.

Ophthalmic delivery via iontophoresis is currently achieved by placing an electrode on the cornea with a counter electrode on the ear or forehead. Here we test the feasibility of placing both electrodes diametrically opposite on a contact lens to create field gradients to transport ionic drugs into the cornea. Commercial lenses loaded with nile blue and fluorescein as hydrophobic and hydrophilic drug analogs, respectively were placed on cadaver rabbit eyes. Electric field gradients were created by placing cathode and anode on the lens diametrically opposite to each other. The incorporation of an electric field (0.125 m-0.250 mA), showed an increased uptake of nile blue and the quantity was a function of the duration of the electric field and the amount of applied current. Similar increases in flux were observed for fluorescein. Confocal fluorescence imaging also shows increased penetration of the dyes in presence of the field. An equivalent circuit model suggests that the field gradients are much stronger in the direction perpendicular to the cornea, which results is minimal short circuiting of current through the tear film. The incorporation of an electric field into a lens could be a less invasive and more effective approach to achieve ophthalmic drug delivery via iontophoresis.

EVALUATION OF EUTHANASIA OF MOON JELLYFISH (AURELIA AURITA) USING SIMPLE SALT SOLUTIONS.

Immersion euthanasia methods reported over the most recent decades for aquatic invertebrates use organic alcohols or halogenated hydrocarbons that can interfere with nuclear magnetic resonance (NMR) analysis. A rolling study design evaluated potassium chloride (KCl), magnesium chloride (MgCl2), and magnesium sulfate (MgSO4) as potential ion-based euthanasia methods for moon jellyfish (Aurelia aurita) destined for metabolomic analysis by NMR spectroscopy. Death was defined as the cessation of autonomous bell pulsing and response to external stimulus. MgCl2 applied at a dose of 142 g/L provided euthanasia within 32 sec of applications without the untoward effects observed with the other two salts. Euthanasia with KCl at the doses tested was associated with abnormal behavior and tissue degradation during dissection. MgSO4 at the doses tested resulted in abnormal behavior and failed to provide rapid euthanasia.

Targeted Transmembrane Delivery of Ca2+ via FA-Nanogel for Synergistically Enhanced Chemotherapy.

Metal ion synergistically enhanced chemotherapy is a promising strategy for cancer treatment. However, targeting delivery of ions toward cancer cells remains challenging for decades. Herein, we developed a novel folic acid-nanogel (termed as FA-nanogel) with alkane chains as diffusion barriers for targeted transmembrane delivery of calcium ions into cancer cells. With the aid of hydrophobic diffusion barriers, the FA-nanogel showed a reduced and sustained speed for release of calcium ions, significantly prolonging the ion effect. Moreover, a pH-sensitive injectable hydrogel-loaded FA-nanogel and chemotherapeutic drug 5-fluorouracil (5-Fu) was synthesized for investigating the synergistic effect of nanogel on chemotherapy. Both in vitro and in vivo experiments confirmed that the intracellular calcium ions were continuously increased because of the targeted delivery ability and ion sustained release ability of the smart FA-nanogel, and the tumor growth was effectively inhibited by the ion synergistic chemotherapy. This study not only provides a powerful nanoplatform for sustained transmembrane delivery of ions into malignant cells but also creates better conditions for improving the therapeutic efficacy of chemotherapy.

The combined effects of nanotopography and Sr ion for enhanced osteogenic activity of bone marrow mesenchymal stem cells (BMSCs).

Both surface topography and chemistry have a significant influence on the biological performance of orthopedic implant coatings. In our study, a surface modification strategy embodying bioactive trace element incorporation and nanotopography construction was employed to enhance the osteogenic activity of calcium silicate (Ca-Si) coatings. We developed strontium-loaded nanolayer on plasma sprayed Ca-Si (CS) coating via hydrothermal treatment which was denoted as Sr-NT-CS. The original CS coating and the CS coating modified with similar nanotopography (NT-CS) were studied in parallel. We investigated the cellular effects of surface topography and released Sr ion on the adhesion, proliferation, differentiation, and mineralization of BMSCs and the associated molecular mechanisms. The results indicated that the nanotopography activated integrin ß1, promoted the spread of BMSCs into a polygonal osteoblastic shape, and induced higher levels of collagen secretion. The Sr incorporation stimulated osteogenic differentiation and mineralization as indicated by the increases in ALP activity and mineralized nodules formation. The examination of gene expressions revealed that Sr ion exerted the effects by interacting with extracellular calcium sensitive receptor (CaSR), and combined with the nanotopographical cue for the up-regulation of osteogenic master transcription factor Runx2. The promoted Runx2 subsequently affected osteoblast (OB) marker genes (BMP-2, BSP, OPN, and OCN), thus driving BMSCs to differentiate into OBs. Moreover, the Sr incorporation inhibited osteoclastogenesis, as indicated by the down-regulation of interleukin-6 (IL-6) and the inhibition of RANKL/RANK system. Those results suggested that our developed Sr-NT-CS coating have combined the effects of nanotopography and Sr ion for enhanced osteogenic activity of BMSCs.

Heterogenic response of prokaryotes toward silver nanoparticles and ions is facilitated by phenotypes and attachment of silver aggregates to cell surfaces.

Tons of anthropogenic silver nanoparticles (AgNPs) are assumed to be released into the environment due to their use in many consumer products. AgNPs are known to be toxic toward microorganisms and thus may harm their specific functions in ecosystems. Here we explore the impact of AgNPs on functioning of single cells in microbial populations at doses typically found in anthropogenic environments. The response of single cells to AgNPs was analyzed by flow cytometry and using the fluorescent dyes propidium iodide and DiBAC4 (3) as markers for cell membrane disintegration and depolarization, respectively. The effects of 10-nm and 30-nm AgNPs on three bacterial species (Mycobacterium frederiksbergense, Pseudomonas putida, and Escherichia coli) showed that the populations split into affected cells and others not showing any malfunction, with varying abundances depending on strains and cell growth states. Further, the dissolution of AgNPs measured with 3 KDa ultrafiltration and inductively coupled plasma-mass-spectrometry to distinguish particle-related effects from toxicity of dissolved Ag revealed that Ag ions were the principal toxicant. AgNP aggregate formation was followed by dynamic light scattering and the aggregates' attachment to cell surfaces was visualized by transmission electron microscopy and scanning electron microscopy-energy dispersive X-ray spectroscopy. An increased AgNP-affected cell fraction relative to the Ag ion impact was identified. The study shows that individual cells in a population cope differently with AgNP induced stress by evolving heterogeneous phenotypes. The response is linked to cell death and cell energy depletion depending on cell type and cell growth states. The attachment of AgNP aggregates to cell surfaces seems to amplify the heterogeneous response. © 2017 International Society for Advancement of Cytometry.

Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF.

Angiogenic capacity of biomaterials is a key asset to drive vascular ingrowth during tissue repair and regeneration. Here we design a unique angiogenic microcarrier based on sol-gel derived mesoporous silica. The microspheres offer a potential angiogenic stimulator, Si ion, 'intrinsically' within the chemical structure. Furthermore, the highly mesoporous nature allows the loading and release of angiogenic growth factor 'extrinsically'. The Si ion is released from the microcarriers at therapeutic ranges (over a few ppm per day), which indeed up-regulates the expression of hypoxia inducing factor 1α (HIF1α) and stabilizes it by blocking HIF-prolyl hydroxylase 2 (PHD2) in HUVECs. This in turn activates the expression of a series of proangiogenic molecules, including bFGF, VEGF, and eNOS. VEGF is incorporated effectively within the mesopores of microcarriers and is then released continuously over a couple of weeks. The Si ion and VEGF released from the microcarriers synergistically stimulate endothelial cell functions, such as cell migration, chemotactic homing, and tubular networking. Furthermore, in vivo neo-blood vessel sprouting in chicken chorioallantoic membrane model is significantly promoted by the Si/VEGF releasing microcarriers. The current study demonstrates the synergized effects of Si ion and angiogenic growth factor through a biocompatible mesoporous microsphere delivery platform, and the concept provided here may open the door to a new co-delivery system of utilizing ions with growth factors for tissue repair and regeneration.

Effects of Excess Copper Ions on Decidualization of Human Endometrial Stromal Cells.

The aim of this study was to investigate the effects of copper ions on decidualization of human endometrial stromal cells (HESCs) cultured in vitro. Firstly, non-toxic concentrations of copper D-gluconate were screened in HESCs based on cell activity. Then, the effects of non-toxic concentrations of copper ions (0~250 µM) were examined on decidualization of human endometrial stromal cells. Our data demonstrated that the mRNA expressions of insulin-like growth factor binding protein (IGFBP-1), prolactin (PRL), Mn-SOD, and FOXO1were down-regulated during decidualization following the treatments with 100 or 250 µM copper ions. Meanwhile, the amount of malonaldehyde (MDA) in the supernatant of HESCs was increased. These results showed that in vitro decidualization of HESCs was impaired by copper treatment.

Magnetically guided delivery of DHA and Fe ions for enhanced cancer therapy based on pH-responsive degradation of DHA-loaded Fe3O4@C@MIL-100(Fe) nanoparticles.

Dihydroartemisinin (DHA) has been investigated in cancer therapy for its reactive oxygen species (ROS) based cytotoxicity originated from interacting with ferrous ions that may reduce or eliminate the multidrug resistance commonly associated with conventional chemotherapy agents. However, synchronously delivery of hydrophobic DHA and Fe (Ⅲ) ions into tumor cells remains a major challenge. In this work, we develop novel Fe3O4@C@MIL-100(Fe) (FCM) nanoparticles for synchronously delivery of DHA and Fe (Ⅲ) for cancer therapy. The MOFs structure based on Fe (Ⅲ) carboxylate materials MIL-100 (Fe) holds great potential for storage/delivery of hydrophobic drug DHA. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show pH-responsive biodegradation and synchronous releasing of DHA and Fe (Ⅲ) upon reaching tumor sites. The intracellular Fe (Ⅲ) will be reduced further to ferrous ion and interact with DHA to increase its cytotoxicity. The potential of this alternative anti-tumor modality is demonstrated in vivo due to an increased intracellular accumulation of DHA in tumor and activated mechanism via co-release of DHA and Fe (Ⅲ), especially under the guidance of an external applied magnetic field.

Permeation of topically applied Magnesium ions through human skin is facilitated by hair follicles.

Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans. Topical magnesium delivery is one of the oldest forms of therapy for skin diseases, for example Dead Sea therapy and Epsom salt baths. Some anecdotal evidence and a few published reports have attributed amelioration of inflammatory skin conditions to the topical application of magnesium. On the other hand, transport of magnesium ions across the protective barrier of skin, the stratum corneum, is contentious. Our primary aim in this study was to estimate the extent of magnesium ion permeation through human skin and the role of hair follicles in facilitating the permeation. Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.

Hydrophilic Ionic Liquids as Ingredients of Gel-Based Dermal Formulations.

Ionic liquids (ILs) have several properties that offer many advantages in dermal drug delivery systems. Depending on the chemical structure, ILs can be used for protection against microorganisms, to enhance skin penetration, and as a solvent. In the present work, SEPINEO™ P 600 formulations and hydroxyethylcellulose gels containing the hydrophilic ILs hexylpyridinium chloride, choline dihydrogen phosphate, and 1-ethyl-3-methylimidazolium ethyl sulfate were prepared, and the influence of the ILs on the formulation properties was evaluated. ILs were successfully incorporated into the emulsion structure, resulting in stable formulations. The antimicrobial activity of the ILs was estimated. The minimal inhibitory concentration values for hexylpyridinium chloride are about 2.5 mg/mL. The other two ILs have no antimicrobial activity. Skin penetration enhancement of caffeine, a hydrophilic model substance, was observed in the presence of hexylpyridinium chloride.

Design and Testing of Electric-Guided Delivery of Charged Particles to the Olfactory Region: Experimental and Numerical Studies.

Neurological drugs delivered to the olfactory region can enter the brain via olfactory pathways and bypass the blood-brain barrier. However, clinical applications of the direct nose-to-brain delivery are rare because of the extremely low olfactory doses using conventional nasal devices. This poor bioavailability is mainly caused by two factors: the complex nasal structure that traps particles in the anterior nose and the complete lack of control over particle motions after their release at the nostrils. In this study, the feasibility of electric-guided delivery to the olfactory region was tested in an anatomically accurate nasal airway model both experimentally and numerically. The nose replicas were prepared using 3-D printing and could be dissembled to reveal the local deposition patterns within the nasal cavity. A test platform was developed that included a dry powder charging system and a particle point-release nozzle. Numerical modeling was conducted using COMSOL and compared to corresponding experiments. Compared to conventional nasal devices, electric-guidance of charged particles noticeably reduced particle losses in the anterior nose and increased depositions in the olfactory region. The thickness and relative permittivity of the wall were observed to affect the electric field strength and olfactory dosages. Consistent deposition patterns were obtained between experiments and numerical simulations in both 2-D and 3-D nose models. Two conceptual designs were proposed to generate, charge, and control aerosols. Results of this study indicate that it is feasible to use an electric field to control charged particles in the human nose. Both electric-guidance and point-release of particles are essential to achieve targeted olfactory delivery. Future studies to refine the aerosol charging and release systems are needed for further enhancement of olfactory dosages.

Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells.

Engineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we investigated the cellular response of lung APCs following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10, which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles. FROM THE CLINICAL EDITOR: Advance in nanotechnology has allowed the production of precise nanoparticles as vaccines. In this regard, pulmonary delivery has the most potential. In this article, the authors investigated the interaction of nanoparticles with various types of lung antigen presenting cells in an attempt to understand the cellular mechanisms. The findings would further help the future design of much improved vaccines for clinical use.

Stimulation of apoptotic pathways in liver cancer cells: An alternative perspective on the biocompatibility and the utility of biomedical glasses.

A host of research opportunities with innumerable clinical applications are open to biomedical glasses if one considers their potential as therapeutic inorganic ion delivery systems. Generally, applications have been limited to repair and regeneration of hard tissues while compositions are largely constrained to the original bioactive glass developed in the 1960s. However, in oncology applications the therapeutic paradigm shifts from repair to targeted destruction. With this in mind, the composition-structure-property-function relationships of vanadium-containing zinc-silicate glasses (0.51SiO2-0.29Na2O-(0.20-X)ZnO-XV2O5, 0 ≤ X ≤ 0.09) were characterized in order to determine their potential as therapeutic inorganic ion delivery systems. Increased V2O5mole fraction resulted in a linear decrease in density and glass transition temperature (Tg).(29)Si MAS NMR peak maxima shifted upfield while(51)V MAS NMR peak maxima were independent of V2O5content and overlapped well with the spectra NaVO3 Increased V2O5mole fraction caused ion release to increase. When human liver cancer cells, HepG2, were exposed to these ions they demonstrated a concentration-dependent cytotoxic response, mediated by apoptosis. This work demonstrates that the zinc-silicate system studied herein is capable of delivering therapeutic inorganic ions at concentrations that induce apoptotic cell death and provide a simple means to control therapeutic inorganic ion delivery.

Effect of charge ratio on lipoplex-mediated gene delivery and liver toxicity.

BACKGROUND: The vast majority of studies investigating gene delivery have utilized cationic delivery vehicles, but anionic nanoparticles can also possess high transfection activity, and offer significant benefits in terms of ease of preparation and reduced toxicity. RESULTS: Our study on lipoplexes possessing cholesterol nanodomains demonstrates that in vitro transfection after exposure to serum can be high at anionic charge ratios, and that this effect is also evident in studies assessing delivery to tumors in vivo, despite reduced circulation times. In addition, accumulation in the liver and lungs is reduced as compared with lipoplexes formulated at cationic charge ratios. CONCLUSION: Lipoplexes prepared at anionic charge ratios offer comparable tumor delivery and reduced liver toxicity despite shorter circulation times.