Experimental models of maternal–fetal interface and their potential use for nanotechnology applications

During pregnancy, the placenta regulates the transfer of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams and is a key determinant of fetal exposure to xenobiotics from the mother. To study the disposition of substances through the placenta, various experimental models are used, especially the perfused placenta, placental villi explants, and cell lineage models. In this context, nanotechnology, an area of study that is on the rise, enables the creation of particles on nanometric scales capable of releasing drugs aimed at specific tissues. An important reason for furthering the studies on transplacental transfer is to explore the potential of nanoparticles (NPs), in new delivery strategies for drugs that are specifically aimed at the mother, the placenta, or the fetus and that involve less toxicity. Due to the fact that the placental barrier is essential for the interaction between the maternal and fetal organisms as well as the possibility of NPs being used in the treatment of various pathologies, the aim of this review is to present the main experimental models used in studying the maternal–fetal interaction and the action of NPs in the placental environment.     

Turgor-dependent unloading of assimilates from coats of developing legume seed. Assessment of the significance of the phenomenon in the whole plant

The in vivo significance of turgor-dependent unloading was evaluated by examining assimilate transport to and within intact developing seeds of Phaseolus vulgaris (cv. Redland Pioneer) and Vicia faba (cv. Coles Prolific). The osmotic potentials of the seed apoplast were low. As a result, the osmotic gradients to the seed coat symplast were relatively small (i.e. 0.1 to 0.3 MPa). Sap concentrations of sucrose and potassium in the seed apoplast and coat symplast accounted for some 45 to 60% of the osmotic potentials of these compartments. Estimated turnover times of potassium and sucrose in the seed apoplast of < 1 h were some 5 to 13 times faster than the respective turnover times in the coat symplast pools. The small osmotic gradient between the seed apoplast and coat symplast combined with the relatively rapid turnover of solutes in the apoplast pool, confers the potential for a small change in assimilate uptake by the cotyledons to be rapidly translated into an amplified shift in the cell turgor of the seed coat. Observed adjustments in the osmotic potentials of solutions infused between the coat and cotyledons of intact seed were consistent with the in vivo operation of turgor-dependent unloading of solutes from the coat. Homeostatic regulation of turgor-dependent unloading was indicated by the maintenance of apoplast osmotic potentials of intact seeds when assimilate balance was manipulated by partial defoliation or elevating pod temperature. In contrast, osmotic potentials of the coat symplast adjusted upward to new steady values over a 2 to 4 h period. The resultant downward shift in coat cell turgor could serve to integrate phloem import into the seed coat with the new rates of efflux to the seed apoplast. Circumstantial evidence for this linkage was suggested by the approximate coincidence of the turgor changes with those in stem levels of ³²P used to monitor phloem transport. The results obtained provide qualified support for the in vivo operation of a turgor homeostat mechanism. It is proposed that the homeostat functions to integrate assimilate demand by the cotyledons with efflux from and phloem import into the coats of developing legume seed.     

Controlled release of adeno-associated virus from alginate hydrogel microbeads with enhanced sensitivity to ultrasound

Adeno-associated virus (AAV)-based gene therapy holds promise as a fundamental treatment for genetic disorders. For clinical applications, it is necessary to control AAV release timing to avoid an immune response to AAV. Here we propose an ultrasound (US)-triggered on-demand AAV release system using alginate hydrogel microbeads (AHMs) with a release enhancer. By using a centrifuge-based microdroplet shooting device, the AHMs encapsulating AAV with tungsten microparticles (W-MPs) are fabricated. Since W-MPs work as release enhancers, the AHMs have high sensitivity to the US with localized variation in acoustic impedance for improving the release of AAV. Furthermore, AHMs were coated with poly-l -lysine (PLL) to adjust the release of AAV. By applying US to the AAV encapsulating AHMs with W-MPs, the AAV was released on demand, and gene transfection to cells by AAV was confirmed without loss of AAV activity. This proposed US-triggered AAV release system expands methodological possibilities in gene therapy.     

Candida biofilms on implanted biomaterials: a clinically significant problem

In recent years there has been an increasing appreciation that microbial biofilms are ubiquitous, which has resulted in a number of studies on infectious diseases from a biofilm perspective. Biofilms are defined as structured microbial communities that are attached to a surface and encased in a matrix of exopolymeric material. A wide range of biomaterials used in clinical practice have been shown to support colonization and biofilm formation by Candida spp., and the increase in Candida infections in the last decades has almost paralleled the increase and widespread use of a broad range of medical implant devices, mainly in populations with impaired host defenses. Formation of Candida biofilms has important clinical repercussions because of their increased resistance to antifungal therapy and the ability of cells within biofilms to withstand host immune defenses. Further recognition and understanding of the role of Candida biofilms in human infection should help in the clinical management of these recalcitrant infections.     

Glutathione-S-transferase,a possible drug-metabolizing enzyme,in Haemonchus contortus: Comparative activity of a cambendazole-resistant and a susceptible strain

Kawalek J. C., Rew R. S. and Heavner J. 1984. Glutathione-S-transferase, a possible drug-metabolizing enzyme in Haemonchus contortus: comparative activity of a cambendazole-resistant and a susceptible strain. International Journal for Parasitology14: 173–175. A drug metabolizing enzyme (DME), glutathione-S-transferase, was detected in homogenates of a cambendazole-susceptible and a cambendazole-resistant strain of Haemonchus contortus. The activity was 1.5–1.8 times higher in the resistant strain. DME activation is a possible mechanism for anthelmintic resistance in H. contortus.     

Use of a gel-forming dipeptide derivative as a carrier for antigen presentation

A dipeptide of the formula Fmoc-Leu-Asp and some other related dipeptides were synthesized in solution by standard methods. When such peptides are dissolved in water at concentrations below 1% at 100 °C and cooled below 60 °C they form turbid solutions and eventaully visocelastic gels at lower temperatures. Such gels are thermoreversible and can also be disrupted by mechanical agitation. At a concentration of 2 mg/ml the peptide Fmoc-Leu-Asp forms an aqueous gel at 60 °C with a shear modulus of 80 Pa measured at a frequency of 1 rad/s. Peptide solutions undergo an abrupt increase in light scattering between 1 and 1.5 mg/ml at both 23 and 60 °C. By analogy with previous observations of other systems, this increse appears to be due to the formation of filamentous micelles and the aggregation of filamaents into a three-dimensional network. When low molecular weight adamantanamine derivatives, which are inherently non-antigenci antiviral drugs, were incorporated into the Fmoc-Leu-Asp gel and injected into rabbits, high titre specific antibodies were efficiently produced without the need for additional adjuvant. Both the physical properties of the gel and its effect on the antigenicity of low molecular weight compounds suggest a number of practical applications.     

Modulation of cisPlatin cytotoxicity by interleukin-1α and resident tumor macrophages

The modulation of cisPlatin cytotoxicity by interleukin-1 (IL-1α) was studied in cultures of SCC-7 tumor cells with and without tumor macrophages to examine potential mechanisms for the synergistic antitumor activity of cisPlatin and IL-1α in SCC-7 solid tumors. Neither IL-1α nor tumor macrophages affected the survival of clonogenic tumor cells and IL-1α had no direct effect on tumor cell growthin vitro. Macrophages had no direct effect on cisPlatin sensitivity (IC₉₀=6.0 μM), but, the addition of IL-1α (500–2000U/ml) to co-cultures of cisPlatin pretreated tumor cells and resident tumor macrophages increased cell killing (IC₉₀=3.1 μM). Similar responses were seen in primary cultures treated with cisPlatin before IL-1α. The modulation of cisPlatin cytotoxicity by IL-1α exhibited a biphasic dose response that paralleled the IL-1α dose dependent release of H₂O₂by resident tumor macrophages. Further, IL-1α modification of cisPlatin cytotoxicity was prompt and inhibited by catalase. CisPlatin and exogenous H₂O₂ (50 μM) produced more than additive SCC-7 clonogenic cell kill and hydroxyl radicals played an important role in the response. Interleukin-1 modulation of cisPlatin cytotoxicity was schedule dependent. IL-1α treatment for 24 hrs, before cisPlatin, produced drug resistance (IC₉₀=11.1 μM). Our study shows that IL-1α can stimulate tumor macrophages to release pro-oxidants that modify cellular chemosensitivity in a schedule and dose dependent fashion. Our findings may also provide a mechanistic explanation for the synergistic antitumor activity of cisPlatin and IL-1αin vivo.     

Glycopeptide dendrimers. Part I.

Glycopeptide dendrimers are branched structures containing both carbohydrates and peptides. Various classes of these compounds differing in composition and structure are mentioned, together with their practical use spanning from catalysis, transport vehicles to synthetic vaccines. The main stress is given to glycopeptide dendrimers, namely multiple antigen glycopeptides (MAGs). In MAGs, the core, branches or both are composed of amino acids or peptides. Other classes of glycodendrimers (PAMAM, polypropylene imine, cyclodextrin, calixarene, etc.) are mentioned too, but to a smaller extent. Their syntheses, physicochemical properties and biological activities are given with many examples. Glycopeptide dendrimers can be used as inhibitors of cell surface protein-carbohydrate interactions, intervention with bacterial adhesion, for studying of recognition processes, diagnostics, imaging and contrast agents, mimetics, for complexation of different cationts, as site-specific molecular delivery systems, for therapeutic purposes, as immunodiagnostics and in drug design. Biomedical applications of glycopeptide dendrimers as drug and gene delivery systems are also given.     

Sibutramine Treatment in Obesity: Predictors of Weight Loss Including Rorschach Personality Data

Objective: To study personality and clinical factors in weight loss by sibutramine (Meridia and Reductil), an anti‐obesity drug enhancing satiety. Research Methods and Procedures: The subjects were 30 obese patients [43 ± 12 years (mean ± SD), BMI 40 ± 4 kg/m²]. The treatment comprised 15 mg of sibutramine administered daily and monthly dietary advice. Weight loss after 6 months of treatment was evaluated. For psychological assessment, the Rorschach method (Comprehensive System) and the Beck Depression Inventory were used. Results: A multiple linear regression model including the Rorschach predictors’ physical demand states (animal movement, designated as FM) being intrusive or difficult to hold and a dependency orientation (food contents) could explain 47% of 6 months of weight loss. A model including initial weight loss in addition to the Rorschach predictors explained 58% of the 6‐month weight loss. Discussion: The personality factors predicted greater weight loss. In particular, patients with difficulties concerning physical demand states, which would include hunger, could have reduced their eating behavior with enhanced satiety, resulting in greater weight loss. Enhanced satiety could also have helped patients with a dependent need for food to limit food intake. Being enrolled in a treatment program could also have provided essential support for patients with dependency needs. Furthermore, initial weight loss was a predictor of greater weight loss in sibutramine treatment, in accordance with prior research.