Lipid-based nanocarriers for oral delivery of peptides

Therapeutic peptides can treat a wide variety of diseases with selective and potent action. Their oral bioavailability is strongly limited by an important proteolytic activity in the intestinal lumen and poor permeation across the intestinal border. We have evaluated the capacity of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to overcome both oral bioavailability limiting aspects, using leuprolide (LEU) as model peptide. Lipidization of LEU by formation of a hydrophobic ion pair (HIP) with sodium docusate enables a significant increase of peptide encapsulation efficiency in both SLN and NLC. The nanocarriers, obtained by high-pressure homogenization, measured 120 nm and were platelet shaped. Regarding the protective effect towards proteolytic degradation, only NLC maintained LEU integrity in presence of trypsin. Intestinal transport, evaluated on Caco-2 (enterocyte-like model) and Caco-2/HT29-MTX (mucin-secreting model) monolayers, showed nanocarriers internalization by enterocytes but no improvement of LEU permeability. Indeed, the combination of nanoparticles platelet-shape with the poor stability of the HIP in the transport medium induces a high burst release of the peptide, limiting nanoparticles capacity to transport LEU across the intestinal border. Stability of peptide lipidization needs to be improved to withstand biorelevant medium to benefit from the advantages of encapsulation in solid lipid nanocarriers and consequently improve their oral bioavailability.

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

β1-tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying six β1-tubulin variants: p.Cys12Leufs12*, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size and a minority no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant, displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets, while had negligible effect on platelet activation, secretion or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.

Analysis of Platelet Shape Al2O3 and TiO2 on Heat Generative Hydromagnetic Nanofluids for the Base Fluid C2H6O2 in a Vertical Channel of Porous Medium

An analytical investigation is performed on the unsteady hydromagnetic flow of nanoparticles Al2O3 and TiO2 in the EG base fluid through a saturated porous medium bounded by two vertical surfaces with heat generation and no-slip boundary conditions. The physics of initial and boundary conditions is designated with the flow model's non-linear partial differential equations. The analytical expressions of nanofluid velocity and temperature with the channel are derived, and Matlab Codes are used to plot the significant results for physical variables. From the physical point of view for nanofluid velocity and temperature results, the base fluid C2H6O2 has a higher viscosity and thermal conductivity than that of water. Physically, the platelet shape Al2O3 nanofluid has the highest velocity than TiO2 nanofluid. It is found that the velocity of nanofluid enhanced the porosity and nanoparticles volume fraction for Al2O3 - EG and TiO2 - EG base nanofluids. However, this trend is reversed for the effects of heat generation. Obtained results indicate that an increase in nanoparticles volume fraction raises the skin friction near the surface, but profiles gradually become linear, due to less frictional effects of nanoparticles. Moreover, due to higher values of nanoparticles volume fraction, the thermal conductivity is raised, and thus the thickness of the thermal boundary layer is declined. The results show that the method provides excellent approximations to the analytical solution of nonlinear system with high accuracy. Metal oxide nanoparticles have wide applications in various fields due to their small sizes, such as the pharmaceutical industry and biomedical engineering. HIGHLIGHTS Impact of platelet shape Al2O3 and TiO2 for base fluid C2H6O2 is studied In Couette and Poiseuille flow, nanoparticles play a vital role to enhance the heat transfer The infinite series solution has been used for solving the non-linear PDE’s The uses of Al2O3 and TiO2 in significant heat transfer applications is overviewed The physiochemical and structural features of metal oxide nanoparticles have diverse biomedical applications GRAPHICAL ABSTRACT

Dominating the Structural, Microstructural and Magnetic Features of Li+ Substituted Strontium Hexaferrite (Sr1-xLi2xFe12O19)

Lithium ion substituted hexagonal strontium ferrite (Sr1-xLi2xFe12O19, where x= 0.1, 0.2, and 0.3) powders have been felicitously fabricated using tartrate precursor scheme. The impact of the Li+ content, as well as the annealing temperature on the phase evolution, microstructure and magnetic performance, was commanded by X-ray diffraction profile (XRD), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). Single phase hexagonal ferrite was consummated at a Li+ ratio of 0.2 and different annealing temperatures, from 1000 to 1200oC for 2h. An impurity α-Fe2O3 phase was noted at a high Li+ concentration of 0.4 and 0.6 at all temperatures. The crystallo-aspects characteristics were altered with Li+ content and annealing temperature. The microstructure of pure hexagonal ferrite sample visualized platelet like structure. A fine spherical shape displayed with platelet shape by enhancing the Li+ content up to 0.4 and 0.6. EDX analysis emphasized Fe, Sr, O, and Li atoms spread between the plate and spherical shapes. Good saturation magnetization (Ms=60.88 emu/g) was realized for Li+ content of 0.2 as the results of increasing the thickness of the nanoplatelet structure.

Platelet Shape Changes during Thrombus Formation: Role of Actin-Based Protrusions

Platelet activation and aggregation are essential to limit blood loss at sites of vascular injury but may also lead to occlusion of diseased vessels. The platelet cytoskeleton is a critical component for proper hemostatic function. Platelets change their shape after activation and their contractile machinery mediates thrombus stabilization and clot retraction. In vitro studies have shown that platelets, which come into contact with proteins such as fibrinogen, spread and first form filopodia and then lamellipodia, the latter being plate-like protrusions with branched actin filaments. However, the role of platelet lamellipodia in hemostasis and thrombus formation has been unclear until recently. This short review will briefly summarize the recent findings on the contribution of the actin cytoskeleton and lamellipodial structures to platelet function.

Molecular Drivers of Platelet Activation: Unraveling Novel Targets for Anti-Thrombotic and Anti-Thrombo-Inflammatory Therapy

Cardiovascular diseases (CVDs) are the leading cause of death globally—partly a consequence of increased population size and ageing—and are major contributors to reduced quality of life. Platelets play a major role in hemostasis and thrombosis. While platelet activation and aggregation are essential for hemostasis at sites of vascular injury, uncontrolled platelet activation leads to pathological thrombus formation and provokes thrombosis leading to myocardial infarction or stroke. Platelet activation and thrombus formation is a multistage process with different signaling pathways involved to trigger platelet shape change, integrin activation, stable platelet adhesion, aggregation, and degranulation. Apart from thrombotic events, thrombo-inflammation contributes to organ damage and dysfunction in CVDs and is mediated by platelets and inflammatory cells. Therefore, in the past, many efforts have been made to investigate specific signaling pathways in platelets to identify innovative and promising approaches for novel antithrombotic and anti-thrombo-inflammatory strategies that do not interfere with hemostasis. In this review, we focus on some of the most recent data reported on different platelet receptors, including GPIb-vWF interactions, GPVI activation, platelet chemokine receptors, regulation of integrin signaling, and channel homeostasis of NMDAR and PANX1.

GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force

Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change.Gpr56−/−mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.

Platelet activation in rabbits with decompression sickness

Platelets are the most easily altered type of peripheral blood cell in decompression sickness (DCS), which can feature decreased platelet count and the appearance of platelet microparticles in plasma. We hypothesized that DCS results in platelet activation in the bloodstream. The present study was carried out on 45 rabbits. The platelet count and concentration of plasma platelet markers were determined in 35 rabbits; the platelet shape was observed under scanning electron microscope in 10 rabbits. All indexes were collected at two points: 24 hours before the simulated dive and 30 minutes after the simulated dive. Platelet count decreased noticeably after DCS, from 380.10 ± 73.61 (G/L) to 330.23 ± 115.72 (G/L), a change of approximately -13.49 ± 25.57 (%). Platelet count was further decreased in the severe DCS group (a change of -45.99 ± 18.57%). Platelet count after DCS was proportional to the survival time of the rabbits after DCS. The concentration of two plasma platelet markers (PF4 and BTG) did not demonstrate statistically significant change at 30 minutes after DCS. However, platelet shape was changed, and the following features were observed: oblong, distortion, flattening shape, sticking together, mixing of membrane, and abundance of pseudopods with a 100- to 200-nm diameter. We conclude there is platelet activation in the bloodstream in cases of DCS.

Nanoparticle and shape factor for improving solidification rate

The main aim of this paper is to examine the discharging process with insertion of wavy surface and changing shape of nanoparticles. Contours were presented in the form of contours and profiles of energy and temperatures. To get the acceptable accuracy, adaptive grid is employed and time steps for each iteration are variable. The outputs indicate that augmenting A and selection of platelet shape lead to a faster solidification. With augment of [Formula: see text], 14% reduction has been reported for ([Formula: see text]). Such percentage augments with the rise of [Formula: see text] and 14.03% reduction were reported for ([Formula: see text]). At [Formula: see text], augmenting [Formula: see text] from 0.1 to 0.3 makes the time to reduce from 44.16[Formula: see text]s to 37.96[Formula: see text]s. Lower level of energy was reported for platelet shapes, which means higher liquid fraction of domain. Temperature declines with augment of [Formula: see text] and [Formula: see text] prolongs process of about 14.03% in the existence of platelet shape.