HEMA-Lysine-Based Cryogels for Highly Selective Heparin Neutralization
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ABSTRACT:
SUBMITTER: Mecca T
PROVIDER: S-EPMC11203617 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:Herein hyperbranched polyethyleneimine (hPEI) cryogels are reported for the selective and reversible adsorption of elemental chlorine. The cryogels are prepared in an aqueous solution by crosslinking with glutaraldehyde at subzero temperatures. The final macroporous composites bearing ammonium chloride groups are obtained after freeze-drying. The cryogels CG1[Cl]-CG3[Cl] adsorb chlorine with capacities of 0.22-0.26 g Cl2/g cryogel as an average over three adsorption-desorption cycles. The adsorption process is based on the reversible and selective halogen bonding of chlorides (Cl-) with chlorine (Cl2) forming the corresponding trichloride ([Cl3]-) species, indicated by Raman spectroscopy. The reversibility of chlorine adsorption is shown by applying heat and vacuum to the loaded cryogel CG1[Cl3] releasing 63% of the adsorbed chlorine within 3 h and 72% within 16 h. The unique ability to selectively adsorb chlorine in the presence of other gases is successfully employed for the selective adsorption of chlorine from a gas mixture, potentially enabling the recycling of chlorine from tail gas streams.
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Project description:Here, poly(2-hydroxyethyl methacrylate) (p(HEMA)) cryogel were prepared in the presence 0.48, 0.96, and 1.92 mL of α-Glucosidase enzyme (0.06 Units/mL) solutions to obtain enzyme entrapped superporous p(HEMA) cryogels, donated as α-Glucosidase@p(HEMA)-1, α-Glucosidase@p(HEMA)-2, and α-Glucosidase@p(HEMA)-3, respectively. The enzyme entrapped p(HEMA) cryogels revealed no interruption for hemolysis and coagulation of blood rendering viable biomedical application in blood contacting applications. The α-Glucosidase@p(HEMA)-1 was found to preserve its' activity% 92.3 ± 1.4 % and higher activity% against free α-Glucosidase enzymes in 15-60℃ temperature, and 4-9 pH range. The Km and Vmax values of α-Glucosidase@p(HEMA)-1 cryogel was calculated as 3.22 mM, and 0.0048 mM/min, respectively versus 1.97 mM, and 0.0032 mM/min, for free enzymes. The α-Glucosidase@p(HEMA)-1 cryogel was found to maintained enzymatic activity more than 50 % after 10 consecutive uses, and also preserved their activity more than 50 % after 10 days of storage at 25 ℃, whereas free α-Glucosidase enzyme maintained only 1.9 ± 0.9 % activity under the same conditions.
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Project description:The extracellular matrix (ECM), an integral component of all organs, is inherently tissue adhesive and plays a pivotal role in tissue regeneration and remodeling. However, man-made three-dimensional (3D) biomaterials that are designed to mimic ECMs do not intrinsically adhere to moisture-rich environments and often lack an open macroporous architecture required for facilitating cellularization and integration with the host tissue post-implantation. Furthermore, most of these constructs usually entail invasive surgeries and potentially a risk of infection. To address these challenges, we recently engineered biomimetic and macroporous cryogel scaffolds that are syringe injectable while exhibiting unique physical properties, including strong bioadhesive properties to tissues and organs. These biomimetic catechol-containing cryogels were prepared from naturally-derived polymers such as gelatin and hyaluronic acid and were functionalized with mussel-inspired dopamine (DOPA) to impart bioadhesive properties. We found that using glutathione as an antioxidant and incorporating DOPA into cryogels via a PEG spacer arm led to the highest tissue adhesion and improved physical properties overall, whereas DOPA-free cryogels were weakly tissue adhesive. As shown by qualitative and quantitative adhesion tests, DOPA-containing cryogels were able to adhere strongly to several animal tissues and organs such as the heart, small intestine, lung, kidney, and skin. Furthermore, these unoxidized (i.e., browning-free) and bioadhesive cryogels showed negligible cytotoxicity toward murine fibroblasts and prevented the ex vivo activation of primary bone marrow-derived dendritic cells. Finally, in vivo data suggested good tissue integration and a minimal host inflammatory response when subcutaneously injected in rats. Collectively, these minimally invasive, browning-free, and strongly bioadhesive mussel-inspired cryogels show great promise for various biomedical applications, potentially in wound healing, tissue engineering, and regenerative medicine.
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Project description:Cryogels based on hydrophobic polymers combining good mechanical properties with fast responsivity are attractive materials for many applications, such as oil spill removal from water and passive sampler for organic pollutants. We present, here, cryogels based on butyl rubber (BR) with a high stretchability, rapid self-recoverability, and excellent reusability for organic solvents. BR cryogels were prepared at subzero temperatures in cyclohexane and benzene at various BR concentrations in the presence of sulfur monochloride (S₂Cl₂) as a crosslinker. Although the properties of BR cryogels are independent of the amount of the crosslinker above a critical value, the type of the solvent, the cryogelation temperature, as well as the rubber content significantly affect their properties. It was found that benzene produces larger pore volumes as compared to cyclohexane due to the phase separation of BR from benzene at low temperatures, producing additional pores. Increasing cryogelation temperature from -18 to -2 °C leads to the formation of more ordered and aligned pores in the cryogels. Increasing BR content decreases the amount of unfrozen microphase of the frozen reaction solution, leading to a decrease in the total porosity of the cryogels and the average diameter of pores. Cryogels formed at -2 °C and at 5% (w/v) BR in cyclohexane sustain up to around 1400% stretch ratios. Cryogels swollen in toluene can completely be squeezed under strain during which toluene is released from their pores, whereas addition of toluene to the squeezed cryogels leads to recovery of their original shapes.
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Project description:Heparin is a widely applied anticoagulant agent. However, in clinical practice, it is of vital importance to reverse its anticoagulant effect to restore the blood-clotting cascade and circumvent side effects. Inspired by protein cages that can encapsulate and protect their cargo from surroundings, we utilize three designed protein copolymers to sequester heparin into inert nanoparticles. In our design, a silk-like sequence provides cooperativity between proteins, generating a multivalency effect that enhances the heparin-binding ability. Protein copolymers complex heparin into well-defined nanoparticles with diameters below 200 nm. We also develop a competitive fluorescent switch-on assay for heparin detection, with a detection limit of 0.01 IU mL-1 in plasma that is significantly below the therapeutic range (0.2-8 IU mL-1). Moreover, moderate cytocompatibility is demonstrated by in vitro cell studies. Therefore, such engineered protein copolymers present a promising alternative for neutralizing and sensing heparin, but further optimization is required for in vivo applications.
| S-EPMC9930113 | biostudies-literature
Project description:The specificity of endothelial binding sites for heparin was investigated with heparin fractions and fragments differing in their Mr, charge density and affinity for antithrombin III, as well as with heparinoids and other anionic polyelectrolytes (polystyrene sulphonates). The affinity for endothelial cells was estimated by determining I50 values in competition experiments with 125I-heparin. We found that affinity for endothelial cells increases as a function of Mr and charge density (degree of sulphation). Binding sites are not specific receptors for heparin. Other anionic polyelectrolytes, such as pentosan polysulphates and polystyrene sulphonates, competed with heparin for binding to endothelial cells. Fractions of standard heparin with high affinity for antithrombin III also had greater affinity for endothelium. However, these two properties of heparin (affinity for antithrombin III and affinity for endothelial cells) could be dissociated. Oversulphated heparins and oversulphated low-Mr heparin fragments had lower anticoagulant activity and higher affinity for endothelial cells than did their parent compounds. Synthetic pentasaccharides, bearing the minimal sequence for binding to antithrombin III, did not bind to endothelial cells. Binding to endothelial cells involved partial neutralization of heparin. Bound heparin exhibited only 5% and 7% of antifactor IIa and antifactor Xa specific activity, respectively. In the presence of 200 nM-antithrombin III, and in the absence of free heparin, a limited fraction (approx. 30%) of bound heparin was displaced from endothelial cells during a 1 h incubation period. These data suggested that a fraction of surface-bound heparin could represent a pool of anticoagulant.
| S-EPMC1147213 | biostudies-other
Project description:Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.
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Project description:Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
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Project description:Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.
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Project description:The development of autoclavable hydrogels has been driven by the need for materials that can withstand the rigors of sterilization without compromising their properties or functionality. Many conventional hydrogels cannot withstand autoclave treatment owing to the breakdown of their composition or structure under the high-temperature and high-pressure environment of autoclaving. Here, the effect of autoclaving on the physical, mechanical, and biological properties of bovine serum albumin methacryloyl (BSAMA) cryogels at three protein concentrations (3, 5, and 10%) was extensively studied. We found that BSAMA cryogels at three concentrations remained little changed after autoclaving in terms of gross shape, pore structure, and protein secondary structure. Young's modulus of autoclaved BSAMA cryogels (BSAMAA) at low concentrations (3 and 5%) was similar to that of BSAMA cryogels, whereas 10% BSAMAA exhibited a higher Young's modulus value, compared with 10% BSAMA. Interestingly, BSAMAA cryogels prolonged degradation. Importantly, cell viability, drug release, and hemolytic behaviors were found to be similar among the pre- and post-autoclaved cryogels. Above all, autoclaving proved to be more effective in sterilizing BSAMA cryogels from bacteria contamination than UV and ethanol treatments. Thus, autoclavable BSAMA cryogels with uncompromising properties would be useful for biomedical applications.
| S-EPMC10530076 | biostudies-literature