Rationally designed ß-cyclodextrin-crosslinked polyacrylamide hydrogels for cell spheroid formation and 3D tumor model construction.

In vitro tumor models are essential for understanding tumor behavior and evaluating tumor biological properties. Hydrogels that can mimic the tumor extracellular matrix have become popular for creating 3D in vitro tumor models. However, designing biocompatible hydrogels with appropriate chemical and physical properties for constructing tumor models is still a challenge. In this study, we synthesized a series of ß-cyclodextrin (ß-CD)-crosslinked polyacrylamide hydrogels with different ß-CD densities and mechanical properties and evaluated their potential for use in 3D in vitro tumor model construction, including cell capture and spheroid formation. By utilizing a combination of ß-CD-methacrylate (CD-MA) and a small amount of N,N'-methylene bisacrylamide (BIS) as hydrogel crosslinkers and optimizing the CD-MA/BIS ratio, the hydrogels performed excellently for tumor cell 3D culture and spheroid formation. Notably, when we co-cultured L929 fibroblasts with HeLa tumor cells on the hydrogel surface, co-cultured spheroids were formed, showing that the hydrogel can mimic the complexity of the tumor extracellular matrix. This comprehensive investigation of the relationship between hydrogel mechanical properties and biocompatibility provides important insights for hydrogel-based in vitro tumor modeling and advances our understanding of the mechanisms underlying tumor growth and progression.

Nomogram to predict ventilator-associated pneumonia in large vessel occlusion stroke after endovascular treatment: a retrospective study.

Background: Ventilator-Associated Pneumonia (VAP) severely impacts stroke patients' prognosis after endovascular treatment. Hence, this study created a nomogram to predict the occurrence of VAP after endovascular treatment. Methods: The individuals with acute ischemic stroke and large vessel occlusion (AIS-LVO) who received mechanical ventilation and endovascular therapy between July 2020 and August 2023 were included in this retrospective study. The predictive model and nomogram were generated by performing feature selection optimization using the LASSO regression model and multifactor logistic regression analysis and assessed the evaluation, verification and clinical application. Results: A total of 184 individuals (average age 61.85 ± 13.25 years, 73.37% male) were enrolled, and the rate of VAP occurrence was found to be 57.07%. Factors such as the Glasgow Coma Scale (GCS) score, duration of stay in the Intensive Care Unit (ICU), dysphagia, Fazekas scale 2 and admission diastolic blood pressure were found to be associated with the occurrence of VAP in the nomogram that demonstrating a strong discriminatory power with AUC of 0.862 (95% CI, 0.810-0.914), and a favorable clinical net benefit. Conclusion: This nomogram, comprising GCS score, ICU duration, dysphagia, Fazekas scale 2 and admission diastolic blood pressure, can aid clinicians in predicting the identification of high-risk patients for VAP following endovascular treatment in large vessel occlusion stroke.

A supramolecular colloidal system based on folate-conjugated ß-cyclodextrin polymer and indocyanine green for enhanced tumor-targeted cell imaging in 2D culture and 3D tumor spheroids.

Indocyanine green (ICG) is an FDA-approved medical diagnostic agent that is widely used as a near-infrared (NIR) fluorescent imaging molecular probe. However, ICG tends to aggregate to form dimers or H-aggregates in water and lacks physical and optical stability, which greatly decreases its absorbance and fluorescence intensity in various applications. Additionally, ICG has no tissue- or tumor-targeting properties, and its structure is not easy to modify, which has further limited its application in cancer diagnosis. In this study, we addressed these challenges by developing a supramolecular colloidal carrier system that targets tumor cells. To this end, we synthesized a water-soluble ß-cyclodextrin (ß-CD) polymer conjugated with folate (FA), denoted PCD-FA, which is capable of forming inclusion complexes with ICG in water through host-guest interactions between the ß-CD moieties and ICG molecules. The inclusion complexes formed by PCD-FA and ICG, called ICG@PCD-FA, dispersed stably in solution as colloidal nanoparticles, greatly improving the physical and optical properties of ICG by preventing ICG dimer formation, where ICG appeared as monomers and even J-aggregates. This resulted in stronger and more stable absorption at a longer wavelength of 900 nm, which may allow for deeper tissue penetration and imaging with reduced interference from biological tissues' autofluorescence. Moreover, ICG@PCD-FA showed a targeting effect on folate receptor-positive (FR+) tumor cells, which specifically highlighted FR+ cells via NIR endoscopic imaging. Notably, ICG@PCD-FA further improved permeation and accumulation in FR+ 3D tumor spheroids. Therefore, this ICG@PCD-FA supramolecular colloidal system may have a great potential for use in tumor NIR imaging and diagnostic applications.

Codelivery of Doxorubicin and p53 Gene by ß-Cyclodextrin-Based Supramolecular Nanoparticles Formed via Host-Guest Complexation and Electrostatic Interaction.

We developed a supramolecular system for codelivery of doxorubicin (Dox) and p53 gene based on a ß-CD-containing star-shaped cationic polymer. First, a star-shaped cationic polymer consisting of a ß-CD core and 3 arms of oligoethylenimine (OEI), named CD-OEI, was used to form a supramolecular inclusion complex with hydrophobic Dox. The CD-OEI/Dox complex was subsequently used to condense plasmid DNA via electrostatic interactions to form CD-OEI/Dox/DNA polyplex nanoparticles with positive surface charges that enhanced the cellular uptake of both Dox and DNA. This supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells. The codelivery of Dox and DNA encoding the p53 gene resulted in reduced cell viability and enhanced antitumor effects at low Dox concentrations. With its enhanced cellular uptake and anticancer efficacy, the system holds promise as a delivery carrier for potential combination cancer therapies.

Rationally designed multifunctional nanoparticles as GSH-responsive anticancer drug delivery systems based on host-guest polymers derived from dextran and ß-cyclodextrin.

Tumor proliferation and metastasis rely on energy provided by mitochondria. The hexokinase inhibitor lonidamine (LND) could suppress the activities in mitochondria, being a potential antitumor drug. However, limited water-solubility of LND may hinder its biomedical applications. Besides, the cancer-killing effect of LND is compromised by the high level of glutathione (GSH) in cancer cells. Therefore, it is urgent to find a proper method to simultaneously deliver LND and deplete GSH as well as monitor GSH level in cancer cells. Herein, a host polymer ß-cyclodextrin-polyethylenimine (ß-CD-PEI) and a guest polymer dextran-5-dithio-(2-nitrobenzoic acid) (Dextran-SS-TNB) were synthesized and allowed to form LND-loaded GSH-responsive nanoparticles through host-guest inclusion complexation between ß-CD and TNB as host and guest molecular moieties, respectively, which functioned as a system for simultaneous delivery of LND and -SS-TNB species into cancer cells. As a result, the delivery system could deplete GSH and elevate reactive oxygen species (ROS) level in cancer cells, further induce LND-based mitochondrial dysfunction and ROS-based immunogenic cell death (ICD), leading to a synergistic and efficient anticancer effect. In addition, -SS-TNB reacted with GSH to release TNB2-, which could be a probe with visible light absorption at 410 nm for monitoring the GSH level in the cells.

Fusion with CTP increases the stability of recombinant neuritin.

Neuritin is a vital neurotrophin that plays an essential role in recovery from nerve injury and neurodegenerative diseases and may become a new target for treating these conditions. However, improving neuritin protein stability is an urgent problem. In this study, to obtain active and stable neuritin proteins, we added a carboxyl-terminal peptide (CTP) sequence containing four O-linked glycosylation sites to the C-terminus of neuritin and cloned it into the Chinese hamster ovary (CHO) expression system. The neuritin-CTP protein was purified using a His-Tag purification strategy after G418 screening of stable high-expression cell lines. Ultimately, we obtained neuritin-CTP protein with a purity >90%. Functional analyses showed that the purified neuritin-CTP protein promoted the neurite outgrowth of PC12 cells, and stability experiments showed that neuritin stability was increased by adding CTP. These results indicate that neuritin protein-CTP fusion effectively increases stability without affecting secretion and activity. This study offers a sound strategy for improving the stability of neuritin protein and provides material conditions for further study of the function of neuritin.

Biomass-based single- and double-network hydrogels derived from cellulose microfiber and chitosan for potential application as plant growing substrate.

A series of hydrogels were synthesized from renewable and low-cost micro-sized cellulose fiber. The single-network hydrogel was composed of cellulose fiber and a small amount of another polysaccharide, chitosan, which 'glued' individual cellulose fiber pieces together through Schiff-base bonding. The double-network hydrogel was constructed by adding a secondary network, the covalently crosslinked polyacrylamide, into the single-network hydrogel, which was synthesized by conducting Schiff-base reaction and free radical polymerization at the same time in a facile one-pot process. In both single- and double-network hydrogels, cellulose fiber constituted the dominant component. Both types of hydrogels exhibited good swelling properties. The double-network hydrogel showed much improved stability against soaking in water and higher salt tolerance. Germination experiment with choy sum seeds sowed on hydrogel surface showed that the seeds were able to germinate and further develop roots, shoots, and true leaves, demonstrating the potential of the biomass-derived hydrogels for soilless plant growing applications.

Neuritin affects the activity of neuralized-like 1 by promoting degradation and weakening its affinity for substrate.

Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. Our previous research revealed the mechanism by which neuritin inhibits Notch signaling through interaction with neuralized-like 1 (Neurl1) to promote neurite growth. However, how neuritin regulates Notch signaling through Neurl1 has not been elucidated. Here, we first confirm that neuritin is an upstream regulator of Neurl1 and inhibits Notch signaling through Neurl1. Neurl1 is an E3 ubiquitin ligase that can promote ubiquitination and endocytosis of the Notch1 ligand Jagged1. Therefore, we observe the effect of neuritin on the ligase activity of Neurl1. The results indicate that neuritin inhibits Neurl1 activity by reducing the ubiquitination level and endocytosis of the target protein Jagged1. Moreover, we find that decreased activity of Neurl1 results in reduced expression of Notch receptor Notch intracellular domain (NICD) and downstream target gene hairy and enhancer of split-1 ( HES1). Furthermore, we investigate how neuritin affects Neurl1 enzyme activity. The results show that neuritin not only weakens the affinity between Neurl1 and Jagged1 but also promotes the degradation of Neurl1 by the 26S proteasome pathway. Taken together, our results suggest that neuritin negatively regulates Notch signaling by inhibiting the activity of Neurl1, promoting the degradation of Neurl1 and weakening the affinity of Neurl1 for Jagged1. Our study clarifies the molecular mechanisms of neuritin in regulating the Notch signaling pathway and provides new clues about how neuritin mediates neural regeneration and plasticity.

Cationic micelles as nanocarriers for enhancing intra-cartilage drug penetration and retention.

There is a tremendous unmet medical need for osteoarthritis (OA) treatment around the world, and pharmacological management is the most common option but presents a limited and short efficacy. Insufficient drug delivery to articular cartilage is the key cause. It is widely accepted that the complex structure of articular cartilage and the rapid clearance of joint liquids largely hinder drug penetration and retention in the cartilage. To address these obstacles, we designed and prepared a positively charged micellar system that can effectively deliver a model drug to the deep zone of the cartilage and prolong the drug retention time. In this work, a triblock copolymer composed of cationic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) and poly(ε-caprolactone) (PCL), denoted as PDMAEMA-PCL-PDMAEMA, was synthesized. A triblock copolymer composed of brush poly[poly(ethylene glycol) methacrylate] (pPEGMA) and PCL, denoted as pPEGMA-PCL-pPEGMA, was prepared for comparison. The two types of triblock copolymers were self-assembled in an aqueous environment to form cationic and neutral micelles, respectively. A hydrophobic fluorescent dye as a model drug was loaded into micelle cores, and the dye-loaded micelles were evaluated for intra-cartilage penetration and retention using porcine knee cartilage explants. The PDMAEMA-PCL-PDMAEMA cationic micelles were found to significantly enhance the intra-cartilage penetration and retention capability due to the electrostatic interaction between the micelles and the negatively charged cartilage extracellular matrix. The confocal microscopy study showed that the cationic micelles could penetrate the full-thickness porcine cartilage explants (around 1.5 mm) within 24 hours. Up to 87% of the cationic micelles were taken up by porcine cartilage explants, and 71% of the absorbed micelles were retained in the tissue for at least 4 days. Although the pPEGMA-PCL-pPEGMA neutral micelles were able to penetrate the full-thickness cartilage, this type of micelle showed lower uptake (44%) and retention (44%) rates. This observation implied that the surface charge of micelles could play an important role in efficient intra-cartilage drug delivery. This study verified the feasibility and effectiveness of the PDMAEMA-PCL-PDMAEM cationic micelles in intra-cartilage drug delivery, showing that cationic micelles could be promising carriers for OA treatment.

Detachment of bovine corneal endothelial cell sheets by cooling-induced surface hydration of poly[(R)-3-hydroxybutyrate]-based thermoresponsive copolymer coating.

Cell sheet technology (CST) is a fascinating scaffoldless tissue engineering technique to generate a physiologically representative tissue replacement from autologous sources. As compared to conventional enzymatic cell harvesting methods, CST enables the preservation of important cell-to-cell junctions and extracellular matrix (ECM) components. However, covalent grafting methods are often employed for CST. In this study, a series of triblock copolymers with a hydrophobic and biocompatible poly[(R)-3-hydroxybutyrate] (PHB) central block flanked by varying lengths of terminal poly(N-isopropylacrylamide) (PNIPAAm) blocks (PNIPAAm-PHB-PNIPAAm) was synthesized via atom transfer radical polymerization of NIPAAm. The thermoresponsive triblock copolymers were explored as a non-covalent surface coating for culturing and detaching bovine corneal endothelial cell (BCEC) sheets. Aqueous solutions of the triblock copolymers produced thermosensitive micelles which can be drop-casted on glass substrates, resulting in a temperature-responsive surface. Importantly, incorporating a central hydrophobic PHB block enabled the anchoring of the coating to the bare substrate and enhanced the proliferation rate of the BCECs studied. Effective detachment of an intact cell sheet was also demonstrated via a cooling treatment at 4 °C for 20 min, and the viability of the detached cell sheet was found to be unaffected by the cooling. This work may potentially inspire more studies involving the non-covalent thermoresponsive polymer coatings for corneal tissue engineering applications.

Synthesis and Characterization of Palmitoyl-block-poly(methacryloyloxyethyl phosphorylcholine) Polymer Micelles for Anticancer Drug Delivery.

We report the synthesis and characterization of an amphiphilic polymer comprising a hydrophobic palmitoyl (Pal) group and a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) block, which is capable of forming micelles as a drug carrier system for delivering hydrophobic anticancer drugs such as doxorubicin (DOX). We hypothesize that the sharp polarity contrast between the Pal domain and the pMPC block would strengthen the micelles and improve the drug loading capacity, while the pMPC shells improve the micelle stability and cellular uptake efficiency. In this study, the Pal-pMPC polymer was characterized and compared with a Pal-poly(ethylene glycol) (Pal-PEG) polymer in terms of their micelle formation, cytotoxicity, and drug loading of DOX. The DOX-loaded Pal-pMPC micelles were further evaluated for the cellular uptake and anticancer activities in cell culture systems including the non-multidrug-resistance HeLa cell line and the multidrug-resistance AT3B-1 cell line. The results showed that the Pal-pMPC polymer had a minimal toxicity. The Pal-pMPC micelles exhibited higher drug loading capacity and enhanced cellular internalization efficiency compared to micelles formed by the Pal-PEG polymer. It was also found that DOX-loaded Pal-pMPC micelles exhibited a more efficient anticancer effect than Pal-PEG micelles in multidrug-resistance cancer cells in an environment with fetal bovine serum.

A field study on using soybean waste-derived superabsorbent hydrogel to enhance growth of vegetables.

Food security is critical and has become a global concern with many of our basic food crops growing in areas with high drought risk. To improve soil water holding capacity, hydrogels are a promising solution. However, the current ones are mostly derived from petroleum products and are environmental unsustainable. In this study, the main objective is to determine if bio-based hydrogel can help in the growth of leafy vegetables while minimizing water use under field conditions. To achieve this, we developed an okara-derived hydrogel (Ok-PAA; OP) from by-products of bean curd and soybean milk production. We incorporated OP into soil and assessed the growth performance of leafy vegetables. We observed that vegetables grown with 0.2% (w/v) OP in soil with a watering frequency of 7 times per week resulted in >60 % and 35 % yield increase for the common Asian leafy vegetables, choy sum (CS) and pak choi (PC), respectively, as compared to without hydrogel supplementation. Both vegetables produced larger leaf areas (20-40 % increment) in the presence of the hydrogel as compared to those without. In addition, with OP amendment, the irrigation water use efficiency improved >60 % and 30 % for CS and PC, respectively. It is estimated that with the use of the hydrogel, a reduction in watering frequency from 21 times to 7 times per week could be achieved, and based on a per hectare estimation, this would result in 196,000 L of water saving per crop cycle. Statistical analysis and modelling further confirmed vegetables grown with 0.2 % (w/v) OP and with a watering frequency of 7 times per week showed the best growth performance and water use efficiency. Such a waste-to-resource approach offers a plant-based soil supplement for crop growers, contributes to waste valorization, and enhances the growth of plants especially under water-limited conditions.

Smart Hydrogel Formed by Alginate-g-Poly(N-isopropylacrylamide) and Chitosan through Polyelectrolyte Complexation and Its Controlled Release Properties.

Smart hydrogels that can respond to external stimuli such as temperature and pH have attracted tremendous interest for biological and biomedical applications. In this work, we synthesized two alginate-graft-poly(N-isopropylacrylamide) (Alg-g-PNIPAAm) copolymers and aimed to prepare smart hydrogels through formation of polyelectrolyte complex (PEC) between the negatively charged Alg-g-PNIPAAm copolymers and the positively charged chitosan (Cts) in aqueous solutions. The hydrogels were expected to be able to respond to both temperature and pH changes due to the nature of Alg-g-PNIPAAm and chitosan. The hydrogel formation was determined by a test tube inverting method and confirmed by the rheological measurements. The rheological measurements showed that the PEC hydrogels formed at room temperature could be further enhanced by increasing temperature over the lower critical solution temperature (LCST) of PNIPAAm, because PNIPAAm would change from hydrophilic to hydrophobic upon increasing temperature over its LCST, and the hydrophobic interaction between the PNIPAAm segments may act as additional physical crosslinking. The controlled release properties of the hydrogels were studied by using the organic dye rhodamine B (RB) as a model drug at different pH. The PEC hydrogels could sustain the RB release more efficiently at neutral pH. Both low pH and high pH weakened the PEC hydrogels, and resulted in less sustained release profiles. The release kinetics data were found to fit well to the Krosmyer-Peppas power law model. The analysis of the release kinetic parameters obtained by the modelling indicates that the release of RB from the PEC hydrogels followed mechanisms combining diffusion and dissolution of the hydrogels, but the release was mainly governed by diffusion with less dissolution at pH 7.4 when the PEC hydrogels were stronger and stabler than those at pH 5.0 and 10.0. Therefore, the PEC hydrogels are a kind of smart hydrogels holding great potential for drug delivery applications.

Facile Construction of a Two-in-One Injectable Micelleplex-Loaded Thermogel System for the Prolonged Delivery of Plasmid DNA.

Nanoparticle-hydrogel systems have recently emerged as a class of interesting hybrid materials with immense potential for several biomedical applications. Remarkably, the incorporation of nanoparticles into a hydrogel may yield synergistic benefits lacking in a singular system. However, most synthetic strategies require laborious steps to achieve the system, severely restricting the process of translational research. Herein, a facile strategy to access a two-in-one system comprising two distinct polyurethane (PU)-based micellar systems is demonstrated and applied as a novel sustained gene delivery platform, where the two PUs are synthesized similarly but with slightly different compositions. One PU forms cationic micelles that complex with plasmid DNA (pDNA), which are loaded into a thermogel formed by another PU micellar system for the prolonged release of pDNA micelleplexes. Specifically, a thermogelling multiblock PU copolymer (denoted as EPH) was synthesized via the step-growth polymerization of poly(ethylene glycol), poly(propylene glycol), and poly(3-hydroxybutyrate). By further introducing a cationic extender, 3-(dimethylamino)-1,2-propanediol, into the reaction feed, a series of cationic PUs (denoted as EPHD) with varying compositions were obtained. The EPHDs formed positively charged micelles in aqueous solutions, efficiently condensed pDNA into nano-sized micelleplexes (<200 nm) at optimized w/w ratios, and mediated transient green fluorescence protein expression in HEK293T cells at 48 h post-transfection. On the other hand, aqueous EPH solution (4 wt %) was injectable at 4 °C and rapidly gelled upon heating to 37 °C to form a stable hydrogel depot. EPHD/pDNA micelleplexes were easily loaded into EPH by mixing the solutions at 4 °C, before heating to 37 °C, leading to the resultant hydrogel system. The in vitro release study revealed that while free pDNA loaded in the thermogel was completely released in 2 weeks, the release of EPHD/pDNA micelleplexes was prolonged to at least 28 days, suggesting substantial micelleplex-hydrogel interactions. Intact, bioactive, and noncytotoxic EPHD/pDNA micelleplexes in the release media were proved by gel retardation, in vitro gene transfection, and CCK-8 cytotoxicity assay results, respectively. Collectively, this work presents a simple approach to achieving and optimizing a novel two-in-one nanoparticle-hydrogel system for the prolonged delivery of pDNA and may be promising for long-term gene delivery applications.

A hydrogel with supramolecular surface functionalization for cancer cell capture and multicellular spheroid growth and release.

A hydrogel scaffold with a non-fouling but specific cancer cell-adhesive surface was fabricated through surface modification using ß-cyclodextrin-based host-guest chemistry. Interestingly, the hydrogel surface not only selectively captured specific cancer cells, but also grew the cells into multicellular spheroids. The spheroids could be released without damaging the cell viability through replacing the host moieties on the scaffold, and the released spheroids showed no changes in size or morphology.

In Situ Synthesis of Magnetic Poly(DMAEAB-co-NIPAm)@Fe3O4 Composite Hydrogel for Removal of Dye from Water.

Water pollution by toxic substances, such as dye molecules, remains a major environmental problem that needs to be solved. In the present work, the magnetic composite hydrogel based on the poly(2-(methacryloyloxy)-N-(2-hydroxyethyl)-N,N-dimethylethan-1-aminium bromide-co-N-isopropylacrylamide) copolymer with incorporated Fe3O4 particles ((poly(DMAEAB-co-NIPAm)@Fe3O4)) was prepared by an in situ synthesis technique for the efficient removal of dye molecules from water. The successfully synthesized magnetic hydrogel was characterized by FTIR, XRD, TGA, and TEM. The removal efficiency of the anionic dye bromophenol blue (BPB) and the cationic dye rhodamine B (RDM) by the prepared hydrogel adsorbents was evaluated. Various adsorption parameters, including the concentration of adsorbents and adsorption time, were also investigated. The results showed that the synthesized magnetic hydrogel had excellent BPB removal performance compared to the removal of RDM. The optimum adsorbent concentration for 0.5 mM BPB solution was approximately 0.5 g/L, and the removal efficiency was more than 99%. The kinetics data of BPB removal fitted well into the pseudo-2nd-order model, indicating that BPB dye adsorption involves chemical adsorption and physical adsorption. In addition, recycling studies were conducted to examine the reusability of the magnetic hydrogel for BPB removal for up to five cycles and the hydrogel could be reused without losing its high removal efficiency. The magnetic hydrogel poly(DMAEAB-co-NIPAm)@Fe3O4 with high removal efficiency, good selectivity, and reusability shows great potential for the removal of anionic dyes in wastewater treatment.

ß-Cyclodextrin-Polyacrylamide Hydrogel for Removal of Organic Micropollutants from Water.

Water pollution by various toxic substances remains a serious environmental problem, especially the occurrence of organic micropollutants including endocrine disruptors, pharmaceutical pollutants and naphthol pollutants. Adsorption process has been an effective method for pollutant removal in wastewater treatment. However, the thermal regeneration process for the most widely used activated carbon is costly and energy-consuming. Therefore, there has been an increasing need to develop alternative low-cost and effective adsorption materials for pollutant removal. Herein, ß-cyclodextrin (ß-CD), a cheap and versatile material, was modified with methacrylate groups by reacting with methacryloyl chloride, giving an average degree of substitution of 3 per ß-CD molecule. ß-CD-methacrylate, which could function as a crosslinker, was then copolymerized with acrylamide monomer via free-radical copolymerization to form ß-CD-polyacrylamide (ß-CD-PAAm) hydrogel. Interestingly, in the structure of the ß-CD-PAAm hydrogel, ß-CD is not only a functional unit binding pollutant molecules through inclusion complexation, but also a structural unit crosslinking PAAm leading to the formation of the hydrogel 3D networks. Morphological studies showed that ß-CD-PAAm gel had larger pore size than the control PAAm gel, which was synthesized using conventional crosslinker instead of ß-CD-methacrylate. This was consistent with the higher swelling ratio of ß-CD-PAAm gel than that of PAAm gel (29.4 vs. 12.7). In the kinetic adsorption studies, phenolphthalein, a model dye, and bisphenol A, propranolol hydrochloride, and 2-naphthol were used as model pollutants from different classes. The adsorption data for ß-CD-PAAm gel fitted well into the pseudo-second-order model. In addition, the thermodynamic studies revealed that ß-CD-PAAm gel was able to effectively adsorb the different dye and pollutants at various concentrations, while the control PAAm gel had very low adsorption, confirming that the pollutant removal was due to the inclusion complexation between ß-CD units and pollutant molecules. The adsorption isotherms of the different dye and pollutants by the ß-CD-PAAm gel fitted well into the Langmuir model. Furthermore, the ß-CD-PAAm gel could be easily recycled by soaking in methanol and reused without compromising its performance for five consecutive adsorption/desorption cycles. Therefore, the ß-CD-PAAm gel, which combines the advantage of an easy-to-handle hydrogel platform and the effectiveness of adsorption by ß-CD units, could be a promising pollutant removal system for wastewater treatment applications.

Neuritin promotes angiogenesis through inhibition of DLL4/Notch signaling pathway.

Neuritin is a member of the neurotrophic factor family, which plays an important role in the promotion and development of the nervous system. Neuritin is also involved in angiogenesis. Neuritin was recently found to be a negative regulatory factor of the Notch 1 signaling pathway. Notch signaling pathway is known as a regulatory pathway of angiogenesis. Thus, neuritin may play a role in angiogenesis through the Notch signaling pathway. In the present study, we investigated the expressions of neuritin and Notch signaling pathway factors in the pulmonary vascular tissue. The results showed that neuritin expression was increased in the paraneoplastic vascular tissue and decreased in the lung cancer vascular tissue. The neuritin expression was increased with the increase of vascular tissue density, and a negative correlation between neuritin expression and delta-like ligand 4 (DLL4) was identified in vascular tissues of lung cancer. Overexpression of neuritin in human umbilical vein endothelial cells (HUVECs) inhibited the expressions of Notch signaling pathway-associated factors, including DLL4, NICD, and Hes-1, and promoted the migration and tubular formation of HUVECs. In conclusion, our results indicated that neuritin is involved in angiogenesis and may play a role in angiogenesis through the Notch signaling pathway. This study provides a theoretical basis for clinical anti-angiogenesis therapy.

Nonviral DNA Delivery System with Supramolecular PEGylation Formed by Host-Guest Pseudo-Block Copolymers.

A cationic supramolecular system based on host-guest pseudoblock copolymers was developed for nonviral DNA delivery. In this system, the macromolecular host was a cationic star-shaped polymer composed of a ß-cyclodextrin (ß-CD) core and multiple poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chains grafted on the core, while the macromolecular guest was a linear adamantyl-ended poly(ethylene glycol) (mPEG-Ad). Pseudoblock copolymers were self-assembled from the polymeric host-guest pairs (typically, 1:1 molar ratio) in aqueous media through the inclusion of an adamantyl group at the end of guest polymer into the ß-CD cavity of host polymers. Through such an approach, the resultant supramolecular system was integrated with not only a superior DNA condensing ability due to the host polymer but also an outstanding polyplex-stabilizing ability as well as biocompatibility due to the guest polymer. The cationic star-shaped host polymers alone were capable of condensing plasmid DNA efficiently into nanoparticles (70-100 nm) with positive surface charge. They showed obviously lower cytotoxicity than PEI 25K (commercial branched polyethylenimine with a molecular weight around 25 kDa) in cell lines of L929, MB231, and Hela under high dose. In serum-free or serum-containing culture conditions, these host polymers exhibited either higher or lower in vitro DNA transfection efficiency as compared with PEI 25K in the three cell lines under study, which was dependent on the N/P ratios and PDMAEMA arm length. Upon incorporation of the PEG block through host-guest complexation with mPEG-Ad (i.e., supramolecular PEGylation), the resulting host-guest supramolecular systems exhibited even lower cytotoxicity than the host polymers alone. The polyplexes between plasmid DNA (pDNA) and the host-guest systems showed significantly improved stability in BSA-PBS buffer solution (pH 7.4) and enhanced in vitro DNA transfection efficiency in the cases of higher N/P ratios or longer PDMAEMA arms in all tested cell lines under both serum-free and serum-containing culture conditions, as compared with the corresponding polyplexes without supramolecular PEGylation. Further, through forming pseudoblock copolymer, the DNA transfection ability of the supramolecular system can be easily modulated and optimized either by changing the ratio between the guest and host or by using different hosts with varied PDMAEMA arm lengths.

Multiple pathophysiological roles of midkine in human disease.

Midkine (MK) is a low molecular-weight protein that was first identified as the product of a retinoic acid-responsive gene involved in embryonic development. Recent studies have indicated that MK levels are related to various diseases, including cardiovascular disease (CVD), renal disease and autoimmune disease. MK is a growth factor involved in multiple pathophysiological processes, such as inflammation, the repair of damaged tissues and cancer. The pathophysiological roles of MK are diverse. MK enhances the recruitment and migration of inflammatory cells upon inflammation directly and also through induction of chemokines, and contributes to tissue damage. In lung endothelial cells, oxidative stress increased the expression of MK, which induced angiotensin-converting enzyme (ACE) expression and the consequent conversion from Ang I to Ang II, leading to further oxidative stress. MK inhibited cholesterol efflux from macrophages by reducing ATP-binding cassette transporter A1 (ABCA1) expression, which is involved in lipid metabolism, suggesting that MK is an important positive factor involved in inflammation, oxidative stress and lipid metabolism. Furthermore, MK can regulate the expansion, differentiation and activation of T cells as well as B-cell survival; mediate angiogenic and antibacterial activity; and possess anti-apoptotic activity. In this paper, we summarize the pathophysiological roles of MK in human disease.