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Nanomotor-based HS donor with mitochondrial targeting function for treatment of Parkinson's disease.Bioactive Materials Jan 2024Reduction of endogenous hydrogen sulfide (HS) is considered to have an important impact on the progress of Parkinson's disease (PD), thus exogenous HS supplementation is...
Reduction of endogenous hydrogen sulfide (HS) is considered to have an important impact on the progress of Parkinson's disease (PD), thus exogenous HS supplementation is expected to become one of the key means to treat PD. However, at present, it is difficult for HS donors to effectively penetrate the blood brain barrier (BBB), selectively release HS in brain, and effectively target the mitochondria of neuron cells. Herein, we report a kind of nanomotor-based HS donor, which is obtained by free radical polymerization reaction between l-cysteine derivative modified-polyethylene glycol (PEG-Cys) and 2-methacryloyloxyethyl phosphorylcholine (MPC). This kind of HS donor can not only effectively break through BBB, but also be specifically catalyzed by cystathionine β-synthase (CBS) in neurons of PD site in brain and 3-mercaptopyruvate sulfurtransferase (3-MST) in mitochondria to produce HS, endowing it with chemotaxis/motion ability. Moreover, the unique chemotaxis effect of nanomotor can realize the purpose of precisely targeting brain and the mitochondria of damaged neuron cytopathic diseases. This kind of nanomotor-based HS donor is expected to enrich the current types of HS donors and provide new ideas for the treatment of PD.
PubMed: 37771932
DOI: 10.1016/j.bioactmat.2023.09.001 -
Polymers Sep 2023Affinity-based organic electrochemical transistor (OECT) sensors offer an attractive approach to point-of-care diagnostics due to their extreme sensitivity and easy...
Affinity-based organic electrochemical transistor (OECT) sensors offer an attractive approach to point-of-care diagnostics due to their extreme sensitivity and easy operation; however, their application in the real world is frequently challenged by the poor storage stability of antibody proteins and the interference from biofouling in complex biofluids. In this work, we developed an antibody-free and antifouling OECT biosensor to detect C-reactive protein (CRP) at ultra-high specificity and sensitivity. The key to this novel biosensor is the gate coated by phosphorylcholine-functionalized poly (3,4-ethylene dioxythiophene) (PEDOT-PC), which possesses large capacitance and low impedance, prevents biofouling of bovine serum albumin (BSA) and the fetal bovine serum (FBS), and interacts specifically with CRP molecules in the presence of calcium ions. This PEDOT-PC-gated OECT biosensor demonstrated exceptional sensitivity when detecting the CRP molecules at 10 pg/mL, while significantly depressing the signal from the nonspecific binding. This indicates that this biosensor could detect the CRP molecules directly without nonspecific binding blocking, the usual process for the earlier transistor sensors before detection. We envision that this PEDOT-PC-gated OECT biosensor platform may offer a potentially valuable tool for point-of-care diagnostics as it alleviates concerns about poor antibody stability and BSA blocking inconstancy.
PubMed: 37765593
DOI: 10.3390/polym15183739 -
Molecules (Basel, Switzerland) Sep 2023The structure and dynamics of copolymers of 2-hydroxyethyl methacrylate (HEMA) with 2-methacryloyloxyethyl phosphorylcholine (MPC) were studied by molecular dynamics...
The structure and dynamics of copolymers of 2-hydroxyethyl methacrylate (HEMA) with 2-methacryloyloxyethyl phosphorylcholine (MPC) were studied by molecular dynamics simulations. In total, 20 systems were analyzed. They differed in numerical fractions of the MPC in the copolymer chain, equal to 0.26 and 0.74, in the sequence of mers, block and random, and the water content, from 0 to 60% by mass. HEMA side chains proved relatively rigid and stable in all considered configurations. MPC side chains, in contrast, were mobile and flexible. Water substantially influenced their dynamics. The copolymer swelling caused by water resulted in diffusion channels, pronounced in highly hydrated systems. Water in the hydrates existed in two states: those that bond to the polymer chain and the free one; the latter was similar to bulk water but with a lower self-diffusion coefficient. The results proved that molecular dynamics simulations could facilitate the preliminary selection of the polymer materials for specific purposes before their synthesis.
PubMed: 37764338
DOI: 10.3390/molecules28186562 -
The Journal of Antimicrobial... Nov 2023To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
METHODS
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
RESULTS
Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults.
CONCLUSIONS
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
Topics: Humans; Adult; Child; Paromomycin; Leishmaniasis, Visceral; Antiprotozoal Agents; Kenya; Phosphorylcholine; Uganda; Treatment Outcome
PubMed: 37726401
DOI: 10.1093/jac/dkad286 -
NPJ Biofilms and Microbiomes Sep 2023Diarrhea is characterized by alterations in the gut microbiota, metabolites, and host response to these changes. Studies have focused on the role of commensal bacteria...
Diarrhea is characterized by alterations in the gut microbiota, metabolites, and host response to these changes. Studies have focused on the role of commensal bacteria in diarrhea; however, the effect of fungi on its pathogenesis remains unexplored. Here, using post-weaned piglets with or without diarrhea, we found an unexpected decrease in the abundance of Candida tropicalis in diarrheal piglets. We also observed increased accumulation of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in the colonic tissues of diarrheal piglets. Using dectin-1-knockout mice, we found that the over-accumulation of ROS killed C. tropicalis by promoting NET formation, which was dependent on dectin-1. The decreased abundance of C. tropicalis resulted in reduced phosphocholine consumption. Then, colonic phosphocholine accumulation drives water efflux by increasing cAMP levels by activating adenylyl cyclase, which promotes the clearance of pathogenic bacteria. Collectively, we demonstrated that phosphocholine is correlated with colonic C. tropicalis and promotes diarrhea and pathogen clearance. Our results suggest that mycobiota colonizing the colon might be involved in maintaining intestinal metabolic homeostasis through the consumption of certain metabolites.
Topics: Animals; Swine; Mice; Candida tropicalis; Phosphorylcholine; Reactive Oxygen Species; Colon; Diarrhea; Mice, Knockout
PubMed: 37666845
DOI: 10.1038/s41522-023-00433-0 -
Biomolecules Jul 2023Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl...
Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl phosphorylcholine (p(PMβCD-co-MPC)) with various monomer ratios were formed on magnetic nanoparticles and characterized. Surface chemistry effects on protein denaturation were evaluated and indicated that unmodified magnetic nanoparticles greatly perturbed the structure of proteins compared to coated particles. Plasma clotting assays were conducted to investigate the stability of plasma in the presence of particles, where a 2:2 monomer ratio yielded the best results for a given total surface area of particles. Total protein adsorption results revealed that modified surfaces exhibited reduced protein adsorption compared to bare particles, and pure MPC showed the lowest adsorption. Immunoblot results showed that fibrinogen, α1-antitrypsin, vitronectin, prekallikrein, antithrombin, albumin, and C3 correlated with film composition. Hemocompatibility testing with whole blood illustrated that the 1:3 ratio of CD to MPC had a negative impact on platelets, as evidenced by the increased activation, reduced response to an agonist, and reduced platelet count. Other formulations had statistically significant effects on platelet activation, but no formulation yielded apparent adverse effects on hemostasis. For the first time, p(PMβCD-co-MPC)-coated MNP were synthesized and their general hemocompatibility assessed.
Topics: Phosphorylcholine; Magnetite Nanoparticles; Adsorption; Antithrombin III; Blood Coagulation
PubMed: 37627230
DOI: 10.3390/biom13081165 -
Biomimetics (Basel, Switzerland) Aug 2023The objective of this study was to investigate the use of the nanocapsule sequential delivery of BMP-2 and SDF-1α through the peripheral circulatory system to promote...
OBJECTIVE
The objective of this study was to investigate the use of the nanocapsule sequential delivery of BMP-2 and SDF-1α through the peripheral circulatory system to promote the healing of osteoporotic fractures.
METHODS
Based on increased vascular permeability in the early hematoma environment around the fracture and the presence of a large number of matrix metalloproteinase MMPs in the inflammatory environment, we designed MMP-sensitive nanocapsules which were formed viain situ free-radical polymerization on the surface of grow factors with 2-(methacryloyloxy) ethyl phosphorylcholine (MPC) and the bisacryloylated VPLGVRTK peptide. The antiphagic effect and biological activity of the growth factors for the nanomicrocapsule delivery system were tested by cell experiments. The 36 SD rats with an osteoporotic fracture model were randomly divided into six groups (A, B, C, D, E, and F). In this paper, the nanocapsules loaded with BMP-2 and SDF-1 are represented as n (BMP-2) and n (SDF-1α). In the six groups, the following different combinations of growth factors were injected into the bone defect site on days 1 and 3 after bone defect surgery: in group A, n (SDF-1α) combined with n (SDF-1α); in group B, n (BMP-2) combined with n (BMP-2); in group C, n (SDF-1α) + n (BMP-2) combined with n (SDF-1α) + n (BMP-2); in group D, n (SDF-1α) combined with n (BMP-2); in group E, n (BMP-2) combined with n (SDF-1α); in group F, nanocapsules without growth factor were used as the control group. Micro-CT was used to observe the effect of n(BMP-2) and n(SDF-1α) sequential delivery inearly healing in osteoporotic fractures. Finally, in this study, we evaluated the safety of the nanocapsules delivery system by detecting ectopic osteogenesis and inflammatory responses in animals.
RESULTS
Nanocapsules have low toxicity and protect the integrity and biological activity of growth factors. The results confirmed that nanocapsules could still be effectively targeted to the fracture site on days 1, 3, and 7 after intravenous administration. Growth factors encapsulated in nanocapsules have better bone repair results than natural growth factors. In particular, groups C and D had the best bone repair results than other groups.In vivo experiments confirmed that nanocapsules did not cause significant ectopic osteogenesis and inflammation.
CONCLUSION
The results confirmed that the special vascular permeability and inflammatory factor microenvironment of the fracture site could be used to deliver two growth factors with a synergistic effect through venous circulation, which could better promote the healing process of osteoporotic fracture.
PubMed: 37622974
DOI: 10.3390/biomimetics8040369 -
ACS Applied Bio Materials Sep 2023Contact lenses are one of the most successful applications of biomaterials. The chemical structure of the polymers used in contact lenses plays an important role in... (Review)
Review
Contact lenses are one of the most successful applications of biomaterials. The chemical structure of the polymers used in contact lenses plays an important role in determining the function of contact lenses. Different types of contact lenses have been developed based on the chemical structure of polymers. When designing contact lenses, materials scientists consider factors such as mechanical properties, processing properties, optical properties, histocompatibility, and antifouling properties, to ensure long-term wear with minimal discomfort. Advances in contact lens materials have addressed traditional issues such as oxygen permeability and biocompatibility, improving overall comfort, and duration of use. For example, silicone hydrogel contact lenses with high oxygen permeability were developed to extend the duration of use. In addition, controlling the surface properties of contact lenses in direct contact with the cornea tissue through surface polymer modification mimics the surface morphology of corneal tissue while maintaining the essential properties of the contact lens, a significant improvement for long-term use and reuse of contact lenses. This review presents the material science elements required for advanced contact lenses of the future and summarizes the chemical methods for achieving these goals.
Topics: Silicones; Hydrogels; Biomimetics; Contact Lenses; Oxygen; Polymers
PubMed: 37616500
DOI: 10.1021/acsabm.3c00296 -
Molecular Therapy. Methods & Clinical... Sep 2023Lipid nanoparticles (LNPs) for delivery of mRNA usually contain ionizable lipid/helper lipid/cholesterol/PEG-lipid in molar ratios of 50:10:38.5:1.5, respectively. These...
Lipid nanoparticles (LNPs) for delivery of mRNA usually contain ionizable lipid/helper lipid/cholesterol/PEG-lipid in molar ratios of 50:10:38.5:1.5, respectively. These LNPs are rapidly cleared from the circulation following intravenous (i.v.) administration, limiting uptake into other tissues. Here, we investigate the properties of LNP mRNA systems prepared with high levels of "helper" lipids such as 1,2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC) or N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine (egg sphingomyelin [ESM]). We show that LNP mRNAs containing 40 mol % DSPC or ESM have a unique morphology with a small interior "solid" core situated in an aqueous compartment that is bounded by a lipid bilayer. The encapsulated mRNA exhibits enhanced stability in the presence of serum. LNP mRNA systems containing 40 mol % DSPC or ESM exhibit significantly improved transfection properties compared with systems containing 10 mol % DSPC or ESM. When injected i.v., LNP mRNAs containing 40 mol % ESM exhibit extended circulation lifetimes compared with LNP mRNA systems containing 10 mol % DSPC, resulting in improved accumulation in extrahepatic tissues. Systems containing 40 mol % ESM result in significantly improved gene expression in spleen and bone marrow as well as liver post i.v. injection compared with 10 mol % DSPC LNP mRNAs. We conclude that LNP mRNAs containing high levels of helper lipid provide a new approach for transfecting hepatic and extrahepatic tissues.
PubMed: 37564393
DOI: 10.1016/j.omtm.2023.06.005 -
Bioengineering (Basel, Switzerland) Jun 2023Osteoarthritis (OA) is a degenerative joint disease causing loss of articular cartilage and structural damage in all joint tissues. Given the limited regenerative...
Osteoarthritis (OA) is a degenerative joint disease causing loss of articular cartilage and structural damage in all joint tissues. Given the limited regenerative capacity of articular cartilage, methods to support the native structural properties of articular cartilage are highly anticipated. The aim of this study was to infiltrate zwitterionic monomer solutions into human OA-cartilage explants to replace lost proteoglycans. The study included polymerization and deposition of methacryloyloxyethyl-phosphorylcholine- and a novel sulfobetaine-methacrylate-based monomer solution within ex vivo human OA-cartilage explants and the encapsulation of isolated chondrocytes within hydrogels and the corresponding effects on chondrocyte viability. The results demonstrated that zwitterionic cartilage-hydrogel networks are formed by infiltration. In general, cytotoxic effects of the monomer solutions were observed, as was a time-dependent infiltration behavior into the tissue accompanied by increasing cell death and penetration depth. The successful deposition of zwitterionic hydrogels within OA cartilage identifies the infiltration method as a potential future therapeutic option for the repair/replacement of OA-cartilage extracellular suprastructure. Due to the toxic effects of the monomer solutions, the focus should be on sealing the OA-cartilage surface, instead of complete infiltration. An alternative treatment option for focal cartilage defects could be the usage of monomer solutions, especially the novel generated sulfobetaine-methacrylate-based monomer solution, as bionic for cell-based 3D bioprintable hydrogels.
PubMed: 37508794
DOI: 10.3390/bioengineering10070767