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PloS One 2024To date, several types of airway stents are available to treat central airway obstructions. However, the ideal stent that can overcome anatomical, mechanical and...
To date, several types of airway stents are available to treat central airway obstructions. However, the ideal stent that can overcome anatomical, mechanical and microbiological issues is still awaited. In addition, therapeutic effect and self-elimination of these stents are desirable properties, which pose an additional challenge for development and manufacturing. We aimed to create a prototype bioresorbable tracheal stent with acceptable clinical tolerance, fit and biocompatibility, that could be tested in a rabbit model and in the future be further optimized to enable drug-elution and ensure local therapeutic effect. Twenty-one New Zealand White Rabbits received five different types of bioresorbable tracheal stents, 3D-printed from poly(D,L-lactide-co-ε-caprolactone) metacrylates. Various configurations were tested for their functionality and improved until the best performing prototype could undergo detailed in vivo assessment, regarding clinical tolerance, migration and biocompatibility. Previously tested types of 3D printed stents in our preliminary study required improvement due to several problems, mainly related to breakage, unreliable stability and/or migration within the trachea. Abandoned or refined pre-prototypes were not analyzed in a comparative way. The final best performing prototype stent (GSP2 (Group Stent Prototype 2), n = 8) allowed a transoral application mode and showed good clinical tolerance, minimal migration and acceptable biocompatibility. The good performance of stent type GSP2 was attributed to the helix-shaped surface structure, which was therefore regarded as a key-feature. This prototype stent offers the possibility for further research in a large animal model to confirm the promising data and assess other properties such as bioresorption.
Topics: Animals; Rabbits; Printing, Three-Dimensional; Stents; Trachea; Absorbable Implants; Materials Testing; Biocompatible Materials; Prosthesis Design; Polyesters
PubMed: 38917158
DOI: 10.1371/journal.pone.0300847 -
TheScientificWorldJournal 2024Pharmaceutical formulations have traditionally relied on plants and their derivatives for various APIs and excipients. In Ghana, the widespread utilization of plantains,...
Pharmaceutical formulations have traditionally relied on plants and their derivatives for various APIs and excipients. In Ghana, the widespread utilization of plantains, irrespective of their ripeness, generates significant waste at every stage of processing, posing disposal issues. Fascinatingly, these wastes, often discarded, possess significant economic potential and can be recycled into valuable raw materials or products. Pectin, a polysaccharide that occurs naturally, has seen a surge in interest in recent times. It has found widespread use in the pharmaceutical sector, particularly as a binding agent in tablet formulations. This study aimed to evaluate pectin from two popular plantain varieties, Apem (M) and Apantu (T) at different ripening stages, for pharmaceutical use as a binding agent in immediate-release tablets. The ripening stages selected were the matured-green (G), half-ripe (H), and full-ripe (R). Acid (D) and alkaline (L) mediums of extraction were employed for each ripening stage for both varieties. Wet granulation method was used to prepare the granules using paracetamol as a model drug, and their flow properties were subsequently assessed. Postcompression tests including, hardness, friability, weight uniformity, disintegration, assay, and in vitro dissolution were also assessed. Granules from all formulation batches had good flow properties indicated by their angle of repose (14.93 ± 1.41-21.80 ± 1.41), Hausner ratio (0.96 ± 0.27-1.22 ± 0.02), and compressibility (%) (7.69 ± 0.002-20.51 ± 0.002). All the tablets passed the uniformity of weight with none deviating by ±5%. The hardness of all the formulated tablets ranged between 3.96 ± 0.32 and 13.21 ± 0.36, while the friability for all tablets was below 1%. The drug content was between 100.1 ± 0.23% and 103.4 ± 0.01%. Tablets formulated with pectin as a binding agent at concentrations of 10% w/v and 15% w/v successfully met the disintegration test criteria for immediate release tablets. However, those prepared with a concentration of 20% w/v (MGL, MHD, MHL, MRD, MRL, TGL, THD, THL, and TRL) did not pass the disintegration test. Consequently, all batches of tablets successfully met the dissolution test requirement (Diss, > 75%), except for the batches that did not pass the disintegration test (Diss, < 75%). Ultimately, pectins extracted from the peels of Apem and Apantu at different ripening stages using acid and alkaline extraction can be commercially exploited as pharmaceutical binders at varying concentrations in immediate-release tablets.
Topics: Pectins; Tablets; Ghana; Plantago; Acetaminophen; Excipients
PubMed: 38915814
DOI: 10.1155/2024/5461358 -
BioRxiv : the Preprint Server For... Jun 2024We present an efficient approach for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to rapidly create a library of...
We present an efficient approach for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to rapidly create a library of complex functional ionizable lipopolymers. We synthesized a diverse library of 155 polymers, formulated them into polyplexes to establish structure-activity relationships crucial for endosomal escape and efficient transfection. After discovering a lead structure, lipopolymer-lipid hybrid nanoparticles are introduced to preferentially deliver to and elicit effective mRNA transfection in lung endothelium and immune cells, including T cells with low toxicity. The lipopolymer-lipid hybrid nanoparticles showed 300-fold improvement in systemic mRNA delivery to the lung compared to -JetPEI . Lipopolymer-lipid hybrid nanoparticles demonstrated efficient delivery of mRNA-based therapeutics for treatment of two different disease models. Lewis Lung cancer progression was significantly delayed after treatment with loaded IL-12 mRNA in U155@lipids after repeated i.v. administration. Systemic delivery of human CFTR (hCFTR) mRNA resulted in production of functional form of CFTR protein in the lungs. The functionality of hCFTR protein was confirmed by restoration of CFTR- mediated chloride secretion in conductive airway epithelia in CFTR knockout mice after nasal instillation of hCFTR mRNA loaded U155@lipids. We further showed that, U155@lipids nanoparticles can deliver complex CRISPR-Cas9 based RNA cargo to the lung, achieving 5.6 ± 2.4 % gene editing in lung tissue. Moreover, we demonstrated successful PD-1 gene knockout of T cells . Our results highlight a versatile delivery platform for systemic delivering of mRNA of various sizes for gene therapy for a variety of therapeutics.
PubMed: 38915714
DOI: 10.1101/2024.06.11.598497 -
BioRxiv : the Preprint Server For... Jun 2024We report the development of a nanotechnology to co-deliver chemocoxib A with a reactive oxygen species (ROS)-activatable and COX-2 targeted pro-fluorescent probe,...
We report the development of a nanotechnology to co-deliver chemocoxib A with a reactive oxygen species (ROS)-activatable and COX-2 targeted pro-fluorescent probe, fluorocoxib Q (FQ) enabling real time visualization of COX-2 and CA drug delivery into solid cancers, using a di-block PPS - -POEGA copolymer, selected for its intrinsic responsiveness to elevated reactive oxygen species (ROS), a key trait of the tumor microenvironment. FQ and CA were synthesized independently, then co-encapsulated within micellar PPS - -POEGA co-polymeric nanoparticles (FQ-CA-NPs), and were assessed for cargo concentration, hydrodynamic diameter, zeta potential, and ROS-dependent cargo release. The uptake of FQ-CA-NPs in mouse mammary cancer cells and cargo release was assessed by fluorescence microscopy. Intravenous delivery of FQ-CA-NPs to mice harboring orthotopic mammary tumors, followed by vital optimal imaging, was used to assess delivery to tumors . The CA-FQ-NPs exhibited a hydrodynamic diameter of 109.2 ± 4.1 nm and a zeta potential (σ) of -1.59 ± 0.3 mV. Fluorescence microscopy showed ROS-dependent cargo release by FQ-CA-NPs in 4T1 cells, decreasing growth of 4T1 breast cancer cells, but not affecting growth of primary human mammary epithelial cells (HMECs). NP-derived fluorescence was detected in mammary tumors, but not in healthy organs. Tumor LC-MS/MS analysis identified both CA (2.38 nmol/g tumor tissue) and FQ (0.115 nmol/g tumor tissue), confirming the FQ-mediated image guidance of CA delivery in solid tumors. Thus, co-encapsulation of FQ and CA into micellar nanoparticles (FQ-CA-NPs) enabled ROS-sensitive drug release and COX-2-targeted visualization of solid tumors.
PubMed: 38915607
DOI: 10.1101/2024.06.07.598019 -
BioRxiv : the Preprint Server For... Jun 2024Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information...
Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers . Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement-recoding-is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a synthetic genome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organism's genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry.
PubMed: 38915524
DOI: 10.1101/2024.06.16.599206 -
BMC Biology Jun 2024The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly...
BACKGROUND
The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear.
RESULTS
This study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models.
CONCLUSIONS
These findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism.
Topics: Vimentin; Integrin beta1; Anoikis; Humans; Animals; Cell Survival; Mice; Cell Line, Tumor; Phosphorylation; p21-Activated Kinases
PubMed: 38915055
DOI: 10.1186/s12915-024-01942-w -
BMC Infectious Diseases Jun 2024Acinetobacter baumannii is a health threat due to its antibiotic resistance. Herein, antibiotic susceptibility and its association with the Toxin-antitoxin (TA) system...
Evaluating the antibacterial effect of meropenem-loaded chitosan/sodium tripolyphosphate (TPP) nanoparticles on Acinetobacter baumannii isolated from hospitalized patients.
BACKGROUND
Acinetobacter baumannii is a health threat due to its antibiotic resistance. Herein, antibiotic susceptibility and its association with the Toxin-antitoxin (TA) system genes in A. baumannii clinical isolates from Iran were investigated. Next, we prepared meropenem-loaded chitosan nanoparticles (MP-CS) and investigated their antibacterial effects against meropenem-susceptible bacterial isolates.
METHODS
Out of 240 clinical specimens, 60 A. baumannii isolates were assessed. Antibiotic resistance of the isolates against conventional antibiotics was determined alongside investigating the presence of three TA system genes (mazEF, relBE, and higBA). Chitosan nanoparticles were characterized in terms of size, zeta potential, encapsulation efficiency, and meropenem release activity. Their antibacterial effects were assessed using the well diffusion method, minimum inhibitory concentration (MIC), and colony-forming unit (CFU) counting. Their cytotoxic effects and biocompatibility index were determined via the MTT, LDH, and ROS formation assays.
RESULTS
Ampicillin, ceftazidime, and colistin were the least effective, and amikacin and tobramycin were the most effective antibiotics. Out of the 60 isolates, 10 (16.7%), 5 (8.3%), and 45 (75%) were multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR), respectively. TA system genes had no significant effect on antibiotic resistance. MP-CS nanoparticles demonstrated an average size of 191.5 and zeta potential of 27.3 mV alongside a maximum encapsulation efficiency of 88.32% and release rate of 69.57%. MP-CS nanoparticles mediated similar antibacterial effects, as compared with free meropenem, against the A. baumannii isolates with significantly lower levels of meropenem. MP-CS nanoparticles remarkably prevented A549 and NCI-H292 cell infection by the A. baumannii isolates alongside demonstrating a favorable biocompatibility index.
CONCLUSION
Antibiotic-loaded nanoparticles should be further designed and investigated to increase their antibacterial effect against A. baumannii and assess their safety and applicability in vivo settings.
Topics: Acinetobacter baumannii; Meropenem; Chitosan; Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Nanoparticles; Acinetobacter Infections; Iran; Polyphosphates
PubMed: 38914964
DOI: 10.1186/s12879-024-09522-7 -
Scientific Reports Jun 2024As genomic databases expand and artificial intelligence tools advance, there is a growing demand for efficient characterization of large numbers of proteins. To this...
As genomic databases expand and artificial intelligence tools advance, there is a growing demand for efficient characterization of large numbers of proteins. To this end, here we describe a generalizable pipeline for high-throughput protein purification using small-scale expression in E. coli and an affordable liquid-handling robot. This low-cost platform enables the purification of 96 proteins in parallel with minimal waste and is scalable for processing hundreds of proteins weekly per user. We demonstrate the performance of this method with the expression and purification of the leading poly(ethylene terephthalate) hydrolases reported in the literature. Replicate experiments demonstrated reproducibility and enzyme purity and yields (up to 400 µg) sufficient for comprehensive analyses of both thermostability and activity, generating a standardized benchmark dataset for comparing these plastic-degrading enzymes. The cost-effectiveness and ease of implementation of this platform render it broadly applicable to diverse protein characterization challenges in the biological sciences.
Topics: Robotics; Escherichia coli; Protein Engineering; High-Throughput Screening Assays; Hydrolases; Polyethylene Terephthalates; Reproducibility of Results
PubMed: 38914665
DOI: 10.1038/s41598-024-64938-0 -
Scientific Reports Jun 2024Sugarcane bagasse fly ash, a residual product resulting from the incineration of biomass to generate power and steam, is rich in SiO. Sodium silicate is a fundamental...
Sugarcane bagasse fly ash, a residual product resulting from the incineration of biomass to generate power and steam, is rich in SiO. Sodium silicate is a fundamental material for synthesizing highly porous silica-based adsorbents to serve circular practices. Aflatoxin B1 (AFB1), a significant contaminant in animal feeds, necessitates the integration of adsorbents, crucial for reducing aflatoxin concentrations during the digestive process of animals. This research aimed to synthesize aluminosilicate and zinc silicate derived from sodium silicate based on sugarcane bagasse fly ash, each characterized by a varied molar ratio of aluminum (Al) to silicon (Si) and zinc (Zn) to silicon (Si), respectively. The primary focus of this study was to evaluate their respective capacities for adsorbing AFB1. It was revealed that aluminosilicate exhibited notably superior AFB1 adsorption capabilities compared to zinc silicate and silica. Furthermore, the adsorption efficacy increased with higher molar ratios of Al:Si for aluminosilicate and Zn:Si for zinc silicate. The N confirmed AFB1 adsorption within the pores of the adsorbent. In particular, the aluminosilicate variant with a molar ratio of 0.08 (Al:Si) showcased the most substantial AFB1 adsorption capacity, registering at 88.25% after an in vitro intestinal phase. The adsorption ability is directly correlated with the presence of surface acidic sites and negatively charged surfaces. Notably, the kinetics of the adsorption process were best elucidated through the application of the pseudo-second-order model, effectively describing the behavior of both aluminosilicate and zinc silicate in adsorbing AFB1.
Topics: Silicates; Adsorption; Aluminum Silicates; Saccharum; Aflatoxin B1; Coal Ash; Cellulose; Zinc Compounds
PubMed: 38914625
DOI: 10.1038/s41598-024-65158-2 -
Scientific Reports Jun 2024The joint impact of tadalafil (Cilais) as a pharmaceutical residue and microplastics on fish is not well comprehended. The current study examined haematological,...
The joint impact of tadalafil (Cilais) as a pharmaceutical residue and microplastics on fish is not well comprehended. The current study examined haematological, biochemical, and antioxidant parameters, along with immunohistochemical and histological indications in tilapia (Oreochromis niloticus) after being exposed to tadalafil, polyethylene microplastics (PE-MPs), and their mixtures for 15 days. The fish were distributed into 1st group control group (The fish was maintained in untreated water without any supplements); 2nd group exposed to 10 mg/L PE-MPs;3rd group exposed to 20 mg/l tadalafil (Cilais); 4th group exposed to 20 mg/l tadalafil (Cilais) + 10 mg/LPE-MPs (in triplicate). The levels of creatinine, uric acid, glucose, AST, ALT, and albumin in fish treated with tadalafil alone or in combination with PE-MPs were significantly higher than those in the control group. Fish exposed to PE-MPs, tadalafil, and tadalafil plus PE-MPs showed significantly lower levels of RBCs, Hb, Ht, neutrophils, and lymphocytes compared to the control group. Serum levels of total antioxidant capacity and reduced glutathione (GSH) were notably lowered in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations in comparison to the control group. Malondialdehyde (MDA) serum levels were notably elevated in fish groups subjected to PE-MPs, tadalafil, and tadalafil + PE-MPs combinations compared to the control group. The most severe impact was observed in the tadalafil + PE-MPs combination group. Interleukin-6 (IL-6) levels were significantly increased in liver tissues following exposure to both tadalafil and microplastics compared to tissues exposed to only one substance or the control group. Changes in the gills, liver, and renal tissues were seen following exposure to PE-MPs, tadalafil, and tadalafil + PE-MPs combination in comparison to the control group of fish. Ultimately, the mixture of tadalafil and PE-MPs resulted in the most detrimental outcomes. Tadalafil and PE-MPs exhibited showed greater adverse effects, likely due to tadalafil being absorbed onto PE-MPs.
Topics: Animals; Tadalafil; Cichlids; Water Pollutants, Chemical; Microplastics; Antioxidants; Tilapia; Glutathione; Gills; Oxidative Stress
PubMed: 38914580
DOI: 10.1038/s41598-024-64282-3