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BioRxiv : the Preprint Server For... Sep 2023, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which...
, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs like lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. Our study shows that a common characteristic of the proteome - stretches of poly-lysine residues such as those found in proteins related to adhesion and pathogenicity - can serve as an effective peptide treatment for infected erythrocytes. A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 hours. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers further increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, our affinity pull-downs and mass-spectrometry identify outer membrane proteins as likely targets for polybasic peptide medications. Since poly-lysine dendrimers are already FDA-approved for drug delivery, their adaptation as antimalarial drugs presents a promising new therapeutic strategy.
PubMed: 37745508
DOI: 10.1101/2023.09.16.558069 -
Theranostics 2024Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant...
Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant therapy has drawbacks of causing indiscriminate damage and inability to penetrate bladder mucosal. Fluorinated polylysine micelles (PLLF) were synthesized by reacting polylysine (PLL) with heptafluorobutyrate anhydride. Anti-apoptotic gene defender against cell death 1 (DAD1) was selected by different gene expression analysis between BCa patients and healthy individuals and identified by several biological function assays. The gene transfection ability of PLLF was verified by multiple and assays. The therapeutic efficiency of PLLF nanoparticles (NPs) targeting DAD1 were confirmed by intravesical administration using an orthotopic BCa mouse model. Decorated with fluorinated chains, PLL can self-assemble to form NPs and condense plasmids with excellent gene transfection efficiency . Loading with the CRISPR-Cas9 system designed to target DAD1 (Cas9-sgDAD1), PLLF/Cas9-sgDAD1 NPs strongly inhibited the expression of DAD1 in BCa cells and induced BCa cell apoptosis through the MAPK signaling pathway. Furthermore, intravesical administration of PLLF/Cas9-sgDAD1 NPs resulted in significant therapeutic outcomes without systemic toxicity . The synthetized PLLF can transmucosally deliver the CRISPR-Cas9 system into orthotopic BCa tissues to improve intravesical instillation therapy for BCa. This work presents a new strategy for targeting DAD1 gene in the intravesical therapy for BCa with high potential for clinical applications.
Topics: Mice; Animals; Humans; Urinary Bladder; Polylysine; CRISPR-Cas Systems; Urinary Bladder Neoplasms; Nanoparticles; Genetic Therapy
PubMed: 38164146
DOI: 10.7150/thno.88550 -
Pharmaceutics Dec 2023Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn...
Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn restricts SF's therapeutic efficacy. Here, a redox-responsive fluorinated peptide (DEN-TAT-PFC) consisting of dendritic poly-lysine, cell-penetrating peptide TAT, and perfluorocarbon was designed and synthesized to co-load siRNA-targeting hypoxia-inducible factors (siHIF-1α) and SF. The unique architecture of the peptide and fluorinated modifications enhanced the siRNA delivery efficiency, including increased siRNA binding, GSH-responsive release, cellular uptake, endosomal escape, and serum resistance. Simultaneously, the DEN-TAT-PFC/SF/siHIF-1α co-delivery system achieved efficient knockdown of HIF-1α at mRNA and protein levels, thus alleviating hypoxia and further substantially reducing VEGF expression. Additionally, the excellent oxygen-carrying ability of DEN-TAT-PFC may facilitate relief of the hypoxic microenvironment. As a result of these synergistic effects, DEN-TAT-PFC/SF/siHIF-1α exhibited considerable anti-tumor cell proliferation and anti-angiogenesis effects. Therefore, DEN-TAT-PFC can be a versatile platform for fabricating fluorine-containing drugs/siRNA complex nano-systems.
PubMed: 38140129
DOI: 10.3390/pharmaceutics15122789 -
Frontiers in Oral Health 2024To determine which components in a new restorative material (Renewal MI) improve its ability to form resin tags within demineralized dentine.
OBJECTIVES
To determine which components in a new restorative material (Renewal MI) improve its ability to form resin tags within demineralized dentine.
METHODS
Varied components included polylysine (PLS), monocalcium phosphate (MCP), powder to liquid ratio (PLR), 4-methacryloyloxyethyl trimellitate anhydride (4META), and polypropylene glycol dimethacrylate (PPGDMA). Urethane dimethacrylate (UDMA), containing PPGDMA (24 wt%) and 4META (3 wt%), was mixed with glass filler with MCP (8 wt%) and PLS (5 wt%). PLR was 3:1 or 5:1. Reducing MCP and/or PLS to 4 and 2 wt% respectively or fully removing MCP, PLS, 4META or PPGDMA gave 16 formulations in total. Renewal MI, Z250 (with or without Scotchbond Universal adhesive) and Activa were used as commercial comparators. Collagen discs were obtained by totally demineralizing 2 mm thick, human, premolar, coronal dentine discs by immersion in formic acid (4M) for 48 h. The restorative materials were then applied on top ( = 3), before dissolving the collagen in sodium hypochlorite (15%). SEM/EDX was employed to determine resin tags length, composition, and surface coverage.
RESULTS
Tags were >400, 20 and 200 µm and covered 62, 55 and 39% of the adhesion interface for Renewal MI, Scotchbond and Activa, respectively. With experimental formulations, they were 200 and >400 µm long with high vs. low PLR and composed primarily of polymerized monomers. Percentages of the adhesion interface covered varied between 35 and 84%. Reducing PLS or MCP caused a decline in coverage that was linear with their concentrations. Reducing MCP had lesser effect when PLS or PLR were low. Removal of 4META caused a greater reduction in coverage than PPGDMA removal.
CONCLUSION
PLS, MCP, 4META, PPGDMA and low PLR together enhance Renewal MI tags formation in, and thereby sealing of, demineralized dentine.
PubMed: 38948090
DOI: 10.3389/froh.2024.1420541 -
International Journal of Biological... Sep 2023Infected wounds are difficult to heal because they are vulnerable to bacterial attacks, inflammatory responses, and oxidative stress. To promote the healing of infected...
Infected wounds are difficult to heal because they are vulnerable to bacterial attacks, inflammatory responses, and oxidative stress. To promote the healing of infected wounds, we developed an injectable dual-network hydrogel TFAEP (TA-Fe, APS, EPL-GMA, PVA) based on ε-poly-l-lysine-graft-glycidyl methacrylate (EPL-GMA), polyvinyl alcohol (PVA), and tannic acid-iron (TA-Fe). TA-Fe formed a stable redox pair, which acted as a dual-autocatalytic system to activate ammonium persulfate, generate free radicals, and subsequently induce EPL-GMA polymerization. Then PVA formed hydrogen bonds with TA molecules. Here, TA-Fe not only simulated peroxidase to convert HO into hydroxyl radicals (OH), but also exhibited good near-infrared photothermal conversion efficiency, which all endowed the hydrogel with excellent antibacterial ability. In addition, the hydrogel could remove excessive reactive oxygen species and reactive nitrogen species, alleviating oxidative stress and reducing inflammation response due to the presence of TA molecules. Moreover, the hydrogel showed good injectability and tissue adhesion, ensuring the close adhesion of the hydrogel to the wound and achieving the maximum function. In vivo experiments demonstrated that the hydrogel promoted infected wound healing by accelerating epidermal regeneration, promoting angiogenesis and collagen deposition, and facilitating the expression of anti-inflammatory factors.
Topics: Hydrogels; Hydrogen Peroxide; Lysine; Polymerization; Wound Healing; Anti-Bacterial Agents; Catalysis
PubMed: 37516228
DOI: 10.1016/j.ijbiomac.2023.125911 -
Journal of Agricultural and Food... Oct 2023ε-Polylysine is a novel food preservative approved by the U.S. Food and Drug Administration (FDA), yet the mechanism of its effect on animal-derived foods remains...
ε-Polylysine is a novel food preservative approved by the U.S. Food and Drug Administration (FDA), yet the mechanism of its effect on animal-derived foods remains unclear. Assessment of the effect of preservatives on goat meat products is necessary. Herein, metabolite accumulation and protein expression of ε-polylysine (0.025%, w/w) spiked with goat meat were investigated by nontarget metabolomics and proteomics combined with ultrahigh performance liquid chromatography quadrupole-Orbitrap high-resolution-mass spectrometry (UHPLC-Q-Orbitrap HRMS) in a simulated in vitro digestion model. The amino side chain of ε-polylysine increased the activity of due to its nucleophilic nature, inducing a significant upregulation of l-arginine (0.43-0.72 mg kg) and creatine (3.98-6.89 mg kg), with an improvement in muscle quality of goat meat. Downregulation of enzyme phenylalanine hydroxylase expression led to upregulation of l-phenylalanine (2.26-3.25 mg kg) and l-tyrosine (0.98-1.29 mg kg). Collectively, this study first revealed the biochemical mechanism of ε-polylysine in goat meat products, which makes available new prospects for more accurate use of ε-polylysine in animal-derived foods.
Topics: United States; Animals; Polylysine; Creatine; Up-Regulation; Arginine; Goats
PubMed: 37793042
DOI: 10.1021/acs.jafc.3c04033 -
Journal of the Science of Food and... Mar 2024ε-polylysine hydrochloride (ε-PLH) is a naturally occurring antimicrobial peptide extensively utilized in the food and medical industries. However, its impact on...
Effects of dietary supplement of ε-polylysine hydrochloride on laying performance, egg quality, serum parameters, organ index, intestinal morphology, gut microbiota and volatile fatty acids in laying hens.
BACKGROUND
ε-polylysine hydrochloride (ε-PLH) is a naturally occurring antimicrobial peptide extensively utilized in the food and medical industries. However, its impact on animal husbandry remains to be further explored. Therefore, the present study aimed to determine the effect of ε-PLH on laying hens' health and laying performance.
RESULTS
Dietary supplementation with ε-PLH to the diet significantly increased average egg weight during weeks 1-8. Meanwhile, compared with the control group, supplementation with ε-PLH decreased the feed egg ratio during weeks 9-12 and egg breakage rate during weeks 9-16 ,whereas it increased eggshell strength during weeks 1-4 and 13-16 . The ε-PLH 0.05% group increased yolk percentage during weeks 5-8 and yolk color during weeks 1-4 . Furthermore, ε-PLH supplementation significantly increased the concentrations of total protein, albumin, globulin and reproductive hormones estradiol, as well as decreased interleukin-1 beta and malondialdehyde in the serum. Compared with the control group, supplementation with 0.05% ε-PLH significantly increased the relative abundance of Cyanobacteria and Gastranaerophilales and decreased the abundance of Desulfovibrio and Streptococcus in the cecum microbiota. In addition, ε-PLH 0.1% supplementation also increased acetic acid content in the cecum.
CONCLUSION
Dietary supplementation with ε-PLH has a positive impact on both productive performance and egg quality in laying hens. Furthermore, ε-PLH can also relieve inflammation by promoting the immunity and reducing oxidative damage during egg production. ε-PLH has been shown to improve intestinal morphology, gut microbial diversity and intestinal health. © 2023 Society of Chemical Industry.
Topics: Animals; Female; Gastrointestinal Microbiome; Polylysine; Chickens; Dietary Supplements; Diet; Fatty Acids, Volatile; Animal Feed
PubMed: 38072654
DOI: 10.1002/jsfa.13198 -
Advanced Healthcare Materials Jun 2024Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn...
Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn intracellular small colony variants (SCVs). Herein, the authors have developed nanogels (NGs) to destroy both planktonic bacteria and SCVs and eliminate excessive inflammations for peritonitis and sepsis therapies. Free gentamicin (GEN) and hydroxyapatite nanoparticles (NPs) with GEN loading and mannose grafts (mHA) are inoculated into ε-polylysine NGs to obtain NG@G1-mHA through crosslinking with phenylboronic acid and tannic acid. The HO consumption after reaction with phenylboronic esters and the elimination of free radicals by tannic acid alleviates the escalated inflammatory status to promote sepsis therapy. After mannose-mediated uptake into macrophages, the acid-triggered degradation of mHA NPs generates Ca to destabilize lysosomes and the efficient lysosomal escape leads to reversion of hypometabolic SCVs into normal phenotype and their sensitivity to GEN. In a peritonitis mouse model, NG@G1-mHA treatment provides strong and persistent bactericidal effects against both extracellular bacteria and intracellular SCVs and extends survival of peritonitis mice without apparent hepatomegaly, splenomegaly, pulmonary edema, and inflammatory cell infiltration. Thus, this study demonstrates a concise and versatile strategy to eliminate SCVs and relieve inflammatory storms for peritonitis and sepsis therapies without infection recurrence.
Topics: Animals; Peritonitis; Gentamicins; Mice; Sepsis; Lysosomes; Nanogels; Anti-Bacterial Agents; RAW 264.7 Cells; Nanoparticles; Polyethylene Glycols; Polyethyleneimine
PubMed: 38416744
DOI: 10.1002/adhm.202303671 -
Journal of Biomedical Materials... Nov 2023Polyetheretherketone (PEEK) is a promising material for use in orthopedic implants, but its bio-inert character and lack of antibacterial activity limit its applications...
Enhanced osteogenic and antibacterial properties of polyetheretherketone by ultraviolet-initiated grafting polymerization of a gelatin methacryloyl/epsilon-poly-L-lysine/laponite hydrogel coating.
Polyetheretherketone (PEEK) is a promising material for use in orthopedic implants, but its bio-inert character and lack of antibacterial activity limit its applications in bone repair. In the present study, considering the advantages of PEEK in self-initiated graft polymerization and of hydrogels in bone tissue engineering, we constructed a hydrogel coating (GPL) consisting of Gelatin methacryloyl (GelMA), methacrylamide-modified ε-poly-l-lysine (ε-PLMA) and Laponite on PEEK through UV-initiated crosslinking. The coating improved the hydrophilicity of PEEK, and the coating degraded slowly so that approximately 80% was retained after incubation in PBS for 8 weeks. In vitro studies revealed that as compared to culturing on PEEK, culturing on PEEK-GPL led to enhanced viability and adhesion of cultured human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs). Due to the synergistic effect of the micron-scale three-dimensional surface and Laponite, PEEK-GPL exhibited a significantly improved induction of osteogenic differentiation of hWJ-MSCs compared to PEEK, as demonstrated by increased alkaline phosphatase activity, matrix mineralization, and expression of osteogenesis-related genes. Furthermore, PEEK-GPL showed antibacterial activity upon contact with Staphylococcus aureus and Escherichia coli, and this activity would be maintained before complete degradation of the hydrogel because the ε-PLMA was cross-linked covalently into the coating. Thus, PEEK-GPL achieved both osteogenesis and infection prevention in a single simple step, providing a feasible approach for the extensive use of PEEK in bone implants.
Topics: Humans; Osteogenesis; Polylysine; Hydrogels; Polymerization; Polyethylene Glycols; Ketones; Anti-Bacterial Agents; Surface Properties
PubMed: 37548424
DOI: 10.1002/jbm.a.37589 -
International Journal of Biological... Feb 2024Traditional absorbent pads are composed of hard-to-degrade polyethylene film and non-woven bottom layer, which have the characteristic of low absorption rate, without...
Traditional absorbent pads are composed of hard-to-degrade polyethylene film and non-woven bottom layer, which have the characteristic of low absorption rate, without antibacterial effect. The objective of this study is to fabricate a novel superabsorbent and antibacterial aerogel, which consists of whey protein isolate (WPI) and chitosan (CS). The citric acid (CA) and ε-polylysine hydrochloride (ε-PLH) are incorporated into WPI/CS-based aerogel as cross-linking and antibacterial agent, respectively. The application in meat preservation as an absorbent pad is investigated. Results of water absorption, water vapor absorption and stress-strain show that aerogel comprised of 6 % WPI, 1.2 % CS, 2.0 % CA, and 2.0 % ε-PLH have the best water absorption capacity and stress. The density of WPI/CS/CA/ε-PLH aerogel is 82.7 ± 6.4 mg/cm, and has a uniform and polyporous microstructure, resulting in superabsorbent capacity. Antibacterial rate of WPI/CS/CA/ε-PLH aerogel against Staphylococcus aureus, Escherichia coli, Salmonella and Listeria monocytogenes reach around 80 %. The WPI/CS/CA/ε-PLH aerogel significantly reduces increased velocity of b, pH, total volatile base nitrogen, and total viable counts and decreased velocity of L and b of chicken meat (P < 0.05). Results indicate WPI/CS/CA/ε-PLH aerogel effectively extends shelf-life of chicken meat to 7 days, and could be used as an absorbent pad in meat preservation.
Topics: Animals; Whey Proteins; Chitosan; Chickens; Anti-Bacterial Agents; Meat; Escherichia coli
PubMed: 38154705
DOI: 10.1016/j.ijbiomac.2023.128961