Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells.

Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.

Hyperuricemia remodels the serum proteome toward a higher inflammatory state.

Gout is an autoinflammatory disease triggered by a complex innate immune response to MSU crystals and inflammatory triggers. While hyperuricemia is an obligatory risk factor for the development of gout, the majority of individuals with hyperuricemia never develop gout but have an increased risk of developing cardiometabolic disorders. Current management of gout aims at MSU crystal dissolution by lowering serum urate. We apply a targeted proteomic analysis, using Olink inflammation panel, to a large group of individuals with gout, asymptomatic hyperuricemia, and normouricemic controls, and we show a urate-driven inflammatory signature. We add in vivo evidence of persistent immune activation linked to urate exposure and describe immune pathways involved in the pathogenesis of gout. Our results support a pro-inflammatory effect of asymptomatic hyperuricemia and pave the way for new research into targetable mechanisms in gout and cardiometabolic complications of asymptomatic hyperuricemia.

Eco-friendly cellulose-based hydrogel functionalized by NIR-responsive multimodal antibacterial polymeric ionic liquid as platform for promoting wound healing.

With the trend of sustainable development and the complex medical environment, there is a strong demand for multimodal antibacterial cellulose wound dressing (MACD) with photothermal therapy (PTT). Herein, a novel MACD fabrication strategy with PTT was proposed and implemented through graft polymerization of an imidazolium ionic liquid monomer containing iron complex anion structure. The fabricated hydrogels exhibited excellent antibacterial properties because of the efficient photothermal conversion ability (68.67 %) of ionic liquids and the intrinsic structural characteristic of quaternary ammonium salts. The antibacterial ratio of cellulosic hydrogel dressings to S. aureus and E. coli could reach 99.57 % and 99.16 %, respectively. Additionally, the fabricated hydrogels demonstrated extremely low hemolysis rates (<5 %) and excellent cell viability (~>85 %). Furthermore, in vivo antibacterial experimental results proved that the fabricated antibacterial dressings could significantly accelerate wound healing. Therefore, the proposed strategy would provide a new method of designing and preparing high-performance cellulose wound dressings.

Cell-Membrane-Coated and Cell-Penetrating Peptide-Conjugated Trimagnetic Nanoparticles for Targeted Magnetic Hyperthermia of Prostate Cancer Cells.

Prostate malignancy represents the second leading cause of cancer-specific death among the male population worldwide. Herein, enhanced intracellular magnetic fluid hyperthermia is applied in vitro to treat prostate cancer (PCa) cells with minimum invasiveness and toxicity and highly specific targeting. We designed and optimized novel shape-anisotropic magnetic core-shell-shell nanoparticles (i.e., trimagnetic nanoparticles - TMNPs) with significant magnetothermal conversion following an exchange coupling effect to an external alternating magnetic field (AMF). The functional properties of the best candidate in terms of heating efficiency (i.e., Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4) were exploited following surface decoration with PCa cell membranes (CM) and/or LN1 cell-penetrating peptide (CPP). We demonstrated that the combination of biomimetic dual CM-CPP targeting and AMF responsiveness significantly induces caspase 9-mediated apoptosis of PCa cells. Furthermore, a downregulation of the cell cycle progression markers and a decrease of the migration rate in surviving cells were observed in response to the TMNP-assisted magnetic hyperthermia, suggesting a reduction in cancer cell aggressiveness.

High-performance functional cellulose foam fabricated with theoretically optimized imidazolium salts for the efficient removal of ciprofloxacin.

With the increasing requirements for sustainable development and environmental protection, the design and development of bio-adsorbent based on the widely sourced cellulose have attracted widespread attention. In this study, a polymeric imidazolium satls (PIMS) functionalized cellulose foam (CF@PIMS) was conveniently fabricated. It was then employed to efficiently remove ciprofloxacin (CIP). Three imidazolium salts containing phenyl groups that can lead to multiple interactions with CIP were elaborately designed and then screened through a combination of molecular simulation and removal experiments to acquire the most significant binding ability of CF@PIMS. Besides, the CF@PIMS retained the well-defined 3D network structure as well as high porosity (90.3 %) and total intrusion volume (6.05 mL g-1) as the original cellulose foam (CF). Therefore, the adsorption capacity of CF@PIMS reached an astonishing value of 736.9 mg g-1, nearly 10 times that of the CF. Furthermore, the pH-affected and ionic strength-affected adsorption experiments confirmed that the non-electrostatic interaction took on a critical significance in the adsorption. The reusability experiments showed that the recovery efficiency of CF@PIMS was higher than 75 % after 10 adsorption cycles. Thus, a high-potential method was proposed in terms of the design and preparation of functionalized bio-adsorbent to remove waste matters from samples of the environment.

The future clinical implications of trained immunity.

INTRODUCTION: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages, and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment. AREAS COVERED: The purpose of this article is to review the current understanding of the TI process and to discuss its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care. EXPERT OPINION: The state of the art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.

Fabrication of efficient protein imprinted materials based on pearl necklace-like MOFs bacterial cellulose composites.

The acquisition of efficient protein isolation substances is vital for proteomic research, whereas it's still challenging nowadays. Herein, an elaborately designed protein imprinted material based on a bacterial cellulose@ZIF-67 composite carrier (BC@ZIF-67) is proposed for the first time. In particular, due to the ultrafine fiber diameter and abundant hydroxyl functional groups of the bacterial cellulose, BC@ZIF-67 presented a compact arrangement structure similar to a pearl necklace, which greatly promoted template immobilization and mass transfer resistance in protein imprinting technology. Therefore, the protein-imprinted material (BC@ZIF-67@MIPs) fabricated by surface imprinting technology and template immobilization strategy could exhibit ultrahigh adsorption capacity (1017.0 mg g-1), excellent recognition (IF = 5.98) and rapid adsorption equilibrium time (50 min). In addition, based on the experiment outcomes, our team employed BC@ZIF-67@MIPs to enrich template protein in blended protein solutions and biosamples, identifying them as underlying candidates for isolating and purifying proteins.

Fabrication of Raspberry-like Cytochrome C Surface-Imprinted Nanoparticles Based on MOF Composites for High-Performance Protein Separation.

The development of high-performance protein-imprinted materials is vital to meet the requirements of proteomics research but remains a challenge. Herein, a new type of raspberry-like cytochrome C-imprinted nanoparticle was first designed and fabricated via surface imprinting technology combined with a template immobilization strategy. In particular, the state-of-the-art metal-organic framework (MOF)/carbon nanoparticle (CN) composites were selected as protein immobilization carriers for two advantages: (1) the composites reflected the intrinsic characteristics of MOFs including flexible design, facile preparation, and extensive interactions with proteins and (2) the utilization of composites also overcame the issue associated with the severe agglomeration of individual MOFs during the post-use process. Therefore, the as-prepared composites exhibited a regular raspberry-like shape with good dispersion (polydispersity index (PDI) < 0.25), high specific surface area (551.4 m2 g-1), and outstanding cytochrome C immobilization capacity (900 mg g-1). Furthermore, a zwitterionic monomer was chosen to participate in the synthesis of an imprinting layer to reduce the nonspecific binding with proteins. As a result, the unique design presented here in both the protein immobilization carrier and the selected polymer composition endowed the imprinted material (noted as CN@UIO-66@MIPs) with the excellent ability for cytochrome C enrichment with extremely high recognition ability (imprinting factor (IF) = 6.1), rapid adsorption equilibrium time (40 min), and large adsorption capacity (815 mg g-1). Furthermore, encouraged by the experimental results, we successfully used CN@UIO-66@MIPs to specifically capture cytochrome C in mixed protein solutions and biological samples, which proved them to be a potential candidate for protein separation and purification.

Zwitterionic polymer chain-assisted lysozyme imprinted core-shell carbon microspheres with enhanced recognition and selectivity.

Constructing imprinting materials with high recognition and selectivity for protein is an always challenge in protein imprinting technology (PIT). In this work, upon the participating of a zwitterionic polymer chain (Poly (1-vinyl-3-sulfopropylimidazolium), PVSP), a lysozyme imprinted core-shell carbon microsphere (CFC-PVSP@MIPs) was prepared by combining template immobilization method and surface imprinting technology. The carboxyl-functionalized carbon microspheres as substrate provided the CFC-PVSP@MIPs satisfactory adsorption capacity (68.1 mg g-1), while the dopamine as a functional monomer and crosslinker allowed the imprinted microspheres to have a thin imprinted shell, thus endowing them a fast adsorption equilibrium rate (120 min). In addition, PVSP could be tightly bound to the imprinted layer through non-covalent interaction, which not only simplified the preparation process of CFC-PVSP@MIPs, but also reduced the non-specific adsorption of imprinted material on proteins. Therefore, the resulting CFC-PVSP@MIPs exhibited a more superior recognition ability towards lysozyme with imprinting factor value of 3.10, compared with the PVSP-free imprinted microsphere (imprinting factor value 1.93). Furthermore, benefiting from the characteristics of zwitterionic groups, CFC-PVSP@MIPs also revealed stronger selectivity in competitive adsorption studies of binary protein mixture samples. Consequently, the proposed strategy would be a promising and convenient way to obtain protein imprinted material with high recognition ability, thus would be conducive to further development and application of PIT.

Bi-Magnetic Core-Shell CoFe2O4@MnFe2O4 Nanoparticles for In Vivo Theranostics.

In this work, we report the synthesis and characterization of three magnetic nanosystems, CoFe2O4, CoFe2O4@ZnFe2O4, and CoFe2O4@MnFe2O4, which were developed as potential theranostic agents for magnetic hyperthermia and magnetic resonance imaging (MRI). These nanosystems have been thoroughly characterized by X-ray Diffraction (XRD), Transmission Electron Miscroscopy (TEM), Dark Field-TEM (DF-TEM), Vibrating Sample Magnetometry (VSM), and inductive heating, in order to elucidate their structure, morphology, and magnetic properties. The bi-magnetic CoFe2O4@ZnFe2O4 and CoFe2O4@MnFe2O4 nanoparticles (NPs) exhibited a core-shell structure with a mean average particle size of 11.2 ± 1.4 nm and 14.4 ± 2.4 nm, respectively. The CoFe2O4@MnFe2O4 NPs showed the highest specific absorption rate (SAR) values (210-320 W/g) upon exposure to an external magnetic field, along with the highest saturation magnetization (Ms). Therefore, they were selected for functionalization with the PEGylated ligand to make them stable in aqueous media. After the functionalization process, the NPs showed high magnetic relaxivity values and very low cytotoxicity, demonstrating that CoFe2O4@MnFe2O4 is a good candidate for in vivo applications. Finally, in vivo MRI experiments showed that PEGylated CoFe2O4@MnFe2O4 NPs produce high T2 contrast and exhibit very good stealth properties, leading to the efficient evasion of the mononuclear phagocyte system. Thus, these bi-magnetic core-shell NPs show great potential as theranostic agents for in vivo applications, combining magnetic hyperthermia capabilities with high MRI contrast.

Effects of waste deposit geometry on the mineralogical and geochemical composition of mine tailings.

The study tailing pond shows a particular geometry resulting from the tailings stockpiles deposited onto the northern part of the beach. This generated three types of superficial waste: (i) tailings of the stockpiles (A-type) (pH=2.2-2.6; soluble fraction average - SF=14.2%), subjected to intense oxidation and evaporation; (ii) tailings of the lowlands of waste, characterized by low oxidation and no evaporation (B-type) (pH=2.7-3.1; SF=7.7%); (iii) salt crusts (C-type) (pH=2.6-3.5; SF=81.5%), formed by the evaporation of leachates accumulated in stagnant pools. Principal Component Analysis (PCA) showed the following sequences of secondary minerals precipitation: A-type waste (I - ferricopiapite, rozenite, ferrihydrite; II - jarosite, coquimbite); B-type (I - Fe oxyhydroxides; II - jarosite, butlerite); C-type (I - ferrihydrite, rozenite; II - alunogen, hexahydrite, epsomite). PCA also revealed that the abundance of Al (1-10% Al2O3 in A and B wastes; 1-5% in C waste) is particularly controlled by primary silicates and clay minerals. Iron (11-23% Fe2O3 in A and B wastes; 5-10% in C waste) is almost exclusively related to pyrite, ferrihydrite, and goethite. Moreover, Zn and Cd were collected by halotrichite, rozenite, jarosite, ferricopiapite, and apjohnite, whereas the clay minerals seem to trap selectively Cu, Pb and As in their structure.

On-command controlled drug release by diels-Alder reaction using Bi-magnetic core/shell nano-carriers.

A novel bi-functional thermo-responsive system, consisting of core/shell bi-magnetic nanoparticles with furan surface functionality, is bonded with N-(2-Carboxyethyl)maleimide through Diels-Alder reaction. The chemotherapeutics doxorubicin is attached onto the surface, with a high loading efficiency of 92%. This system with high responsiveness to a high frequency external alternating magnetic field shows a very good therapeutic efficiency in hyperthermia and drug release at relatively low temperatures (50°C). Polyhedron-shaped bi-magnetic nanoparticles (Zn0.4Co0.6Fe2O4@Zn0.4Mn0.6Fe2O4) exhibit a significant increase of the specific energy absorption rate up to 455W/g compared with the core nanoparticles (200W/g). Real-time florescence spectroscopy studies demonstrate rapid release of doxorubicin up to 50% in 5min and up to 92% after 15min upon exposure to high frequency external alternating magnetic field. The stability is evaluated for 8 weeks in phosphate buffer saline with a doxorubicin payload of 85%. In vitro studies using standard MTT cell assays with HeLa and Hep G2 lines prove an excellent biocompatibility with about 90% of cell viability after 24h of treatment within the highest concentration of functionalized magnetic nanoparticles (200µg/mL). The results indicate a controlled drug release mediated by thermo-responsive switching under applied alternating magnetic field.

Imino-chitosan biopolymeric films. Obtaining, self-assembling, surface and antimicrobial properties.

The paper reports the preparation of twelve imino-chitosan biopolymer films by acid condensation of the amino groups of chitosan with various aldehydes, in aqueous medium, followed by slow water removal. FTIR spectroscopy has shown drastic conformation changes of chitosan macromolecular chains­from a stiff coil to a straight one, while wide angle X-ray diffraction evidenced a layered morphology of the biopolymer films. Contact angle and surface free energy determination indicated a higher biocompatibility of the new biopolymers as compared to the chitosan parent, while the microbiological screening demonstrated their self-defense properties against common and virulent pathogen agents. It was concluded that the reversibility of imine forming promotes the self-assembling of imino-chitosan biopolymer films into a lamellar morphology and, on the other hand, the slow release of the antimicrobial aldehyde in the microbiological culture. The obtained results demonstrate that chitosan polyamine is a challenging workbench to functional biodynamic materials.

Investigations on nanoconfinement of low-molecular antineoplastic agents into biocompatible magnetic matrices for drug targeting.

Magnetic mesoporous silica nanoparticles are employed as biocompatible matrices to host low-molecular antineoplastic drugs. 5-Fluorouracil is a well-known antimetabolite drug used to treat many malignancies: colon, rectal, breast, head and neck, pancreatic, gastric, esophageal, liver and G-U (bladder, penile, vulva, prostate), skin cancers (basal cell and keratosis). Unfortunately severe gastrointestinal, hematological, neural, cardiac and dermatological toxic effects are often registered due to its cytotoxicity. Thus, this work focuses on development of a magnetic silica nanosystem, capable of hosting high amounts of 5-fluorouracil and delivers it in a targeted manner, under the influence of external magnetic field. There are few reports on nanoconfinement of this particular small molecule antimetabolite on mesoporous silica hosts. Therefore we have investigated different ways to confine high amounts of 5-FU within amino-modified and non-modified mesopores of the silica shell, from water and ethanol, under magnetic stirring and ultrasound irradiation. Also, we have studied the adsorption process from water as a function of pH in order to rationalize drug-support interactions. It is shown that nature of the solvent has great influence on diffusion of small molecules into mesopores, which is slower from alcoholic solutions. More importantly, sonication is proven as an excellent alternative to long adsorption tests, since the time necessary to reach equilibrium is drastically reduced to 1h and higher amounts of drug may be immobilized within the mesopores of amino-modified magnetic silica nanoparticles. These results are highly important for optimization of drug immobilization process in order to attain desired release profile.