N-type semiconducting hydrogel.

Hydrogels are an attractive category of biointerfacing materials with adjustable mechanical properties, diverse biochemical functions, and good ionic conductivity. Despite these advantages, their application in electronics has been restricted because of their lack of semiconducting properties, and they have traditionally only served as insulators or conductors. We developed single- and multiple-network hydrogels based on a water-soluble n-type semiconducting polymer, endowing conventional hydrogels with semiconducting capabilities. These hydrogels show good electron mobilities and high on/off ratios, enabling the fabrication of complementary logic circuits and signal amplifiers with low power consumption and high gains. We demonstrate that hydrogel electronics with good bioadhesive and biocompatible interface can sense and amplify electrophysiological signals with enhanced signal-to-noise ratios.

The safety of trastuzumab deruxtecan (DS-8201) with a focus on interstitial lung disease and/or pneumonitis: A systematic review and single-arm meta-analysis.

BACKGROUND: Previous studies involving risk-benefit analysis of trastuzumab deruxtecan (DS-8201) have indicated the benefit of this treatment, although it may increase the risk of interstitial lung disease (ILD) and/or pneumonitis in certain patients. This study aimed to assess the safety of DS-8201. METHODS: A search was done for relevant articles in four electronic databases: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. All reports published up until November 2, 2022, were included, and study types were restricted to clinical trials; the last search was then updated to January 10, 2023. We also assessed the quality of the literature with the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Index for Non-Randomized Studies tool, and then performed a meta-analysis with R version 4.2.1. RESULTS: A total of 1428 patients reported in 13 articles were included in this study. The analysis revealed that the most common all-grade treatment-emergent adverse events (TEAEs) were nausea and fatigue. The most common TEAE of grade 3 or above (grade ≥3) was neutropenia. The incidences of ILD and/or pneumonitis for all-grade and grade ≥3 TEAEs were 12.5% and 2.2%, respectively. CONCLUSIONS: This comprehensive summary of the incidence of TEAEs associated with DS-8201 in clinical trials provides an important guide for clinicians. The most common TEAEs were gastrointestinal reactions and fatigue; meanwhile, the most common grade ≥3 TEAE was hematological toxicity. ILD and/or pneumonitis were specific adverse drug reactions associated with DS-8201, of which physicians should be particularly aware for their higher morbidity and rates of grade ≥3 TEAEs.

Differential Toxicity of Electronic Cigarette Aerosols Generated from Different Generations of Devices In Vitro and In Vivo.

Electronic cigarettes (e-cigs) have become increasingly popular, especially among youth, raising concerns about their potential health risks. JUUL and Tank devices are two common types of e-cigs that deliver aerosols with varying nicotine levels and flavors. However, the differences in the aerosols generated from different devices and their corresponding cytotoxicity and pulmonary injury effects remain poorly understood. This study addresses these knowledge gaps by characterizing the aerosols of JUUL and Tank e-cig devices and testing their toxic effects on THP-1 and BEAS-2B human cell lines as well as the C57BL/6J mouse model. In our study, the lower-voltage device, the 3.7 V JUUL generates 2.72 mg/puff aerosols by using e-liquid containing 3% nicotine salt (i.e., nicotine benzoate), which is less than the 11.06 mg/puff aerosols generated by the 7.5 V Tank using e-liquid containing 2.4% freebase nicotine. Yet, the cytotoxicity results reveal that JUUL aerosols induced higher toxicity and increased production of pro-inflammation cytokines compared to Tank aerosols per puff. Additionally, we observed that JUUL induced more severe pulmonary inflammation and DNA damage compared to Tank after normalizing for cotinine, a nicotine metabolite, in vivo. Our findings suggest that the device design plays a more important role in e-cig aerosol-induced toxicity than the composition of the e-liquid or voltage. These results provide valuable insights into the health risks associated with various electronic-cig devices and offer an approach for evaluating them.

The Correlation of miR-671-5p with Diagnosis and Prognosis in Multiple Myeloma.

BACKGROUND: This study aimed to investigate the value of miR-671-5p in multiple myeloma (MM) in diagnostics and prognosis and developed a potential biomarker to improve the prognosis of MM. METHODS: Plasma cells were isolated from bone marrow samples of 80 MM patients, in which miR-671-5p levels were determined. The correlation between miR-671-5p expression with serum creatinine, ß-2-microglobulin, lactate dehydrogenase, bone lesions, International Staging System staging, chromosomal abnormalities, and albumin was analyzed. The association between miR-671-5p expression with progression-free survival and overall survival in MM patients was determined. RESULTS: miR-671-5p expression was reduced and predicted an increased risk of MM. miR-671-5p expression was negatively correlated with serum creatinine, ß-2-microglobulin, lactate dehydrogenase, bone lesions, International Staging System staging, and chromosomal abnormalities, and positively correlated with albumin. miR-671-5p expression was augmented in complete response patients and overall response rate patients, and differentiated CR and ORR patients from Non-CR and Non-ORR patients. Furthermore, miR-671-5p low expression was associated with unfavorable progression-free survival and overall survival in MM patients. CONCLUSIONS: In a word, miR-671-5p is associated with worsening clinical properties, increased ISS staging, unfavorable chromosomal abnormalities, and poor prognosis in MM patients.

Pulmonary Delivery of Specialized Pro-Resolving Mediators-Based Nanotherapeutics Attenuates Pulmonary Fibrosis in Preclinical Animal Models.

Pulmonary fibrosis (PF) is a chronic lung disease characterized by excess extracellular matrix deposition and prolonged inflammation that fails to resolve and is druggable. Using resolvins and their precursors for inflammation resolution, we demonstrate a nano-enabled approach for accomplishing robust antifibrotic effects in bleomycin- or engineered nanomaterial-induced mouse and rat PF models. Targeting the lipid peroxidation-triggered NLRP3 inflammasome and NF-κB pathway in macrophages and the ROS-mediated TGF-ß/Smad and S1P signaling in epithelial cells results in these potent protective effects at the ng/mL dosimetry. We further develop an inhalable biocompatible nanoparticle that encapsulates fish oil, a chosen resolvin precursor, with phosphatidylcholine and polyethylene glycol to enhance drug permeability and facilitate crossing the mucosal barrier, forming "fish-oilsome" (FOS). Oropharyngeal aspiration and inhalation of FOS improved the anti-inflammatory status, histological characteristics, and pulmonary function in fibrotic lungs, which was mechanistically supported by transcriptomic and proteomic analyses. Further, scale-up engineered FOS samples with the desired physicochemical properties, anti-PF efficacy, and in vivo biocompatibility were validated in different batch sizes (up to 0.2 L/batch). This study provides a practical and translatable approach to promoting inflammation resolution and PF treatment.

Enrichment of nano delivery platforms for mRNA-based nanotherapeutics.

Lipid-based nanoparticles (LNP) have shown significant progress in delivering mRNA for therapeutics, particularly with the success of coronavirus disease 2019 (COVID-19) vaccines. However, there are still challenges, such as organ-specific targeting, sustained protein expression, immunogenicity, and storage that need to be addressed. Therefore, there is interest in developing additional nano drug delivery systems (DDS) to complement LNP technology. Some of these include polymer, lipid-polymer hybrid, organic/inorganic hybrid nanostructure, and inorganic nanoparticle. In our opinion, LNP technology may not be suitable for every disease scenario in categories such as infection disease, cancer, pulmonary disease, autoimmune disorders and genetic rare disease (among others). This is because different diseases may require distinct administration routes, doses, and treatment durations, as well as considerations for biological barriers that may lower the efficacy and/or exert safety concern. In this perspective, we will highlight the need and potential for enhancing the diversity of nano delivery platforms for mRNA-based nanotherapeutics.

Effect of leaching time on phytotoxicity of dissolved organic matter derived from black carbon based on spectroscopy.

Black carbon (BC) exports huge amounts of its derived DOM from terrestrial ecosystems annually through a variety of ways (i.e., erosion or runoff migration). The pyrolytic feedstock type and temperature resulted in DOM derived from highly condensed aromatic and non-aromatic BC. However, the behaviors of low aromatic BC-derived DOM at diverse leaching time are poorly understood. In this work, low aromatic BCs were prepared by pyrolysis corn straws at 250 °C, 350 °C and 450 °C. Extraction experiments for four leaching time (6 h, 10 h, 15 h and 21 h) were set up to simulate BC-derived DOM generative process in nature. The phytotoxicity of BC-derived DOM was evaluated via germination index (GI). Spectral characteristics were discussed to analyze the phytotoxicity variations of fluorescence components composition at different time, including the excitation-emission matrix-parallel factor, two-dimensional correlation spectra and Fourier transform infrared spectroscopy. The results suggested that low aromatic BC-derived DOM might contain aromatic phenolic compounds. A longer time contributed to accumulate the complex, hard-to-use organic matters, leading to lower GI. These results would supplement the dynamic spectral characteristics of low aromatic BC-derived DOM and its environmental risks during the leaching process.

Understanding Nanomaterial-Liver Interactions to Facilitate the Development of Safer Nanoapplications.

Nanomaterials (NMs) are widely used in commercial and medical products, such as cosmetics, vaccines, and drug carriers. Exposure to NMs via various routes such as dermal, inhalation, and ingestion has been shown to gain access to the systemic circulation, resulting in the accumulation of NMs in the liver. The unique organ structures and blood flow features facilitate the liver sequestration of NMs, which may cause adverse effects in the liver. Currently, most in vivo studies are focused on NMs accumulation at the organ level and evaluation of the gross changes in liver structure and functions, however, cell-type-specific uptake and responses, as well as the molecular mechanisms at cellular levels leading to effects at organ levels are lagging. Herein, the authors systematically review diverse interactions of NMs with the liver, specifically on major liver cell types including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes as well as the detailed molecular mechanisms involved. In addition, the knowledge gained on nano-liver interactions that can facilitate the development of safer nanoproducts and nanomedicine is also reviewed.

Determination of the nanoparticle- and cell-specific toxicological mechanisms in 3D liver spheroids using scRNAseq analysis.

Engineered nanomaterials (ENMs) are commonly used in consumer products, allowing exposure to target organs such as the lung, liver, and skin that could lead to adverse health effects in humans. To better reflect on toxicological effects in liver cells, it is important to consider the contribution of hepatocyte morphology, function, and intercellular interactions in a dynamic 3D microenvironment. Herein, we used a 3D liver spheroid model containing hepatocyte and Kupffer cells (KCs) to study the effects of three different material compositions, namely vanadium pentoxide (V2O5), titanium dioxide (TiO2), or graphene oxide (GO). Additionally, we used single-cell RNA sequencing (scRNAseq) to determine the nanoparticle (NP) and cell-specific toxicological responses. A general finding was that hepatocytes exhibit more variation in gene expression and adaptation of signaling pathways than KCs. TNF-α production tied to the NF-κB pathway was a commonly affected pathway by all NPs while impacts on the metabolic function of hepatocytes were unique to V2O5. V2O5 NPs also showed the largest number of differentially expressed genes in both cell types, many of which are related to pro-inflammatory and apoptotic response pathways. There was also evidence of mitochondrial ROS generation and caspase-1 activation after GO and V2O5 treatment, in association with cytokine production. All considered, this study provides insight into the impact of nanoparticles on gene responses in key liver cell types, providing us with a scRNAseq platform that can be used for high-content screening of nanomaterial impact on the liver, for use in biosafety and biomedical applications.

Use of a Liver-targeting Nanoparticle Platform to Intervene in Peanut-induced anaphylaxis through delivery of an Ara h2 T-cell Epitope.

To address the urgent need for safe food allergen immunotherapy, we have developed a liver-targeting nanoparticle platform, capable of intervening in allergic inflammation, mast cell release and anaphylaxis through the generation of regulatory T-cells (Treg). In this communication, we demonstrate the use of a poly (lactide-co-glycolide acid) (PLGA) nanoparticle platform for intervening in peanut anaphylaxis through the encapsulation and delivery of a dominant protein allergen, Ara h 2 and representative T-cell epitopes, to liver sinusoidal endothelial cells (LSECs). These cells have the capacity to act as natural tolerogenic antigen-presenting cells (APC), capable of Treg generation by T-cell epitope presentation by histocompatibility (MHC) type II complexes on the LSEC surface. This allowed us to address the hypothesis that the tolerogenic nanoparticles platform could be used as an effective, safe, and scalable intervention for suppressing anaphylaxis to crude peanut allergen extract. Following the analysis of purified Ara h 2 and representative MHC-II epitopes Treg generation in vivo, a study was carried out to compare the best-performing Ara h 2 T-cell epitope with a purified Ara h 2 allergen, a crude peanut protein extract (CPPE) and a control peptide in an oral sensitization model. Prophylactic as well as post-sensitization administration of the dominant encapsulated Ara h 2 T-cell epitope was more effective than the purified Ara h2 in eliminating anaphylactic manifestations, hypothermia, and mast cell protease release in a frequently used peanut anaphylaxis model. This was accompanied by decreased peanut-specific IgE blood levels and increased TGF-ß release in the abdominal cavity. The duration of the prophylactic effect was sustained for two months. These results demonstrate that targeted delivery of carefully selected T-cell epitopes to natural tolerogenic liver APC could serve as an effective platform for the treatment of peanut allergen anaphylaxis.

Salts of 2-hydroxybenzylamine with improvements on solubility and stability: Virtual and experimental screening.

2-Hydroxybenzylamine (2-HOBA) is a drug used to effectively treat oxidative stress. To improve its aqueous solubility and thermal stability, salt screening and synthesis was carried out. The conductor-like screening model for the real solvents model (COSMO-RS) was applied to virtual screening of coformers among 200 commonly used candidates for salification of 2-HOBA. As a result, 40 hit compounds were subjected to experimental liquid-assisted grinding (LAG) with 2-HOBA, then 21 systems were characterized as new solid phases by PXRD. Nine multicomponent single crystals of 2-HOBA with succinic acid, p-aminobenzoic acid, p-nitrobenzoic acid, o-nitrobenzoic acid, p-toluic acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, p-nitrophenol, and 5-hydroxyisophthalic acid were obtained and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. All of them were salts and exhibited higher decomposition temperatures compared with pure 2-HOBA. The apparent aqueous solubility of three new salts, i.e., those with succinic acid, p-aminobenzoic acid, and p-nitrophenol were higher than the equilibrium solubility of 2-HOBA. The accelerated stability test indicated that all salts show excellent stability under conditions (40 °C and 75% RH) for 4 weeks. Overall, this work introduced a protocol that combined the virtual screening tool based on the COSMO-RS model and the experimental LAG method to screen new salts for a target compound. The feasibility of this protocol was confirmed in the case of 2-HOBA whose new salts were successfully obtained and represented an improvement for aqueous solubility and thermal stability.

Porous electrospun microfibers for low flow-resistant solid phase extraction of fluoroquinolones in tap water, egg and milk samples.

In this work, porous electrospun microfibers (PEMFs) were prepared using a polyimide/polyvinylpyrrolidone/polyethylene glycol (PI/PVP/PEG) solution mixture with coaxial ultrasonic water vapor spraying. After removing PVP and PEG by ultrasonic water washing, the PEMFs were successfully demonstrated as adsorbents for solid phase extraction (SPE). Most non-porous electrospun nanofibers are hundreds of nanometers in diameter, with a specific surface area of dozens of square meters per gram. In contrast, the diameter of the as-prepared PEMFs was tuned between 3 and 8 µm, the specific surface area was 76 m2g-1 and the pore size was ca 25 nm. Therefore, the flow resistance of the PEMF-SPE cartridges was similar to those of conventional commercial SPE cartridges, and much lower than those of SPE cartridges packed with electrospun nanofibers. Using the PEMF-SPE cartridges with ultra-performance liquid chromatography-fluorescence detector (UPLC-FLD), five fluoroquinolones (FQs) in tap water, egg and milk samples were extracted and quantified successfully. After optimizing the extraction conditions, FQs in water samples were extracted and eluted with high recoveries of 84.8-114.8%. The inter-batch and intra-batch relative standard deviation (RSD) values for the FQs were in the range of 1.9-9.5% (n=3), and the limits of detection were between 0.0024-0.014 µg L-1. The method was linear in the concentration range of 0.005-10 µg L-1. The reliability of the developed method was validated by analyzing tap water, egg and milk samples, and the recovery values were found to be in the range of 74.8-116.6% under the optimized conditions.

NLRP3 inflammasome activation determines the fibrogenic potential of PM2.5 air pollution particles in the lung.

Airborne fine particulate matter (PM2.5) is known to cause respiratory inflammation such as chronic obstructive pulmonary disease and lung fibrosis. NLRP3 inflammasome activation has been implicated in these diseases; however, due to the complexity in PM2.5 compositions, it is difficult to differentiate the roles of the components in triggering this pathway. We collected eight real-life PM2.5 samples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis. In vitro assays showed that although the PM2.5 particles did not induce significant cytotoxicity at the dose range of 12.5 to 100 µg/mL, they induced potent TNF-α and IL-1ß production in PMA differentiated THP-1 human macrophages and TGF-ß1 production in BEAS-2B human bronchial epithelial cells. At the dose of 100 µg/mL, PM2.5 induced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release, leading to IL-1ß production. This was confirmed by using NLRP3- and ASC-deficient cells as well as a cathepsin B inhibitor, ca-074 ME. Administration of PM2.5 via oropharyngeal aspiration at 2 mg/kg induced significant TGF-ß1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21 days post-exposure, suggesting PM2.5 has the potential to induce pulmonary fibrosis. The ranking of in vitro IL-1ß production correlates well with the in vivo total cell count, TGF-ß1 production, and collagen deposition. In summary, we demonstrate that the PM2.5 is capable of inducing NLRP3 inflammasome activation, which triggers a series of cellular responses in the lung to induce fibrosis.

Nanocellulose Length Determines the Differential Cytotoxic Effects and Inflammatory Responses in Macrophages and Hepatocytes.

Nanocellulose including cellulose nanocrystal (CNC) and cellulose nanofiber (CNF) has attracted much attention due to its exceptional mechanical, chemical, and rheological properties. Although considered biocompatible, recent reports have demonstrated nanocellulose can be hazardous, including serving as drug carriers that accumulate in the liver. However, the nanocellulose effects on liver cells, including Kupffer cells (KCs) and hepatocytes are unclear. Here, the toxicity of nanocellulose with different lengths is compared, including the shorter CNCs (CNC-1, CNC-2, and CNC-3) and longer CNF (CNF-1 and CNF-2), to liver cells. While all CNCs triggered significant cytotoxicity in KCs and only CNC-2 induced toxicity to hepatocytes, CNFs failed to induce significant cytotoxicity due to their minimal cellular uptake. The phagocytosis of CNCs by KCs induced mitochondria ROS generation, caspase-3/7 activation, and apoptotic cell death as well as lysosomal damage, cathepsin B release, NLRP3 inflammasome and caspase-1 activation, and IL-1ß production. The cellular uptake of CNC-2 by hepatocytes is through clathrin-mediated endocytosis, and it induced the caspase-3/7-mediated apoptosis. CNC-2 shows the highest levels of uptake and cytotoxicity among CNCs. These results demonstrate the length-dependent mechanisms of toxicity on liver cells in a cell type-dependent fashion, providing information to safely use nanocellulose for biomedical applications.

Lateral size of graphene oxide determines differential cellular uptake and cell death pathways in Kupffer cells, LSECs, and hepatocytes.

As a representative two-dimensional (2D) nanomaterial, graphene oxide (GO) has shown high potential in many applications due to its large surface area, high flexibility, and excellent dispersibility in aqueous solutions. These properties make GO an ideal candidate for bio-imaging, drug delivery, and cancer therapy. When delivered to the body, GO has been shown to accumulate in the liver, the primary accumulation site of systemic delivery or secondary spread from other uptake sites, and induce liver toxicity. However, the contribution of the GO physicochemical properties and individual liver cell types to this toxicity is unclear due to property variations and diverse cell types in the liver. Herein, we compare the effects of GOs with small (GO-S) and large (GO-L) lateral sizes in three major cell types in liver, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatocytes. While GOs induced cytotoxicity in KCs, they induced significantly less toxicity in LSECs and hepatocytes. For KCs, we found that GOs were phagocytosed that triggered NADPH oxidase mediated plasma membrane lipid peroxidation, which leads to PLC activation, calcium flux, mitochondrial ROS generation, and NLRP3 inflammasome activation. The subsequent caspase-1 activation induced IL-1ß production and GSDMD-mediated pyroptosis. These effects were lateral size-dependent with GO-L showing stronger effects than GO-S. Amongst the liver cell types, decreased cell association and the absence of lipid peroxidation resulted in low cytotoxicity in LSECs and hepatocytes. Using additional GO samples with different lateral sizes, surface functionalities, or thickness, we further confirmed the differential cytotoxic effects in liver cells and the major role of GO lateral size in KUP5 pyroptosis by correlation studies. These findings delineated the GO effects on cellular uptake and cell death pathways in liver cells, and provide valuable information to further evaluate GO effects on the liver for biomedical applications.

Dissolution of 2D Molybdenum Disulfide Generates Differential Toxicity among Liver Cell Types Compared to Non-Toxic 2D Boron Nitride Effects.

2D boron nitride (BN) and molybdenum disulfide (MoS2 ) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS2 could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS2 , dispersed in Pluronic F87 (designated BN-PF and MoS2 -PF) is compared with aggregated forms of these materials (BN-Agg and MoS2 -Agg) in liver cells. MoS2 induces dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non-toxic. The effect of MoS2 could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS2 -Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1ß, and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS2 in impacting KC viability.

Antigen- and Epitope-Delivering Nanoparticles Targeting Liver Induce Comparable Immunotolerance in Allergic Airway Disease and Anaphylaxis as Nanoparticle-Delivering Pharmaceuticals.

The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating poly(lactic-co-glycolic acid) (PLGA) nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in nontargeted antigen-presenting cells system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with nontargeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg-sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NPOVAversus nontargeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung was accompanied by increased Foxp3+ Treg recruitment and TGF-ß production in both platforms. As OVA incorporates IgE-binding as well as non-IgE-binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA323-339 and OVA257-264 epitopes in liver-targeting NPs to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the major histocompatibility complex (MHC)-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNPOVA efficacy. The epitope-specific effect was transduced by TGF-ß-producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting versus pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve response outcomes similar to those of the intact allergens.

Mechanistic Differences in Cell Death Responses to Metal-Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes.

The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal-based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1-6 cells. Five NPs (Ag, CuO, ZnO, SiO2 , and V2 O5 ) exhibit cytotoxicity in both cell types, while SiO2 and V2 O5 induce IL-1ß production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO2 in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL-1ß release, and cleavage of gasdermin-D. This releases pore-performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V2 O5 induces IL-1ß release and delays caspase 1 activation by vanadium ion interference in membrane Na+ /K+ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1-6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal-based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.

Functionalized Gold and Silver Bimetallic Nanoparticles Using Deinococcus radiodurans Protein Extract Mediate Degradation of Toxic Dye Malachite Green.

BACKGROUND: Biodegradation of toxic organic dye using nanomaterial-based microbial biocatalyst is an ecofriendly and promising technique. MATERIALS AND METHODS: Here, we have investigated the novel properties of functionalized Au-Ag bimetallic nanoparticles using extremophilic Deinococcus radiodurans proteins (Drp-Au-AgNPs) and their degradation efficiency on the toxic triphenylmethane dye malachite green (MG). RESULTS AND DISCUSSION: The prepared Drp-Au-AgNPs with an average particle size of 149.8 nm were capped by proteins through groups including hydroxyl and amide. Drp-Au-AgNPs demonstrated greater degradation ability (83.68%) of MG than D. radiodurans cells and monometallic AuNPs. The major degradation product was identified as 4-(dimethylamino) benzophenone, which is less toxic than MG. The degradation of MG was mainly attributed to the capping proteins on Drp-Au-AgNPs. The bimetallic NPs could be reused and maintained MG degradation ability (>64%) after 2 cycles. CONCLUSION: These results suggest that the easily prepared Drp-Au-AgNPs have potential applications as novel nanomedicine for MG detoxification, and nanomaterial for biotreatment of a toxic polyphenyl dye-containing wastewater.

Aberrant expression of long non-coding RNAs in peripheral blood mononuclear cells isolated from patients with gouty arthritis.

Gouty arthritis (GA) is the most common inflammatory and immune-associated disease, and its prevalence and incidence exhibit yearly increases. The aim of the present study was to analyse the expression profile variation of long non-coding RNAs (lncRNAs) in GA patients and to explore the role of lncRNAs in the pathogenesis of GA. The peripheral blood mononuclear cells of GA patients and of healthy controls (HCs) were used to detect for the differentially expressed lncRNAs by microarray. The functional annotations and classifications of the differentially expressed transcripts were predicted using Gene Ontology (GO) and pathway analysis. The results were then verified by reverse transcription-quantitative (RT-q)PCR. A total of 1,815 lncRNAs and 971 mRNAs with a >2-fold difference in the levels of expression in the GA patients compared with those in the HCs were identified. According to the GO functional enrichment analysis, the differentially expressed lncRNAs were accumulated in terms including protein binding, catalytic activity and molecular transducer activity. The pathways predicted to be involved were the tumor necrosis factor signaling pathway, osteoclast differentiation, NOD-like receptor signaling pathway and NF-κB signaling pathway. The expression of six lncRNAs was measured by RT-qPCR and the results were consistent with those of the microarrays. Among these lncRNAs, AJ227913 was the most differentially expressed lncRNA in GA patients vs. HCs. The expression of several lncRNAs was significantly changed in GA patients compared with that in HCs, which suggests that these lncRNAs with differential expression levels may have an important role in the development and progression of GA.