COVID-19 InfoVaccines: A WHO-supported educational project to promote COVID-19 vaccination information among professionals and the general population.

COVID-19 vaccine uptake varied across countries, in part due to vaccine hesitancy fueled by a lack of trustworthy information. To help health workers provide evidence-based answers to common questions about COVID-19 vaccines and vaccination, and thereby, assist individuals´ decisions on vaccine acceptance, COVID-19 InfoVaccines, a joint WHO-EU project, was launched in February 2021 to support COVID-19 vaccine rollout in 6 Eastern European countries. COVID-19 InfoVaccines was made available in seven languages and shared on social media networks. A total of 262,592 users accessed COVID-19 InfoVaccines.com between February 11, 2021, and January 31st, 2023. The users were most interested in: general questions; vaccine efficacy and duration of protection; vaccine safety; vaccine co-administration, and dose-interval and interchangeability; though the interest in a specific theme varied in function of the epidemiological situation. A total of 118,510 (45.1%) and 46,644 (17.7%) users scrolled up to 35% and 75% of the COVID-19 InfoVaccines webpage, respectively. The average engagement rate was 71.61%. The users accessed COVID-19 InfoVaccines from 231 countries and territories, but the majority were in Ukraine (N = 38,404; 14.6%), Spain (N = 23,327; 8.9%), and Argentina (N = 21,167; 8.1%). Older Facebook users were more interested in COVID-19 information than younger individuals (X2 p-value < .0001). Two hundred twenty-eight videos were shared on YouTube. The average Click-Through-Rate on Facebook was 7.82%, and that on YouTube was 4.4%, with 60 videos having a Click-Through-Rate >5%, falling in the range of average YouTube video Click-Through-Rate (2% - 10%). As misinformation about vaccines and vaccination spreads easily and can negatively impact health-related decisions, initiatives like COVID-19 InfoVaccines are crucial to facilitate access to reliable information.

Meroterpenoids with divers' rings systems from Phyllosticta capitalensis and their anti-inflammatory activity.

Four undescribed sesquiterpene-shikimates (1-4), eight undescribed monoterpene-shikimates (5-12), together with two known ones were isolated and identified from the 95% ethanol extract of the plant endophytic fungus Phyllosticta capitalensis cultured in rice medium. Capitalensis A (1) was identified as the first sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid degradation product, while capitalensis B (2) is a sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid with a unique D-ring formed by a C-2-O-C-9' connection. The structures of these previously undescribed compounds were elucidated by multiple techniques, including IR, HR-ESI-MS, and NMR analysis. Furthermore, their absolute configurations were established through the comprehensive approach that involved the calculations of ECD spectra, optical rotation values, and single-crystal X-ray analysis. Moreover, the anti-inflammatory activity of all isolated compounds was evaluated using a lipopolysaccharide (LPS)-induced inflammation model in BV2 microglial cells. Meanwhile, these compounds exhibited activity in inhibiting NO production. Four compounds, capitalensis C (3), capitalensis D (4), 15-hydroxyl tricycloalternarene 5b (13) and guignarenone A (14) showed strong inhibitory effects with IC50 values of 21.6 ± 1.33, 12.2 ± 1.08, 18.6 ± 1.27, and 15.8 ± 1.20 µM, respectively. In addition, the structure-activity relationship of the anti-inflammatory activity of the compounds was discussed.

Ultralow Ru Single Atoms Confined in Cerium Oxide Nanoglues for Highly-Sensitive and Robust H2 O2 -Related Biocatalytic Diagnosis.

Exploring highly efficient, portable, and robust biocatalysts is a great challenge in colorimetric biosensors. To overcome the challenging states in creating single-atom biocatalysts, such as insufficient activity and stability, here, this work has engineered a unique CeO2 support as nanoglue to tightly anchor the Ru single-atom sites (CeO2 -Ru) with strong electronic coupling for achieving highly sensitive and robust H2 O2 -related biocatalytic diagnosis. The morphology and chemical/electronic structure analysis demonstrates that the Ru atoms are well-dispersed on CeO2 surface to form high-density active sites. Benefiting from the unique structure, the prepared CeO2 -Ru exhibits outstanding peroxidase (POD) like catalytic activity and selectivity to H2 O2 . Steady-state kinetic study results show that the CeO2 -Ru presents the highest Vmax and turnover number than the state-of-the-art POD-like biocatalysts. Consequently, the CeO2 -Ru discloses a high efficiency, good selectivity, and robust stability in the colorimetric detection of L-cysteine, glucose, and uric acid. Notably, the limit of detection (LOD) can reach 0.176 × 10-3 m for the L-cysteine, 0.095 × 10-3 m for the glucose, and 0.088 × 10-3 m for the uric acid via cascade reaction. This work suggests that the proposed unique CeO2 nanoglue will offer a new path to create single-atom noble metal biocatalysts and take a step closer to future biotherapeutic and biocatalytic applications.

Photobiomodulation at 660 nm promotes collagen synthesis via downregulation of HIF-1α expression without photodamage in human scleral fibroblasts in vitro in a hypoxic environment.

PURPOSE: The increasing prevalence of myopia is a global public health issue. Because of the complexity of myopia pathogenesis, current control methods for myopia have great limitations. The aim of this study was to explore the effect of photobiomodulation (PBM) on human sclera fibroblasts (HSFs) under hypoxia, in the hope of providing new ideas for myopia prevention and control. METHODS: Hypoxic cell model was established at 0, 6, 12, and 24 h time points to simulate myopia microenvironment and explore the optimal time point. Control, hypoxia, hypoxia plus light, and normal plus light cell models were set up for the experiments, and cells were incubated for 24 or 48 h after PBM (660 nm, 5 J/cm2), followed by evaluation of hypoxia-inducible factor 1α (HIF-1α) and collagen I a1 (COL1A1) proteins using Western blotting and immunofluorescence, and photo damage was detected by CCK-8, scratch test, and flow cytometry assays. We also used transfection technology to further elucidate the regulatory mechanism. RESULTS: The change of target proteins is most obvious when hypoxia lasts for 24 h (p < 0.01). PBM at 660 nm increased extracellular collagen content (p < 0.001) and downregulated expression of HIF-1α (p < 0.05). This treatment did not affect the migration and proliferation of cells (p > 0.05), and effectively inhibited apoptosis under hypoxia (p < 0.0001). After overexpression of HIF-1α, the effect of PBM was attenuated (p > 0.05). CONCLUSIONS: Photobiomodulation at 660 nm promotes collagen synthesis via downregulation of HIF-1α expression without photodamage.

[Effect and Persistent Effect of Thiolated Montmorillonite on Safe Production in Cadmium-contaminated Cropland].

To explore the effect and persistent effect of thiolated montmorillonite (TM) on safe production in cadmium (Cd) contaminated cropland, a two-year field experiment was conducted with different application amounts of TM. By adding to highly contaminated soils containing 2.46-3.81 mg·kg-1 Cd with no replenishment, the impacts of TM on concentrations of Cd in different parts of rice and available Cd in soils were investigated. The results showed that TM could significantly reduce the contents of Cd in brown rice as well as the contents and proportions of available Cd in soils, and its persistent effects on the passivation of Cd were obvious. After applying 0.5% or 1% TM to soils, the contents of Cd in different parts of the rice decreased significantly in the first season compared with that in the control. The contents of Cd in brown rice in the first season decreased to 0.16 mg·kg-1 and 0.08 mg·kg-1, respectively, by 84.0% and 91.9% compared with that of the control (0.98 mg·kg-1). Contents of Cd in brown rice were significantly lower than the maximum allowable amount (0.2 mg·kg-1) set by China (GB 2762-2017). Under the 0.5% and 1% treatments, the contents of Cd in brown rice of the subsequent three seasons under successive planting decreased by 50.2%-67.8% and 56.0%-81.6%, respectively, which were within the allowable amount. The proportions of available Cd in soils in the first season decreased from 48.4% under the control to 27.9% and 18.4%, respectively, which decreased by 20.5% and 29.9% under the 0.5% and 1% treatments. Compared with that in the control, proportions of available Cd in soils of the following three seasons decreased by 10.0%-17.1% and 12.4%-20.8%. There was a significant positive correlation between available Cd contents in soils and Cd contents in various parts of the rice. TM mainly reduced available Cd contents in soils, then reduced the absorption and accumulation of Cd in rice. The results of the two-year field experiment showed significant and continuous effects of TM on inhibiting Cd uptake by rice, which could be applied to the safe production in heavily Cd contaminated cropland.

Semiconducting Titanate Supported Ruthenium Clusterzymes for Ultrasound-Amplified Biocatalytic Tumor Nanotherapies.

The external-stimulation-induced reactive-oxygen-species (ROS) generation has attracted increasing attention in therapeutics for malignant tumors. However, engineering a nanoplatform that integrates with efficient biocatalytic ROS generation, ultrasound-amplified ROS production, and simultaneous relief of tumor hypoxia is still a great challenge. Here, we create new semiconducting titanate-supported Ru clusterzymes (RuNC/BTO) for ultrasound-amplified biocatalytic tumor nanotherapies. The morphology and chemical/electronic structure analysis prove that the biocatalyst consists of Ru nanoclusters that are tightly stabilized by Ru-O coordination on BaTiO3 . The peroxidase (POD)- and halogenperoxidase-like biocatalysis reveals that the RuNC/BTO can produce abundant •O2 - radicals. Notably, the RuNC/BTO exhibits the highest turnover number (63.29 × 10-3 s-1 ) among the state-of-the-art POD-mimics. Moreover, the catalase-like activity of the RuNC/BTO facilitates the decomposition of H2 O2 to produce O2 for relieving the hypoxia of the tumor and amplifying the ROS level via ultrasound irradiation. Finally, the systematic cellular and animal experiments have validated that the multi-modal strategy presents superior tumor cell-killing effects and suppression abilities. We believe that this work will offer an effective clusterzyme that can adapt to the tumor microenvironment-specific catalytic therapy and also provide a new pathway for engineering high-performance ROS production materials across broad therapeutics and biomedical fields.

Electrocatalytic Porphyrin/Phthalocyanine-Based Organic Frameworks: Building Blocks, Coordination Microenvironments, Structure-Performance Relationships.

Metal-porphyrins or metal-phthalocyanines-based organic frameworks (POFs), an emerging family of metal-N-C materials, have attracted widespread interest for application in electrocatalysis due to their unique metal-N4 coordination structure, high conjugated π-electron system, tunable components, and chemical stability. The key challenges of POFs as high-performance electrocatalysts are the need for rational design for porphyrins/phthalocyanines building blocks and an in-depth understanding of structure-activity relationships. Herein, the synthesis methods, the catalytic activity modulation principles, and the electrocatalytic behaviors of 2D/3D POFs are summarized. Notably, detailed pathways are given for modulating the intrinsic activity of the M-N4 site by the microenvironments, including central metal ions, substituent groups, and heteroatom dopants. Meanwhile, the topology tuning and hybrid system, which affect the conjugation network or conductivity of POFs, are also considered. Furthermore, the representative electrocatalytic applications of structured POFs in efficient and environmental-friendly energy conversion areas, such as carbon dioxide reduction reaction, oxygen reduction reaction, and water splitting are briefly discussed. Overall, this comprehensive review focusing on the frontier will provide multidisciplinary and multi-perspective guidance for the subsequent experimental and theoretical progress of POFs and reveal their key challenges and application prospects in future electrocatalytic energy conversion systems.

Elevated expression of interleukin-27, IL-35, and decreased IL-12 in patients with thyroid-associated ophthalmopathy.

PURPOSE: Thyroid-associated ophthalmopathy (TAO) is a chronic autoimmune disease. The interleukin-12 (IL-12) family includes IL-12, IL-23, IL-27, and IL-35, all of which play important roles in autoimmunity. Thus far, the relationship between IL-12, IL-27, and IL-35 and the TAO has not been evaluated. METHODS: Seventy-five serum samples from patients with TAO were collected. Serum samples from 90 healthy controls (HC), 55 patients with Graves' disease (GD), 38 patients with uveitis (UV), 17 patients with Sjogren's syndrome (SS), and 65 patients with rheumatoid arthritis (RA) were collected as controls. The associations between IL-27, IL-35, IL-12, and other clinical parameters were analyzed. RESULTS: Elevated serum levels of IL-27/IL-35 and decreased serum IL-12 levels were observed in TAO patients compared to those in HC (p < 0.001). For HC, we observed good diagnostic ability to predict TAO (area under the curve = 0.74, 0.78, and 0.78, for IL-27, IL-35, and IL-12, respectively). For other autoimmune diseases, IL-27, IL-35, and IL-12 had the ability to discriminate between UV, RA, and SS (area under the curve = 0.80, 0.83, and 0.85 for IL-27; 0.52, 0.69, and 0.67 for IL-35). The positive detection rates of IL-12 were significantly lower in the TAO group than in the UV and RA groups (p = 0.002, 0.01). CONCLUSION: IL-12, IL-27, and IL-35 have the potential as biomarkers for TAO.

Cytokines in Thyroid-Associated Ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED) or Graves' orbitopathy (GO), is a complex autoimmune condition causing visual impairment, disfigurement, and harm to patients' physical and mental health. The pathogenesis of TAO has not been fully elucidated, and the mainstream view is that coantigens shared by the thyroid and orbit trigger remodeling of extraocular muscles and orbital connective tissues through an inflammatory response. In recent years, cytokines and the immune responses they mediate have been crucial in disease progression, and currently, common evidence has shown that drugs targeting cytokines, such as tocilizumab, infliximab, and adalimumab, may be novel targets for therapy. In this review, we summarize the research development of different cytokines in TAO pathogenesis in the hope of discovering new therapeutic targets.

Vergence Formula for Estimating the Refractive Status of Aphakic Eyes in Pediatric Patients.

Clinical Relevance: A vergence formula may provide a simple and reliable calculation of the refractive status of aphakic eyes. Background: Measuring the refractive error of pediatric eyes with aphakia is difficult. This study investigated the accuracy and applicability of a vergence formula for estimating the refractive status of such eyes. Methods: A retrospective review of the medical records, created between January 2016 and December 2018, of pediatric patients with aphakia was conducted. A vergence formula, based on axial length, was used to calculate the refractive status of the aphakic eyes. The refractive values determined using retinoscopy, an automatic refractometer, and the vergence formula were compared. Results: A total of 72 eyes (47 patients) were analyzed. The spherical equivalents of the refractive errors (mean ± standard deviation) of the eyes were determined using retinoscopy (13.01 ± 3.27 D), automatic refractometry (12.90 ± 3.23 D), and the vergence formula (12.70 ± 3.4 D). The correlation coefficient between retinoscopy values determined using retinoscopy and the vergence formula, automatic refractometry and the vergence formula, and retinoscopy and automatic refractometry were 0.968, 0.987, and 0.979, respectively. The Bland-Altman consistency analysis revealed that the mean differences in the spherical equivalent values between retinoscopy and automatic refractometry, retinoscopy and the vergence formula, and automatic refractometry and the vergence formula were 0.11 D, 0.31 D, and 0.21 D, respectively, with 95% limits of agreement of-1.20 to 1.41 D,-1.37 to 2.00 D, and-0.90 to 1.31 D, respectively. Conclusion: The vergence formula was effective for evaluating the refractive status of aphakic eyes in pediatric patients.

CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.

Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.

π-Conjugated Copper Phthalocyanine Nanoparticles as Highly Sensitive Sensor for Colorimetric Detection of Biomarkers.

Though numerous nanomaterials with enzyme-like activities have been utilized as probes and sensors for detecting biological molecules, it is still challenging to construct highly sensitive detectors for biomarkers using polymeric materials. Benefiting from the π-d delocalization effect of electrons, excellent metal-chelating property, high electron transferability, and good chemical stability of π-conjugated phthalocyanine, the design of the copper phthalocyanine-based conjugated polymer nanoparticles (Cu-PcCP NPs) as a colorimetric sensor for a variety of biomarkers is reported. The Cu-PcCP NPs are synthesized through a simple microwave-assisted polymerization, and their chemical structures are thoroughly characterized. The colorimetric results of Cu-PcCP NPs demonstrate excellent peroxidase-like detecting activity and also great substrate selectivity than most of the reported Cu-based nanomaterials. The Cu-PcCP NPs can achieve a detection limit of 4.88 µM for the H2 O2 , 4.27 µM for the L-cysteine, and 21.10 µM for the glucose via a cascade catalytic system, which shows comparable detecting sensitivity as that of many earlier reported enzyme-like nanomaterials. Moreover, Cu-PcCP NPs present remarkable resistance to harsh conditions, including high temperature, low pH, and excessive salts. These highly specific π-conjugated copper-phthalocyanine nanoparticles not only overcome the current limitation of polymeric material-based sensors but also provide a new direction for designing next-generation enzyme-like nanomaterial-based colorimetric biosensors.

Light Signaling and Myopia Development: A Review.

INTRODUCTION: The aim of this article was to comprehensively review the relationship between light exposure and myopia with a focus on the effects of the light wavelength, illuminance, and contrast on the occurrence and progression of myopia. METHODS: This review was performed by searching PubMed data sets including research articles and reviews utilizing the terms "light", "myopia", "refractive error", and "illuminance", and the review was concluded in November 2021. Myopia onset and progression were closely linked with emmetropization and hyperopia. To better elucidate the mechanism of myopia, some of the articles that focused on this topic were included. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. RESULTS: The pathogenesis and prevention of myopia are not completely clear. Studies have provided evidence supporting the idea that light could affect eye growth in three ways. Changing the corresponding conditions will cause changes in the growth rate and mode of the eyes, and preliminary results have shown that FR/NIR (far red/near-infrared) light is effective for myopia in juveniles. CONCLUSION: This review discusses the results of studies on the effects of light exposure on myopia with the aims of providing clues and a theoretical basis for the use of light to control the development of myopia and offering new ideas for subsequent studies.

Anchoring Fe-N-C Sites on Hierarchically Porous Carbon Sphere and CNT Interpenetrated Nanostructures as Efficient Cathodes for Zinc-Air Batteries.

Engineering efficient zinc-air batteries have attracted tremendous attention because of their essential role in the field of renewable energy systems. However, the sluggish reaction kinetics of the oxygen reduction reaction (ORR) at the air cathode impair the battery performance significantly. Recently, metal-N-C-based porous carbon nanoarchitectures have emerged as promising ORR electrocatalysts in zinc-air batteries. Herein, taking advantage of metal-organic complexation and mesoporous silica templates, we successfully anchor Fe-N-C sites on hierarchically porous carbon sphere and carbon nanotube interpenetrated nanostructures (Fe-N-C/HPCS@CNT) to serve as efficient cathodes for zinc-air batteries. Benefiting from its synergistic effects between the highly active Fe-N-C sites, ultrahigh surface areas, and unique hierarchically porous nanostructures, Fe-N-C/HPCS@CNT exhibits preferable ORR performance (E1/2 = 0.873 V) compared to commercial Pt/C (E1/2 = 0.841 V). Most importantly, when used as a cathode catalyst for homemade zinc-air batteries, Fe-N-C/HPCS@CNT exhibits gratifying peak power density (164.0 mW cm-2), large specific capacity (762.0 mAh g-1), superior long-term stability, extraordinary rate capability, and excellent charge/discharge performance. We believe that this report will not only offer new insights into the design of Fe-N-C-based catalysts but also promote the practical utilization of Fe-N-C-based cathodes for a wide range of energy applications.

Sinomenine improve diabetic nephropathy by inhibiting fibrosis and regulating the JAK2/STAT3/SOCS1 pathway in streptozotocin-induced diabetic rats.

AIMS: To investigate the therapeutic effects and potent mechanism of sinomenine (SIN) nanoliposomes on nephropathy in diabetic rats. MAIN METHODS: The protective efficacies of SIN on the oxidative injury in renal HK-2 cell induced by hydrogen peroxide (H2O2) were investigated via the CCK-8 assay. Forty SD rats with streptozotocin (STZ)-induced diabetic kidney disease (DKD) were assigned to the saline group and three SIN groups (10, 20 and 40 mg/kg). During 6-week treatment, body weight, fasting glucose level and other metabolic parameters were recorded. H&E staining and changes in renal functions as well as expression levels of apoptosis and fibrosis-related factors in renal tissues were assessed. The qPCR and western blotting (WB) methods were used to detect relative expression levels of JAK/STAT/SOCS pathway-related factors in the renal tissues. KEY FINDINGS: Cell viabilities of HK-2 cells with oxidative injury were obviously improved by incubating with SIN at 320 µg/mL for 92.9%. Significantly up-regulated GPX1, SOD2 and GSH contributed to the down-regulated ROS content in SIN-treated groups. Moreover, 6-week administration of SIN improved renal functions and worsening nephropathy morphology of DKD rats. SIN also ameliorated gradually increased renal cell apoptosis, suppressed expression levels of fibrosis-related proteins as well as IL-6 and ICAM-1, and regulated JAK2/STAT3/SOCS1 pathway, thereby exhibited protective effects on renal tissues of DKD rats. CONCLUSION: SIN protects nephrocytes and decreases renal tissue injury via inhibiting oxidative stress, reducing renal cell apoptosis and fibrosis, regulating the JAK2/STAT3/SOCS1 pathway in DKD rats.

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles.

Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56+ NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34+ hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs). UCB56-NK cells also displayed a more potent cytotoxicity compared to UCB34-NK cells. NK cells derived from iPSCs (iPSC-NK cells) were found to have variable KIR expression, with certain iPSC-NK cell populations expressing high levels of KIRs and others not expressing KIRs. Notably, KIR expression on UCB56 and iPSC-NK cells had limited effect on cytotoxic activity when stimulated by tumor target cells that express high levels of cognate HLA class I, suggesting that in vitro differentiation and expansion may override the KIR-HLA class I mediated inhibition when used across HLA barriers. Together our results give a better understanding of the cell surface receptor, transcriptional, and functional differences between NK cells present in umbilical cord blood and hematopoietic progenitor-derived NK cells which may prove important in selecting the most active NK cell populations for treatment of cancer or other therapies.

Bioinspired liquid gating membrane-based catheter with anticoagulation and positionally drug release properties.

Catheters are indispensable medical devices that are extensively used in daily medical treatment. However, existing catheter materials continue to encounter many problems, such as thrombosis, single functionality, and inadaptability to environmental changes. Inspired by blood vessels, we develop a self-adaptive liquid gating membrane-based catheter with anticoagulation and positionally drug release properties. Our multifunctional liquid gating membrane-based catheter significantly attenuates blood clot formation and can be used as a general catheter design strategy to offer various drugs positionally releasing applications to comprehensively enhance the safety, functionality, and performance of medical catheters' materials.

Magnetic targeting cobalt nanowire-based multifunctional therapeutic system for anticancer treatment and angiogenesis.

In order to improve the anticancer therapeutic efficacy and postoperative recovery efficacy, the novel anticancer therapeutic system should have the ability to promote angiogenesis after anticancer therapy besides the excellent anticancer therapeutic efficacy. We present herein a magnetic targeting multifunctional anticancer therapeutic system based on cobalt nanowires (CoNWs) for anticancer therapy and angiogenesis. Magnetic characterization shows that the CoNWs can be concentrated in desired locations under the external magnetic field, which is favorable for anticancer target therapy. Besides, drug loading/release characterization reveals that the CoNWs interact with doxorubicin (DOX) by electrostatic interaction, and accordingly form a composite which can release DOX with temperature increase under near-infrared light (NIR) treatment. And anticancer test reveals that the nanowires loaded with the DOX (CoNWs-DOX) can produce an effective chemo-photothermal synergistic therapeutic effect against murine breast cancer cell lines (4T1) and human osteosarcoma cell lines (MG63) under NIR treatment. Furthermore, angiogenesis assessment reveals that the released cobalt ion from the nanowires can significantly enhance the angiogenesis efficacy after cancer treatment. These results suggest that the constructed anticancer therapeutic system provides a promising multifunctional platform for cancer treatment and postoperative recovery.

Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity.

Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer (NK) cells. Here, we develop human CISH-knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH-/- iPSC-NK cells demonstrate increased IL-15-mediated JAK-STAT signaling activity. Consequently, CISH-/- iPSC-NK cells exhibit improved expansion and increased cytotoxic activity against multiple tumor cell lines when maintained at low cytokine concentrations. CISH-/- iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model. Mechanistically, CISH-/- iPSC-NK cells display improved metabolic fitness characterized by increased basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration, and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signaling that directly contributes to enhanced NK cell function. Together, these studies demonstrate that CIS plays a key role to regulate human NK cell metabolic activity and thereby modulate anti-tumor activity.

High-mobility Group Box 1 Facilitates CD4 T Cell Self-aggregation Via Integrin and STAT3 Activation Before Homing.

BACKGROUND: High-mobility group box 1 (HMGB1) is one of the delayed pro-inflammatory cytokines produced in the later stages of pathogenesis and plays an important role in the progression of various inflammatory and autoimmune diseases. High-mobility group box 1 is able to stimulate interaction between integrins and cell adhesion molecules to facilitate cell-cell aggregation in "tissue-specific" endothelium; however, whether and how HMGB1 affects the adhesive capability of early acting immune cells in bloodstream remains largely unknown. METHODS: Human peripheral blood samples were collected from healthy adult donors. The CD4 T cells were isolated from blood using CD4 T cell isolation kit and identified using flow cytometry and immunofluorescence staining. The effect of HMGB1 on adhesive ability of CD4 T cells was accessed by cell self-aggregation assay and endothelial adhesion assay. The migratory ability of CD4 T cells was evaluated by cell migration assay. Secretion of pro-inflammatory cytokines or chemokine C-X-C motif chemokine 12 (CXCL12) were detected by ELISA. Expression of integrins ß1, ß7, and α4ß7 were determined by flow cytometric analysis. Inhibition of integrins was achieved with anti-integrin antibodies or cyclic peptide inhibitors. Activation of signal transducers and activators of transcription 3 (STAT3) was measured by flow cytometry and fluorescent staining. RESULTS: High-mobility group box 1 facilitated CD4 T cell self-aggregation with simultaneous reduction of CD4 T single-cell counts in the bloodstream. The CD4 T cell self-aggregation induced by HMGB1 resulted in upregulation of integrins ß1, ß7, and α4ß7; release of other pro-inflammatory cytokines or chemokine CXCL12; and activation of STAT3 signaling. Intriguingly, pro-inflammatory cytokines induced by HMGB1 could further amplify CD4 T cell self-aggregation. HMGB1 induced CD4 T cell apoptosis via activation of caspase-3/7. Furthermore, HMGB1 promoted migration and adhesion of CD4 T cells to endothelial cells. CONCLUSIONS: These results provide proof of concept that HMGB1 promotes CD4 T cell self-aggregation before homing to inflammatory sites and highlight the potential of blocking immune cell self-aggregation in blood as a novel therapeutic approach against the development and progression of HMGB1-related inflammatory diseases.HMGB1 induces CD4 T cell self-aggregation in blood resulting in upregulation of integrins expression and release of pro-inflammatory cytokines/chemokines via activation of STAT3 signaling. This study highlights the potential of preventive and therapeutic intervention on immune cell self-aggregation in the bloodstream.