SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.

Particulate Standard Establishment for Absolute Quantification of Nanoparticles by LA-ICP-MS.

The development of nanotechnology has transformed many cutting-edge studies related to single-molecule analysis into nanoparticle (NP) detection with a single-NP sensitivity and ultrahigh resolution. While laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been successful in quantifying and tracking NPs, its quantitative calibration remains a major challenge due to the lack of suitable standards and the uncertain matrix effects. Herein, we frame a new approach to prepare quantitative standards via precise synthesis of NPs, nanoscale characterization, on-demand NP distribution, and deep learning-assisted NP counting. Gold NP standards were prepared to cover the mass range from sub-femtogram to picogram levels with sufficient accuracy and precision, thus establishing an unambiguous relationship between the sampled NP number in each ablation and the corresponding mass spectral signal. Our strategy facilitated for the first time the study of the factors affecting particulate sample capture and signal transductions in LA-ICP-MS analysis and culminated in the development of an LA-ICP-MS-based method for absolute NP quantification with single-NP sensitivity and single-cell quantification capability. The achievements would herald the emergence of new frontiers cut across a spectrum of toxicological and diagnostic issues related to NP quantification.

Antimony-Assisted Assembly of Basic Supertetrahedral Clusters into Heterometallic Chalcogenide Supraclusters.

Reported here are two new heterometallic chalcogenide supraclusters ([Ga56Sb16S136] and [In36Sb6S75]), which present new self-assembly modes of basic supertetraheral clusters with the assistance of antimony ions. This work demonstrates the crucial role of the added metal ions with nontetrahedral coordination geometry in developing supertetrahedral-cluster-based supraclusters with a new level of complexity.

Toxicity of Two Different Size Ceria Nanoparticles to Mice After Repeated Intranasal Instillation.

Ceria nanoparticles (nanoceria) have been used as a fuel-borne catalyst, and are emitted in the particulate phase in the diesel exhaust. To evaluate the potential health risks of airborne nanoceria, the pulmonary and systemic consequences of nanoceria to ICR mice were studied under repeated transnasal instillation. Two different size nanoceria (7-nm and 25-nm) were chose, representing the nanoceria mostly used as fuel additives and the combustion products of the very nanoceria, respectively. As the first target organ of nanoceria, the lungs suffered serious damages manifested in the results of their biochemical and pathological examinations. The results demonstrated the penetration of nanoceria through air-blood barrier after the lung burden. Nanoceria were further transferred to the secondary target organs, mainly the liver and spleen. Nanoceria could also arrive at the central neural system via olfactory nerve pathway. The systemic accumulation of nanoceria finally triggered lipid peroxidation in multiple organs. Generally, the smaller nanoceria induced more severe pulmonary damage but similar systemic toxicity when compared with the larger one. These findings imply that using nanoceria as diesel fuel catalyst may cause health concerns. Additional studies are warranted to investigate the pulmonary and systemic health consequences of nanoceria additive to diesel fuel.

Synthesis, Photothermal Effect and Cytotoxicity of Fe3O4@Au Nanocomposites.

It is currently a very active research area to develop multifunctional nanocomposites (NCs) which integrate the novel properties from various nanomaterials for multimodal imaging and simultaneous therapy. These theranostic nanoplatforms can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging-guided focused tumor therapy. Among them, core/shell Fe3O4@Au NCs have attracted wide attention due to their unique advantages in magnetic targeting, multimodal imaging and photothermal therapy. This study developed a layer-by-layer assembling approach to synthesize Fe3O4@Au NCs with high photothermal conversion efficiency. The as-synthesized NCs showed significant photothermal ablation capability to HeLa cells in vitro under near infrared laser irradiation. To ensure the safety for medical applications, the bio-effects of Fe3O4@Au NCs on RAW264.7 cells were carefully assessed, in terms of cell viability, oxidative stress and apoptosis. We have demonstrated that Fe3O4@Au NCs had good biocompatibility in RAW264.7 cells and no significant cytotoxicity was found. Therefore, the Fe3O4@Au NCs synthesized in this study have great potential as an ideal candidate for CT/MR imaging and photothermal therapy.

Trophic Transfer and Transformation of CeO2 Nanoparticles along a Terrestrial Food Chain: Influence of Exposure Routes.

The trophic transfer and transformation of CeO2 nanoparticles (NPs) through a simulated terrestrial food chain were investigated using a radiotracer technique and X-ray absorption near edge structure (XANES). Radioactive 141CeO2 NPs were applied to head lettuce ( Lactuca sativa), treated via root exposure in its potting soil (5.5 or 11 mg/plant) for 30 days or foliar exposure (7.2 mg/plant, with half of the leaves treated and the other half not) for 7 days. Subsequently, two groups of land snails ( Achatina fulica) were exposed to 141Ce via either a direct (i.e., feeding on the lettuce leaves with 141Ce-contaminated surfaces) or an indirect/trophic (i.e., feeding on the lettuce leaves with systemically distributed 141Ce) route. To evaluate the influence of exposure routes, the Ce contents of the lettuce, snail tissues, and feces were determined by radioactivity measurements. The results show that both assimilation efficiencies (AEs) and food ingestion rates of Ce are greater for the trophic (indirect) exposure. The low AEs indicate that the CeO2 NPs ingested by snails were mostly excreted subsequently, and those that remained in the body were mainly concentrated in the digestive gland. XANES analysis shows that >85% of Ce was reduced to Ce(III) in the digestive gland under direct exposure, whereas Ce in the rest of the food chain (including feces) was largely in its original oxidized (IV) state. This study suggests that CeO2 NPs present in the environment may be taken up by producers and transferred to consumers along food chains and trophic transfer may affect food safety.

Comparative effects of nano and bulk-Fe3O4 on the growth of cucumber (Cucumis sativus).

Cucumber (Cucumis sativus) plants were cultivated in hydroponic media with nano and bulk- iron oxide (Fe3O4) (50, 500 and 2000 mg/L) over a period of 21 days. At the low concentration (50 mg/L), nano-Fe3O4 resulted in reduction of biomass and enzyme activities compared to the control. However, at the higher concentration of nano-Fe3O4 dosage (2000 mg/L), there was a significant increase in biomass, antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD). In contrary, the high concentration of bulk-Fe3O4 caused phytotoxicity in terms of biomass and enzymes activity. The phytotoxicity was dependent on the particles property (mainly sizes and aggregation) for nano-F3O4 and concentration dependent for bulk-Fe3O4. The particle size is an important factor that can influence the bioavailability of nanomaterials, which need to be included when evaluating the exposure of nanomaterials and their deleterious effects in the environment. These promising results can help to develop the possible application of Fe3O4 NPs which may improve nutrient management to overcome food security.

Xylem and Phloem Based Transport of CeO2 Nanoparticles in Hydroponic Cucumber Plants.

Uptake and translocation of manufactured nanoparticles (NPs) in plants have drawn much attention due to their potential toxicity to the environment, including food webs. In this paper, the xylem and phloem based transport of CeO2 NPs in hydroponic cucumber plants was investigated using a split-root system. One half of the root system was treated with 200 or 2000 mg/L of CeO2 NPs for 3 days, whereas the other half remained untreated, with both halves sharing the same aerial part. The quantitative distribution and speciation of Ce in different plant tissues and xylem sap were analyzed by inductively coupled plasma-mass spectrometry, transmission electron microscope, X-ray absorption near edge structure, and X-ray fluorescence. Results show that about 15% of Ce was reduced from Ce(IV) to Ce(III) in the roots of the treated-side (TS), while almost all of Ce remained Ce(IV) in the blank-side (BS). The detection of CeO2 or its transformation products in the xylem sap, shoots, and BS roots indicates that Ce was transported as a mixture of Ce(IV) and Ce(III) from roots to shoots through xylem, while it was transported almost only in the form of CeO2 from shoots back to roots through phloem. To our knowledge, this is the first report of root-to-shoot-to-root redistribution after transformation of CeO2 NPs in plants, which has significant implications for food safety and human health.

Influence of Speciation of Thorium on Toxic Effects to Green Algae Chlorella pyrenoidosa.

Thorium (Th) is a natural radioactive element present in the environment and has the potential to be used as a nuclear fuel. Relatively little is known about the influence and toxicity of Th in the environment. In the present study, the toxicity of Th to the green algae Chlorella pyrenoidosa (C. pyrenoidosa) was evaluated by algal growth inhibition, biochemical assays and morphologic observations. In the cultural medium (OECD TG 201), Th(NO3)4 was transformed to amorphous precipitation of Th(OH)4 due to hydrolysis. Th was toxic to C. pyrenoidosa, with a 96 h half maximum effective concentration (EC50) of 10.4 µM. Scanning electron microscopy shows that Th-containing aggregates were attached onto the surface of the algal cells, and transmission electron microscopy indicates the internalization of nano-sized Th precipitates and ultrastructural alterations of the algal cells. The heteroagglomeration between Th(OH)4 precipitation and alga cells and enhanced oxidative stress might play important roles in the toxicity of Th. To our knowledge, this is the first report of the toxicity of Th to algae with its chemical species in the exposure medium. This finding provides useful information on understanding the fate and toxicity of Th in the aquatic environment.

Toxicity of cerium and thorium on Daphnia magna.

Cerium (Ce) and thorium (Th) are always thought to be chemically similar and have comparable toxic properties on living organisms. In the present study, the acute and chronic toxicity of these two elements to freshwater crustacean Daphnia magna were investigated in the modified reconstituted water (6mg/L KCl, 123mg/L MgSO4·7H2O, and 294mg/L CaCl2·2H2O in Milli-Q water, pH 7.8). It seemed that Ce and Th had comparable acute toxicity on Daphnia: 24/48h EC50 for Th and Ce were 7.3/4.7µM and 16.4/10.7µM, respectively. However, Ce was present as soluble ions while all of Th was present as particulate ThO2 in the exposure medium. Considering their different chemical forms and bioavailability, the toxic mechanisms of Ce3+ and ThO2 on Daphnia would be totally different. To our knowledge, this is the first time to investigate the aquatic toxicity of thorium and cerium based on their actual chemical speciation in the exposure medium. The results also suggest that more attention should be paid on the detrimental effect of Th in the form of particulate ThO2.

Where Does the Transformation of Precipitated Ceria Nanoparticles in Hydroponic Plants Take Place?

Cerium oxide nanoparticles (CeO2 NPs) have been found to be partly biotransformed from Ce(IV) to Ce(III) in plants, yet the transformation process and mechanism are not fully understood. Here, we try to clarify the specific site and necessary conditions for the transformation of precipitated CeO2 NPs in hydroponic cucumber plants. Three different treatment modes were adopted according to whether the NPs were incubated with roots all the time or not. Results showed that exposure modes significantly affect the translocation and transformation of CeO2 NPs. In the normal exposure mode, Ce was present as a Ce(IV) and Ce(III) mixture in the roots and shoots, and the proportion of Ce(III) in the shoots was enhanced obviously with the increase of exposure time. The results of short-time incubation and petiole exposure modes suggested that CeO2 NPs could not be reduced within a short incubation time (3 h) or be further reduced inside the plant tissues. It was deduced that root surfaces are the sites, and the physicochemical interaction between the NPs and root exudates at the nanobio interface is the necessary condition for the transformation of CeO2 NPs in plant systems. These results will contribute to understanding the transformation mechanism of CeO2 and other metal-based NPs and properly evaluate their ecological effects.

Acquired superoxide-scavenging ability of ceria nanoparticles.

Ceria nanoparticles (nanoceria) are well known as a superoxide scavenger. However, inherent superoxide-scavenging ability has only been found in the nanoceria with sizes of less than 5 nm and with very limited shape diversity. Reported herein is a strategy to significantly improve the superoxide-scavenging activity of nanoceria sized at greater than 5 nm. The nanoceria with sizes of greater than 5 nm, with different shapes, and with a negligible Ce(3+)/Ce(4+) ratio can acquire remarkable superoxide-scavenging abilities through electron transfer. This method will make it possible to develop nanoceria-based superoxide-scavengers with long-acting activity and tailorable characteristics.

Expression and prognostic significance of CIP2A in cutaneous malignant melanoma.

OBJECTIVE: We investigated the expression and clinical significance of Cancerous inhibitor of protein phosphatase 2A (CIP2A) in Cutaneous malignant melanoma (CMM). METHODS: CIP2A expression was analyzed by immunohistochemistry and western blot. We tested the invasion and migration capability of A375 cells with Matrigel invasion assay, Scratch migration assay and Matrigel migration assay after down-regulating CIP2A expression using siRNA. RESULTS: CIP2A immunostaining level was correlated with Breslow thickness, Clark's Level and lymphovascular invasion. High-CIP2A expression implied poor survival for patients. Downregulation of CIP2A attenuated metastasis of CMM cells. CONCLUSIONS: CIP2A may serve as a novel marker to predict the prognosis for CMM patients.

Comparative pulmonary toxicity of two ceria nanoparticles with the same primary size.

Ceria nanoparticles (nano-ceria) have recently gained a wide range of applications, which might pose unwanted risks to both the environment and human health. The greatest potential for the environmental discharge of nano-ceria appears to be in their use as a diesel fuel additive. The present study was designed to explore the pulmonary toxicity of nano-ceria in mice after a single exposure via intratracheal instillation. Two types of nano-ceria with the same distribution of a primary size (3-5 nm), but different redox activity, were used: Ceria-p, synthesized by a precipitation route, and Ceria-h, synthesized by a hydrothermal route. Both Ceria-p and Ceria-h induced oxidative stress, inflammatory responses and cytotoxicity in mice, but their toxicological profiles were quite different. The mean size of Ceria-p agglomerates was much smaller compared to Ceria-h, thereby causing a more potent acute inflammation, due to their higher number concentration of agglomerates and higher deposition rate in the deep lung. Ceria-h had a higher reactivity to catalyzing the generation of reactive oxygen species (ROS), and caused two waves of lung injury: bronchoalveolar lavage (BAL) inflammation and cytotoxicity in the early stage and redox-activity-evoked lipid peroxidation and pro-inflammation in the latter stage. Therefore, the size distribution of ceria-containing agglomerates in the exhaust, as well as their surface chemistry are essential characteristics to assess the potential risks of using nano-ceria as a fuel additive.

Neutrophil-Driven M2-Like Macrophages Are Critical for Skin Fibrosis in a Systemic Sclerosis Model.

Systemic sclerosis (SSc) is a challenging autoimmune disease characterized by progressive fibrosis affecting the skin and internal organs. Despite the known infiltration of macrophages and neutrophils, their precise contributions to SSc pathogenesis remain elusive. In this study, we elucidated that CD206hiMHCIIlo M2-like macrophages constitute the predominant pathogenic immune cell population in the fibrotic skin of a bleomycin-induced SSc mouse model. These cells emerged as pivotal contributors to the profibrotic response by orchestrating the production of TGF-ß1 through a MerTK signaling-dependent manner. Notably, we observed that neutrophil infiltration was a prerequisite for accumulation of M2-like macrophages. Strategies such as neutrophil depletion or inhibition of CXCR1/2 were proven effective in reducing M2-like macrophages, subsequently mitigating SSc progression. Detailed investigations revealed that in fibrotic skin, neutrophil-released neutrophil extracellular traps were responsible for the differentiation of M2-like macrophages. Our findings illuminate the significant involvement of the neutrophil-macrophage-fibrosis axis in SSc pathogenesis, offering critical information for the development of potential therapeutic strategies.

JUNO high purity nitrogen plant.

The Jiangmen Underground Neutrino Observatory (JUNO) is a 20 kt low level radioactivity liquid scintillator detector in a laboratory 650 m underground. An excellent energy resolution and a large volume offer exciting opportunities for addressing many important topics in neutrino physics. High purity nitrogen is an important factor to ensure the low background of the JUNO detector. High Purity Nitrogen (HPN) is used for detector purging, pipe cleaning, and scintillator purification, among other things in JUNO. According to JUNO's requirements, the radon concentration in HPN should be less than 10 µBq/m3. To meet this requirement, A high-purity nitrogen plant with 100 Nm3/h maximum rate was designed and constructed. Low-temperature adsorption technology is used to remove radioactive impurities in nitrogen. High purification efficiency was ensured by using an activated carbon column with high column height-to-diameter ratio. Electrostatic collection and low-temperature enrichment methods are combined to measure radon in nitrogen. After ten days of continuous operation at 50 Nm3/h flux rate, the plant can to reduce the radon concentration in nitrogen from 37.4±1.8µBq/m3 to less than 1.33 µBq/m3. After HPN with flow rate of 50 Nm3/h passing through low-background pipeline (About 1.3 km), the radon concentration of HPN is 5.6±0.6µBq/m3.

Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan.

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.

Nitric oxide-dependent immunosuppressive function of thymus-derived mesenchymal stromal/stem cells.

BACKGROUND: The thymus is required for T cell development and the formation of the adaptive immunity. Stromal cells, which include thymic epithelial cells (TECs) and mesenchymal stromal cells (MSCs), are essential for thymic function. However, the immunomodulatory function of thymus-derived MSCs (T-MSCs) has not been fully explored. METHODS: MSCs were isolated from mouse thymus and their general characteristics including surface markers and multi-differentiation potential were characterized. The immunomodulatory function of T-MSCs stimulated by IFN-γ and TNF-α was evaluated in vitro and in vivo. Furthermore, the spatial distribution of MSCs in the thymus was interrogated by using tdTomato-flox mice corssed to various MSC lineage Cre recombinase lines. RESULTS: A subset of T-MSCs express Nestin, and are mainly distributed in the thymic medulla region and cortical-medulla junction, but not in the capsule. The Nestin-positive T-MSCs exhibit typical immunophenotypic characteristics and differentiation potential. Additionally, when stimulated with IFN-γ and TNF-α, they can inhibit activated T lymphocytes as efficiently as BM-MSCs, and this function is dependent on the production of nitric oxide (NO). Additionally, the T-MSCs exhibit a remarkable therapeutic efficacy in acute liver injury and inflammatory bowel disease (IBD). CONCLUSIONS: Nestin-positive MSCs are mainly distributed in medulla and cortical-medulla junction in thymus and possess immunosuppressive ability upon stimulation by inflammatory cytokines. The findings have implications in understanding the physiological function of MSCs in thymus.

Comparative toxicity of nanoparticulate/bulk Yb2O3 and YbCl3 to cucumber (Cucumis sativus).

With the increasing utilization of nanomaterials, there is a growing concern for the potential environmental and health effects of them. To assess the environmental risks of nanomaterials, better knowledge about their fate and toxicity in plants are required. In this work, we compared the phytotoxicity of nanoparticulate Yb(2)O(3), bulk Yb(2)O(3), and YbCl(3)·6H(2)O to cucumber plants. The distribution and biotransformation of the three materials in plant roots were investigated in situ by TEM, EDS, as well as synchrotron radiation based methods: STXM and NEXAFS. The decrease of biomass was evident at the lowest concentration (0.32 mg/L) when exposed to nano-Yb(2)O(3), while at the highest concentration, the most severe inhibition was from YbCl(3). The inhibition was dependent on the actual amount of toxic Yb uptake by the cucumber plants. In the intercellular regions of the roots, Yb(2)O(3) particles and YbCl(3) were all transformed to YbPO(4). We speculate that the dissolution of Yb(2)O(3) particles induced by the organic acids exuded from roots played an important role in the phytotoxicity. Only under the nano-Yb(2)O(3) treatment, YbPO(4) deposits were found in the cytoplasm of root cells, so the phytotoxicity might also be attributed to the Yb internalized into the cells.

Two new metal-chalcogenide-cluster-based frameworks with single metal ions of Zn2+(/Sb3+) serving as inter-cluster linkers.

Two new metal-chalcogenide-cluster-based frameworks, in which P1-ZnSnS clusters are linked to each other by both corner-shared S2- ions and single metal ions of Zn2+ (or Sb3+) to form one new 3D (3,4)-connected network (MCCF-22) and one 2D-layered framework (MCCF-23), respectively, are reported. Notably, MCCF-22 exhibits good performance toward photodegradation of methylene blue compared with its analogue framework with only S2- ions as the linker.