Anti-inflammatory protective effect of ADAMTS-13 in murine arthritis models.

BACKGROUND: Patients with rheumatoid arthritis (RA) have frequent thrombotic events with endothelial dysfunction. Von Willebrand factor (VWF) has been shown to bind neutrophil extracellular traps (NETs) and NETs are part of RA etiology. OBJECTIVES: This study aims to elucidate whether this prothrombotic status exacerbates inflammation in arthritis. Here we focus on the involvement of A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif, member 13 (ADAMTS-13), an enzyme cleaving VWF and its effect on NET deposition and RA development. METHODS: We evaluated the influence of the Adamts13 gene and recombinant human ADAMTS-13 (rhADAMTS-13) on arthritis in the mouse models of collagen-induced arthritis (CIA). We also assessed VWF and NETs in synovial tissue. RESULTS: Several Adamts13-/- mice developed arthritis, while Adamts13+/+ siblings did not. Synovial tissue from Adamts13-/- showed accumulation of NETs. Treatment of DBA/1 J mice, an arthritis-susceptible strain, with well-tolerated doses of rhADAMT13 reduced arthritis incidence and alleviated the severity of arthritis. Mice treated with rhADAMT13 presented less serum interleukin 6 and less bone erosion determined by micro-computed tomography. The effects on arthritis severity were observed both when administering rhADAMTS-13 prophylactically and also when given after arthritis has developed. In both conditions, rhADAMTS-13 reduced VWF and NET deposition on proliferated synovial tissue evaluated by immunoblotting. CONCLUSIONS: Our results demonstrate the inhibitory role of Adamts13 in murine arthritis and the effectiveness of rhADAMTS-13 treatment. Additionally, this study suggests that deposition of VWF in the synovium and subsequent pathogenic NET retention promotes arthritis. Treatment with rhADAMTS-13 provides a potential therapeutic approach targeting inflammation and pro-thrombotic state in arthritis.

The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in C57BL/6 Mice.

OBJECTIVE: Genome-wide association studies have connected PADI4, encoding peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 promotes neutrophil extracellular trap (NET) formation. This study was undertaken to investigate the origin of PAD4 and the importance of NET formation in a C57BL/6 mouse model of arthritis. METHODS: To permit the effective use of C57BL/6 mice in the collagen-induced arthritis (CIA) model, we introduced the administration of granulocyte colony-stimulating factor (G-CSF) for 4 consecutive days in conjunction with the booster immunization on day 21. Mice with global Padi4 deficiency (Padi4-/- ) and mice with hematopoietic lineage-specific Padi4 deficiency (Padi4Vav1Cre/+ ) were evaluated in the model. RESULTS: G-CSF significantly increased the incidence and severity of CIA. G-CSF-treated mice showed elevated citrullinated histone H3 (Cit-H3) levels in plasma, while vehicle-treated mice did not. Immunofluorescence microscopy revealed deposition of Cit-H3 in synovial tissue in G-CSF-treated mice. Padi4-/- mice developed less severe arthritis and had lower levels of serum interleukin-6 and plasma Cit-H3, lower levels of Cit-H4 in synovial tissue, and less bone erosion on micro-computed tomography than Padi4+/+ mice in the G-CSF-modified CIA model. Similarly, Padi4Vav1Cre/+ mice developed less severe arthritis, compared with Padi4fl/fl mice, and presented the same phenotype as Padi4-/- mice. CONCLUSION: We succeeded in developing an arthritis model suitable for use in C57BL/6 mice that is fully compliant with high animal welfare standards. We observed a >90% incidence of arthritis in male mice and detectable NET markers. This model, with some features consistent with human RA, demonstrates that hematopoietic PAD4 is an important contributor to arthritis development and may prove useful in future RA research.

Growing phosphorus dilemma: The opportunity from aquatic systems' secondary phosphorus retention capacity.

The essential cause of phosphorus scarcity and phosphorus-induced risks, i.e. phosphorus dilemma, mainly lies in current low phosphorus flow efficiency (PFE) in agricultural systems. Improving PFE largely depends on secondary phosphorus retention along the phosphorus flow chain from phosphate mining to terrestrial agricultural systems, to aquatic systems, and ultimately to seabed deposition. Our review found that aquatic systems will have the opportunity and growing capacity to retain seaward secondary phosphorus carried by the runoff, due to its location between land and water systems, its ability of converting secondary phosphorus from both land and aquatic systems into aquatic products, and its rapid expansion with low PFE. However, a knowledge gap exists in secondary phosphorus retention in aquatic systems compared to in terrestrial systems. Although the phosphorus retention literature continues to grow in environmental and agricultural & biological sciences, only 8.8% of the documents are related to aquatic systems with few quantification studies. Based on the literature with phosphorus retention quantification since 1979, we divided the reported phosphorus interceptors into abiotic and biotic groups, further into 7 categories and more subcategories. By 2020, eight categories of interceptors had been reported, increased from only one interceptor in 1979. However, most of them focused on wetlands, only a few studies on aquatic organisms which concentrated in 8 countries before 2000. Thus, it is urgent to emphasize aquatic systems' secondary phosphorus retention capacity and its systemic benefits for a sustainable phosphorus use.

A Novel Derivative of (-)mycousnine Produced by the Endophytic Fungus Mycosphaerella nawae, Exhibits High and Selective Immunosuppressive Activity on T Cells.

An endophytic fungus, Mycosphaerella nawae ZJLQ129, was isolated from the leaves of the traditional Chinese medicine Smilax china. From the fermentation broth and mycelium, a dibenzofurane compound (-)mycousnine (1) was isolated. Chemical modification of it to the amide derivative (-)mycousnine enamine (2), which is new to science, was found to have high and selective immunosuppressive activity: similar to cyclosporin A, (-)mycousnine enamine (2) selectively inhibited T cell proliferation, suppressed the expression of the surface activation antigens CD25 and CD69 and the formation and expression of the cytokines interleukin-2 as well as interferon γ in activated T cells, but did not show any effect on the proliferation of B cells and cancer cells (PANC-1 and A549) and the activation of macrophages. Furthermore, the cytotoxicity of (-)mycousnine enamine was lower than that of cyclosporin A, and its therapeutic index (TC50/EC50) was 4,463.5, which is five-fold higher than that of cyclosporin A. We conclude that (-)mycousnine enamine (2), the semi-synthestic product prepared from the native product (-)mycousnine (1) of the endophyte M. nawae is a novel effective immunosuppressant showing low toxicity and high selectivity.

Triclosan: A review on systematic risk assessment and control from the perspective of substance flow analysis.

Triclosan (TCS) is a broad spectrum antibacterial agent mainly used in Pharmaceutical and Personal Care Products. Its increasing use over recent decades have raised its concentration in the environment, with commonly detectable levels found along the food web-from aquatic organisms to humans in the ecosystem. To date, there is shortage of information on how to investigate TCS's systematic risk on exposed organisms including humans, due to the paucity of systematic information on TCS flows in the anthroposphere. Therefore, a more holistic approach to mass flow balancing is required, such that the systematic risk of TCS in all environmental matrices are evaluated. From the perspective of Substance Flow Analysis (SFA), this review critically summarizes the current state of knowledge on TCS production, consumption, discharge, occurrence in built and natural environments, its exposure and metabolism in humans, and also the negative effects of TCS on biota and humans. Recent risk concerns have mainly focused on TCS removal efficiencies and metabolism, but less attention is given to the effect of mass flows from source to fate during risk exposure. However, available data for TCS SFA is limited but SFA can derive logical systematic information from limited data currently available for systematic risk assessment and reduction, based on mass flow analysis. In other words, SFA tool can be used to develop a comprehensive flow chart and indicator system for the risk assessment and reduction of TCS flows in the anthroposphere, thereby bridging knowledge gaps to streamline uncertainties related to policy-making on exposure pathways within TCS flow-lines. In the final analysis, specifics on systematic TCS risk assessment via SFA, and areas of improvement on human adaptation to risks posed by emerging contaminants are identified and directions for future research are suggested.

Bioactive metabolites from Phoma species, an endophytic fungus from the Chinese medicinal plant Arisaema erubescens.

Through bioassay-guided fractionation, the EtOAc extract of a culture broth of the endophytic fungus Phoma species ZJWCF006 in Arisaema erubescens afforded a new α-tetralone derivative, (3S)-3,6,7-trihydroxy-α-tetralone (1), together with cercosporamide (2), ß-sitosterol (3), and trichodermin (4). The structures of compounds were established on the basis of spectroscopic analyses. Compounds 1, 2, and 3 were obtained from Phoma species for the first time. Additionally, the compounds were subjected to bioactivity assays, including antimicrobial activity, against four plant pathogenic fungi (Fusarium oxysporium, Rhizoctonia solani, Colletotrichum gloeosporioides, and Magnaporthe oryzae) and two plant pathogenic bacteria (Xanthomonas campestris and Xanthomonas oryzae), as well as in vitro antitumor activities against HT-29, SMMC-772, MCF-7, HL-60, MGC80-3, and P388 cell lines. Compound 1 showed growth inhibition against F. oxysporium and R. solani with EC50 values of 413.22 and 48.5 µg/mL, respectively. Additionally, compound 1 showed no cytotoxicity, whereas compound 2 exhibited cytotoxic activity against the six tumor cell lines tested, with IC50 values of 9.3 ± 2.8, 27.87 ± 1.78, 48.79 ± 2.56, 37.57 ± 1.65, 27.83 ± 0.48, and 30.37 ± 0.28 µM, respectively. We conclude that endophytic Phoma are promising sources of natural bioactive and novel metabolites.

[Protective effect of Yiqi Mingmu solution on rat's retina with ischemia reperfusion injury].

OBJECTIVE: To investigate the protective effect of the Yiqi Mingmu solution irrigated into rat on retinal injury of rat induced by ischemia reperfusion. METHODS: SD rats were divided into four groups randomly: negative control group, model control group, low and high dose group. Increasing the intraocular pressure with anterior chambers infused liquid induced the models of retinal ischemia reperfusion of rats. Different doses of Yiqi Mingmu solution were respectively irrigated into rats 7 days before ischemia in low and high dose group. Normal salire instead was used in normal and model control group. At 1, 3, 7, 15 days after the ischemia reperfusion injury, the content of MDA and activity of SOD in rat's retina were measured. The histopathologic changes were observed with transmission electron microscopy and light microscopy. RESULTS: At 3, 7, 15 days after the ischemia reperfusion injury, the activity of SOD in Yiqi Mingmu solution low and high dose group were higher than in the model control group, the content of MDA in Yiqi Mingmu solution high dose group were lower than in the model control group. The histopathologic injury of retina in the Yiqi Mingmu solution low and high dose group were less than in the model control group. CONCLUSION: Yiqi Mingmu solution has protective effect on rat's retina ischemia reperfusion injury, and it is an effective traditional Chinese recipe to treat the diseases of retina ischemia.

[Cytotoxic effects of three kinds of eye drops for Chinese herbal medicines on various cell lines in vitro].

OBJECTIVE: To study the cytotoxic effects of three kinds of eye drops on human cancer cells and normal cells. METHODS: Cytotoxic effects of Yuxingcao Eye Drop (YXC), Gegensu Eye Drop (GGS) and Shuanghuanglian Eye Drop (SHL) on 6 cell lines (CNE2, Glc-82, HRPE, Fibro, 3T3 and ECV-304) were assayed using MTF method. And cytotoxic efficacy was evaluated using fifty percent of inhibitory concentration (IC50). RESULTS: IC50 of YXC to human cancer cells CNE2 and Glc-82 were (11.5 +/- 0.25) microl/ml and (24.0 +/- 0.8) microl/ml; to normal cells HRPE, Fibro, 3T3 and ECV-304 were (18.0 +/- 3.5) microl/ml, (52.0 +/- 14.0) microl/ml, (17.5 +/- 3.5) microl/ml and (17.5 +/- 1.3) microl/ml, respectively. IC50 of GGS to CNE2, Glc-82, ECV-304 cells were (9.8 +/- 2.3) microl/ml, (17.0 +/- 5.0) microl/ml and (10.5 +/- 0.95) microl/ml, respectively. Under the concentration of 100 microl/ml, the average survival rates of HRPE, Fibro and 3T3 cells were 60.0%, 87.8% and 58.2%, respectively. IC50 of SHL to CNE2, Glc-82 and HRPE cells were (18.9 +/- 5.0) microl/ ml, (23.9 +/- 0.6) micorl/ml and (113.9 +/- 25.6) microl/ml. At the concentration of 100 microl/ml, the average survival rates of Fibro, 3T3 and ECV-304 Cells were 89.6%, 77.2% and 74.7%. CONCLUSION: YXC has evident cytotoxicities to human cancer cells and normal cells. While, GGS and SHL has not obvious cytotoxic effects to normal cells.