Introduction T oxoplasma gondii is an opportunistic intracellular parasite that is a major pathogenic factor in miscarriage, especially when it occurs early in pregnancy. We have previously demonstrated that the regulation of forkhead box transcription factor (Foxp3) is associated with abortion in early pregnancy caused by excretory-secretory antigen (ESA) of strain China 1. We aimed to reveal the underlying mechanism of miscarriage caused by ESA. Methods A TLR4 −/− pregnant mouse model was successfully constructed. Pregnant mice at gestational day 5 (G5) were injected with ESA. All animals were sacrificed on G13, pregnancy outcomes were observed, and abortion rates were calculated. Placental status observed by Hematoxylin-eosin staining; gene expression was measured by IHC; flow cytometry analysis was used to determine the number and function of regulatory T cells. In EL4 cells, real-time PCR and Western blot were used to evaluate gene expression and cytokines assay. Results In vivo studies revealed that ESA injection caused 83% abortion in pregnant mice but only 35% abortion in TLR4−/− pregnant mice. In addition, ESA attenuated the number and function of regulatory T cells, further suppressed Foxp3, FOXO1 levels, and upregulated CD127 expression. TLR4 −/− mice partially reversed this inhibitory effect on regulatory T cells. Furthermore, in vitro studies revealed that ESA inhibited TLR4/NF-κB signaling pathway expression and that TLR4 agonists significantly restored the ESA-induced decrease in Foxp3. Discussion These findings suggest that ESA suppresses Foxp3 expression by blocking TLR4/NF-κB signaling, resulting in miscarriage. More importantly, the results indicated that miscarriage caused by ESA is TLR4 dependent.
Malignant pleural effusion (MPE) is a common complication of advanced malignancy with a median survival of less than 5 months. Intrapleural injection is the main treatment for MPE, but there are problems such as the concentration of drugs not being durable and stable in the thoracic cavity, limiting therapeutic efficacy, rapid metabolism of drugs leading to systemic toxicity, a single mechanism of drug. Esculentoside A (EsA) exhibits multi-targeted effects that are potentially valuable to improve the immunosuppressive microenvironment in the thoracic cavity and suppress the development of MPE. But the toxicity and short half-life of EsA severely limit its use. We have developed an EsA delivery system based on a temperature-sensitive hydrogel (PLEL) for local treatment of MPE by intrapleural injection. The EsA/PLEL hydrogel supported slow-release of EsA and maintained a stable intrathoracic drug concentration, which not only significantly inhibited the progression of MPE and prolonged survival, but also reduced the side effects of EsA. We found that downregulating of CXCL1/CXCL2/CXCL3-CXCR2 axis expression to reduce tumour-associated macrophages (TAMs) infiltration and tumour angiogenesis was a potential molecular mechanism for EsA/PLEL hydrogel to control lung cancer MPE. Therefore, this EsA/PLEL hydrogel delivery system has high potential for intrapleural injection therapy of MPE.
Gan Qiuping,Wang Benzhi,Chen Judan,Tian Jianniao,Isimjan Tayirjan Taylor,Yang Xiulin
The developing high-efficiency urea fuel cells have an irreplaceable role in solving the increasingly severe environmental crisis and energy shortages. The sluggish six-electron dynamic anodic oxidation reaction is the bottleneck of the rapid progress of urea fuel-cell technology. To tackle this challenge, we select the NiCr bimetallic system due to the unique synergic effect between the Ni and the Cr. Moreover, better conductivity is assured using carbon nanotubes (CNTs) as the support. Most importantly, we use a simple hydrothermal method in catalyst preparation for easy scale-up at a low cost. The results show that the hybrid catalysts of NiCrx-oxide-CNTs with different Ni/Cr ratios show much better catalytic performance in terms of active surface area and current density as compared to that of Ni-hydro-CNTs. The optimized NiCr2-oxide-CNTs catalyst exhibits not only the largest electrochemically active surface area (ESA, 50.7 m2 g−1) and the highest urea electrocatalytic current density (115.6 mA cm−2), but also outstanding long-term stability. The prominent performance of the NiCr2-oxide-CNTs catalyst is due to the combined effect of the improved charge transfer between Ni and Cr species, the large ESA, along with an elegant balance between the oxygen-defect sites and hydrophilicity. Moreover, we have proposed a synergistically enhanced urea catalytic mechanism.
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