Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and hemorrhagic transformation. The ...rapid activation of immune cells plays a critical role in BBB disruption after ischemic stroke. Infiltrating blood-borne immune cells (neutrophils, monocytes, and T lymphocytes) increase BBB permeability, as they cause microvascular disorder and secrete inflammation-associated molecules. In contrast, they promote BBB repair and angiogenesis in the latter phase of ischemic stroke. The profound immunological effects of cerebral immune cells (microglia, astrocytes, and pericytes) on BBB disruption have been underestimated in ischemic stroke. Post-stroke microglia and astrocytes can adopt both an M1/A1 or M2/A2 phenotype, which influence BBB integrity differently. However, whether pericytes acquire microglia phenotype and exert immunological effects on the BBB remains controversial. Thus, better understanding the inflammatory mechanism underlying BBB disruption can lead to the identification of more promising biological targets to develop treatments that minimize the onset of life-threatening complications and to improve existing treatments in patients. However, early attempts to inhibit the infiltration of circulating immune cells into the brain by blocking adhesion molecules, that were successful in experimental stroke failed in clinical trials. Therefore, new immunoregulatory therapeutic strategies for acute ischemic stroke are desperately warranted. Herein, we highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke. Using a robust theoretical background, we discuss potential and effective immunotherapeutic targets to regulate BBB permeability after acute ischemic stroke.
The aim of this study was to investigate the differences in main characteristics, reporting and methodological quality between prospectively registered and nonregistered systematic reviews.
PubMed ...was searched to identify systematic reviews of randomized controlled trials published in 2015 in English. After title and abstract screening, potentially relevant reviews were divided into three groups: registered non-Cochrane reviews, Cochrane reviews, and nonregistered reviews. For each group, random number tables were generated in Microsoft Excel, and the first 50 eligible studies from each group were randomly selected. Data of interest from systematic reviews were extracted. Regression analyses were conducted to explore the association between total Revised Assessment of Multiple Systematic Review (R-AMSTAR) or Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) scores and the selected characteristics of systematic reviews.
The conducting and reporting of literature search in registered reviews were superior to nonregistered reviews. Differences in 9 of the 11 R-AMSTAR items were statistically significant between registered and nonregistered reviews. The total R-AMSTAR score of registered reviews was higher than nonregistered reviews mean difference (MD) = 4.82, 95% confidence interval (CI): 3.70, 5.94. Sensitivity analysis by excluding the registration-related item presented similar result (MD = 4.34, 95% CI: 3.28, 5.40). Total PRISMA scores of registered reviews were significantly higher than nonregistered reviews (all reviews: MD = 1.47, 95% CI: 0.64-2.30; non-Cochrane reviews: MD = 1.49, 95% CI: 0.56-2.42). However, the difference in the total PRISMA score was no longer statistically significant after excluding the item related to registration (item 5). Regression analyses showed similar results.
Prospective registration may at least indirectly improve the overall methodological quality of systematic reviews, although its impact on the overall reporting quality was not significant.
With visible‐light irradiation, a mild, simple, and efficient metal‐free photocatalytic system for the facile construction of sp3–sp3 CC bonds between tertiary amines and activated CH bonds has ...been achieved. Spectroscopic study and product analysis demonstrate for the first time that photoinduced electron transfer from N‐aryl tetrahydroisoquinolines to eosin Y bis(tetrabutylammonium salt) (TBA‐eosin Y) takes place to generate TBA‐eosin Y radical anion, which can subsequently react with nucleophiles and molecular oxygen. More strikingly, electron spin resonance (ESR) measurements provide direct evidence for the formation of superoxide radical anions (O2−.) rather than singlet oxygen (1O2) during visible‐light irradiation. This active species is therefore believed to be responsible for the large rate of acceleration of the aerobic photocatalytic reactions.
Light work: With visible‐light irradiation (λ>450 nm), a mild, simple and efficient metal‐free photocatalytic system for the facile construction of sp3–sp3 CC bonds between tertiary amines and activated CH bonds has been achieved (see scheme). Electron spin resonance measurements offer direct evidence for the formation of superoxide radical anions (O2−.) during visible‐light irradiation.
An iodine‐mediated radical cyclization of o‐vinylaryl isocyanides with disulfides or diselenides was developed. The atom‐economic reaction provides a method for regioselective construction of the ...2‐chalcogenated quinolines in 42–93% yields by incorporation of both chalcogen atoms of disulfides or diselenides into quinolines.
The melt of silicon, hindering nitridation for its agglomeration, should be avoided in the direct nitridation of silicon to synthesize silicon nitride powders, although liquid phase facilitates ...nitridation. Therefore, we proposed a method to nitride molten silicon without agglomeration. Thermogravimetric and in situ Raman studies on the nitridation process of molten silicon were performed. The as‐prepared silicon nitride samples were found to be micron clusters composed of submicron grains with high α‐Si3N4 content. The nitridation of molten silicon at 1500°C was completed after 500 s and 109 times faster than the nitridation of solid silicon at 1350°C. β‐Si3N4 is produced dominantly by α–β‐phase transition. Less nitridation time and low temperature can decrease the β‐Si3N4 content. The rapid nitridation was owning to core–shell structure Si@Si3N4, which was formed after the initial nitridation of silicon particles and hindered the agglomeration of molten silicon.
Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage ...possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.
Umami, as one of the five basic tastes, is important to the taste of food. In this study, gel filtration chromatography and reversed‐phase high‐performance liquid chromatography were used to isolate ...and purify Leccinum extremiorientale cooked at high temperature. Sensory evaluation and taste dilution analysis were used to identify the most umami component in L. extremiorientale. Most umami components were determined by LC‐MS/MS. Three umami peptides were identified, and they were Asp‐Gln‐Glu‐Asp‐Leu‐Asp‐Glu‐Ser‐Leu‐Ile‐Gly‐Val‐Lys (DQEDLDESLIGVK), Phe‐Asn‐Glu‐Ile‐Ile‐Lys‐Glu‐Thr‐Ser‐Thr (FNEIIKETST), Tyr‐Asn‐Glu‐Tyr‐Pro‐Pro‐Leu‐Gly‐Arg (YNEYPPLGR). As far as we know, this is the first time that umami peptides have been extracted from Boletus. This study can provide a basis for the development of delicious food with Boletus characteristics.
Novelty impact statement
Three umami peptides were isolated and purified from Leccinum extremiorientale for the first time. The structure characteristics of the umami peptides were analyzed according to the sequence. The results can provide practical application for the food industry.
Mesenchymal stem/stromal cells (MSCs) have been widely used to treat various inflammatory diseases. The immunomodulatory capabilities of MSCs are usually licensed by inflammatory cytokines and may ...vary depending on the levels and the types of inflammatory cytokines. However, how the inflammatory microenvironment affects the fate of MSCs remains elusive. Here we characterized the molecular mechanism underlying the apoptosis of mouse MSCs triggered by the synergistic action of IFNγ and TNFα.
We isolated and expanded MSCs by flushing the femoral and tibial bone marrow of wild-type, iNOS
, and Fas
mice. BM-MSCs were treated with IFNγ and TNFα in vitro, and cell viability was evaluated by a CCK-8 kit. Apoptosis was assessed by Annexin V/propidium iodide-stained flow cytometry. Expression of genes related to apoptosis and endoplasmic reticulum (ER) stress was measured by reverse transcription-polymerase chain reaction (RT-PCR). Apoptosis and autophagy-related proteins were examined by Western blot analysis.
IFNγ and TNFα synergistically trigger apoptosis of mouse BM-MSCs. The two cytokines were shown to stimulate the expression of inducible nitric oxide synthase (iNOS) and consequently the generation of nitric oxide (NO), which is required for the apoptosis of mouse BM-MSCs. The two cytokines similarly induced apoptosis in Fas
BM-MSCs. iNOS and NO were shown to upregulate Fas in mouse MSCs and sensitize them to Fas agonist-induced apoptosis. Moreover, NO stimulated by IFNγ/TNFα impairs autophagy, which aggravates ER stress and promotes apoptosis.
IFNγ/TNFα-induced apoptosis in mouse MSCs is mediated by NO. Our findings shed new light on cytokine-induced apoptosis of MSCs and have implications in MSC-based therapy of inflammatory diseases.
Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite ...frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR.
Synopsis
Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context.
Sema4D was increased in aqueous fluid of DR patients and in retinas of several mouse DR models.
Sema4D/PlexinB1 signaling induced both endothelial cell and pericyte dysfunction.
Inhibition of Sema4D/PlexinB1 alleviated vascular dysfunction in DR models.
Anti‐Sema4D and anti‐VEGF exhibited a synergistic therapeutic effect.
Retinal pericyte loss, vascular leakage and neovascularization are the main pathological changes during Diabetic Retinopathy (DR). Here we show that Sema4D/PlexinB1 signaling critically contributes to these processes, and is a therapeutic target in this context.
Abstract
Cryptococcosis is a potentially lethal disease that is primarily caused by the fungus
Cryptococcus neoformans
, treatment options for cryptococcosis are limited. Here, we show ...glucuronoxylomannan, the major polysaccharide component of
C. neoformans
, induces the recruitment of neutrophilic myeloid-derived suppressor cells in mice and patients with cryptococcosis. Depletion of neutrophilic myeloid-derived suppressor cells enhances host defense against
C. neoformans
infection. We identify C-type lectin receptor-2d recognizes glucuronoxylomannan to potentiate the immunosuppressive activity of neutrophilic myeloid-derived suppressor cells by initiating p38-mediated production of the enzyme arginase-1, which inhibits T-cell mediated antifungal responses. Notably, pharmacological inhibition of arginase-1 expression by a specific inhibitor of p38, SB202190, or an orally available receptor tyrosine kinase inhibitor, vandetanib, significantly enhances T-cell mediated antifungal responses against cryptococcosis. These data reveal a crucial suppressive role of neutrophilic myeloid-derived suppressor cells during cryptococcosis and highlight a promising immunotherapeutic application by inhibiting arginase-1 production to combat infectious diseases.
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