Theoretical insight into the single-atom catalytic mechanism of CeO2-supported Ag catalysts in CO oxidation.

Revealing the accurate active center structure and the functional mechanism of CeO2-supported Ag catalysts during catalysis is extremely important for their accurate synthesis. In this work, a series of AgnCeO2 (n = 1, 2, 3, 4 and 10) model catalysts was constructed, and a DFT investigation of the reaction mechanism of CO oxidation, as a probe reaction on those catalysts, was carried out. It was found that the entire catalytic reaction was completed coordinately by Ag, lattice O and O vacancies, which could be considered as the active centers. Noticeably, the mobility of Ag atoms played an important role in the reaction process, leading to the observation of a single-atom catalytic mechanism, wherein a series of single Ag atomic species was formed during the reaction, which was beneficial to CO oxidation. With the completion of some elementary reactions, the single Ag formed during the migration of CO-Ag could return to the Ag cluster again. As expected, the single-AgCeO2 catalyst exhibited extremely high activity due to the absence of the binding effect of Ag-Ag. Nevertheless, the AgnCeO2 (n > 1) catalysts showed similar catalytic activity, which was slightly worse than that of single AgCeO2, indicating that the size effect of the Ag cluster was not obvious. These results provide the theoretical basis for further understanding the functional mechanism of the AgnCeO2 catalyst and are helpful for designing various catalysts with tailored functionalities.

Clopidogrel reduces lipopolysaccharide-induced inflammation and neutrophil-platelet aggregates in an experimental endotoxemic model.

Platelet activation contributes to organs failure in inflammation and plays an important role in endotoxemia. Clopidogrel inhibits platelet aggregation and activation. However, the role of clopidogrel in modulating inflammatory progression of endotoxemia remains largely unexplored. Therefore, we investigated the role of clopidogrel on the activation of platelet and leukocytes in lipopolysaccharide (LPS)-induced inflammation in mice. Animals were treated with clopidogrel or vehicle before LPS induction. The expression of neutrophil-platelet aggregates and platelet activation and tissue factor was determined. Immunofluorescence was used to analyze platelet-leukocyte interactions and tissue factor (TF) expression on leukocytes. Clopidogrel pretreatment markedly decreased lung damage, inhibited platelet-neutrophil aggregates and TF expression. In addition, clopidogrel reduced thrombocytopenia and affected the number of circulating white blood cell in endotoxemia mice. Moreover, clopidogrel also reduced platelet shedding of CD40L and CD62P in endotoxemic mice. Taken together, clopidogrel played an important role through reducing platelet activation and inflammatory process in endotoxemia.

Simultaneous Trapping of C2 H2 and C2 H6 from a Ternary Mixture of C2 H2 /C2 H4 /C2 H6 in a Robust Metal-Organic Framework for the Purification of C2 H4.

The removal of C2 H2 and C2 H6 from C2 H4 streams is of great significance for feedstock purification to produce polyethylene and other commodity chemicals but the simultaneous adsorption of C2 H6 and C2 H2 over C2 H4 from a ternary mixture has never been realized. Herein, a robust metal-organic framework, TJT-100, was designed and synthesized, which demonstrates remarkably selective adsorption of C2 H2 and C2 H6 over C2 H4 . Breakthrough experiments show that TJT-100 can be used as an adsorbent for high-performance purification of C2 H4 from a ternary mixture of C2 H2 /C2 H4 /C2 H6 (0.5:99:0.5) to afford a C2 H4 purity greater than 99.997 %, beyond that required for ethylene polymerization. Computational studies reveal that the uncoordinated carboxylate oxygen atoms and coordinated water molecules pointing towards the pore can trap C2 H2 and C2 H6 through the formation of multiple C-H⋅⋅⋅O electrostatic interactions, while the corresponding C2 H4 -framework interaction is unfavorable.

The arginine methyltransferase PRMT5 promotes mucosal defense in the intestine.

PRMT5 is a type II arginine methyltransferase abundantly expressed in the colonic epithelium. It is up-regulated in inflammatory bowel disease and colorectal cancer. However, its role in mucosal defense against enteric infection has not been studied. Here, we report that Prmt5 in the murine colon is up-regulated in response to Citrobacter rodentium infection. Pathogen clearance in mice with haploinsufficient expression of Prmt5 is significantly delayed compared with wildtype littermate controls. Transcriptomic analyses further reveal that PRMT5 regulates the expression of canonical crypt goblet cell genes involved in mucus production, assembly, and anti-microbial responses via methyltransferase activity-dependent and -independent mechanisms. Together, these findings uncover PRMT5 as a novel regulator of mucosal defense and a potential therapeutic target for treating intestinal diseases.

HSF1 Alleviates Microthrombosis and Multiple Organ Dysfunction in Mice with Sepsis by Upregulating the Transcription of Tissue-Type Plasminogen Activator.

Sepsis is a life-threatening complication of infection closely associated with coagulation abnormalities. Heat shock factor 1 (HSF1) is an important transcription factor involved in many biological processes, but its regulatory role in blood coagulation remained unclear. We generated a sepsis model in HSF1-knockout mice to evaluate the role of HSF1 in microthrombosis and multiple organ dysfunction. Compared with septic wild-type mice, septic HSF1-knockout mice exhibited a greater degree of lung, liver, and kidney tissue damage, increased fibrin/: fibrinogen deposition in the lungs and kidneys, and increased coagulation activity. RNA-seq analysis revealed that tissue-type plasminogen activator (t-PA) was upregulated in the lung tissues of septic mice, and the level of t-PA was significantly lower in HSF1-knockout mice than in wild-type mice in sepsis. The effects of HSF1 on t-PA expression were further validated in HSF1-knockout mice with sepsis and in vitro in mouse brain microvascular endothelial cells using HSF1 RNA interference or overexpression under lipopolysaccharide stimulation. Bioinformatics analysis, combined with electromobility shift and luciferase reporter assays, indicated that HSF1 directly upregulated t-PA at the transcriptional level. Our results reveal, for the first time, that HSF1 suppresses coagulation activity and microthrombosis by directly upregulating t-PA, thereby exerting protective effects against multiple organ dysfunction in sepsis.

Electrochemical reduction of functionalized carbonyl compounds: enhanced reactivity over tailored nanoporous gold.

The effect of the pore size of nanoporous gold on electrochemical reduction of functionalized carbonyl compounds was investigated. NPG with a pore size of ∼30 nm significantly enhanced the reactivity with high chemo-selectivity at a low-potential. Typically, p-nitrobenzaldehyde reduction demonstrates a high turnover frequency (TOF) up to 232 000 h-1.

Anodically Triggered Aldehyde Cation Autocatalysis for Alkylation of Heteroarenes.

Alkylation of heteroarenes by using aldehydes is a direct approach to increase molecular complexity, which however often involves the use of stochiometric oxidant, strong acid, and high temperature. This study concerns an energy-efficient electrochemical alkylation of heteroarenes by using aldehydes under mild conditions without mediators. Interestingly, the graphite anode can trigger aldehyde cationic species, which act as the effective autocatalysts to react with a range of heteroarenes to produce the corresponding products with excellent regioselectivity and in high yields. Compared to the traditional electro-synthesis approaches, this electro-triggered reaction provides an electricity-saving and eco-friendly route to high-value chemicals.

The direct trifluoromethylsilylation and cyanosilylation of aldehydes via an electrochemically induced intramolecular pathway.

The initiator-free electrochemical trifluoromethylsilylation and cyanosilylation of aldehydes were developed in an undivided cell. A DFT study reveals that the direct cathodic activation of trimethylsilyl reagents significantly released the congestion around the 'Si' atom, allowing the Si-O bond affinity to form concerted anion intermediates with aldehydes. Thus, intramolecular -CF3 and -CN migration make the reactions much easier to carry out without initiators.

Inhibition of Aerobic Glycolysis Promotes Neutrophil to Influx to the Infectious Site Via CXCR2 in Sepsis.

Recent evidences suggest that metabolic reprogramming plays an important role in the regulation of innate inflammatory response; however, the specific mechanism is unclear. In this study, we found that glycolytic inhibitor 2-deoxyglucose (2-DG) significantly improved the survival rate in cecal ligation and puncture (CLP)-induced septic mice. 2-DG-treated mice developed increased neutrophil migration to the infectious site and more efficient bacterial clearance than untreated mice. 2-DG reversed the down-regulation of chemokine receptor 2 (CXCR2) and the impaired chemotaxis induced by CLP in mice or lipopolysaccharides (LPS) in human neutrophils. Furthermore, 2-DG reversed the down-regulation of CXCR2 in neutrophils by decreasing the expression of G protein-coupled receptor kinase-2 (GRK2), a serin-threonine protein kinase that mediated the internalization of chemokine receptors, which was induced via the inhibition of extracellular regulated protein kinases (ERK) phosphorylation and the promotion of P38 phosphorylation. Finally, SB225002, a CXCR2 antagonist, partially blocked the protective effects of 2-DG in sepsis. Together, we found a novel mechanism for the migration of neutrophils regulated by metabolism and suggested that aerobic glycolysis might be a potential target of intervention in sepsis.

The role of PSGL-1 in pathogenesis of systemic inflammatory response and coagulopathy in endotoxemic mice.

INTRODUCTION: Endotoxemia often results in systemic inflammatory response syndrome (SIRS), coagulation disturbance and acute lung injury (ALI), and such a condition is associated with the activation of platelets, leukocytes and vascular endothelial cells (VECs). P-selectin glycoprotein ligand 1 (PSGL-1) is a key regulatory molecule in the activation of platelets, leukocytes and VECs. However, it still remains largely unexplored whether PSGL-1 plays an important role in SIRS, coagulation dysfunction and ALI of endotoxemia. In the present study, we aimed to study the role of PSGL-1 in above-mentioned situations using endotoxemic mice. MATERIALS AND METHODS: An endotoxemia model was established in BALB/c mice via lipopolysaccharide (LPS) administration. Moreover, the mice were simultaneously injected with PSGL-1 antibody for intervention. The survival rate, morphologic changes of lung tissues, platelet-leukocyte adhesion, tissue factor expression on leukocytes, fibrinogen deposition in lung tissues, serum levels of inflammatory factors and the activation of VECs were determined. RESULTS: The results showed that the aggregation and recruitment of platelets and leukocytes in lung tissues, the expression of tissue factor on leukocytes, the serum levels of inflammatory factors, the activation of VECs, and the fibrinogen deposition in lung tissues were increased in endotoxemic mice, which were significantly alleviated by administration of PSGL-1 antibody. Moreover, blockade of PSGL-1 markedly increased survival rate, and alleviated coagulation disturbance and lung injury in endotoxemic mice. CONCLUSIONS: Taken together, PSGL-1 played an important role in pathogenesis of SIRS and coagulation dysfunction and ALI in endotoxemic mice.

Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome.

OBJECTIVES: We sought to characterize the effects of clopidogrel on the activation of circulating platelets, the activation and aggregation of ex vivo platelets, and the interactions with leukocytes in patients with a non-ST-segment elevation in acute coronary syndromes (ACS). BACKGROUND: The significant benefits of clopidogrel in cardiovascular trials suggest that blockage of the P2Y(12) receptor may be associated with important biologic consequences. METHODS: Blood samples obtained from 23 ACS patients before and 24 h after a loading dose of clopidogrel (300 mg) were analyzed by whole-blood flow cytometry, light transmission aggregometry in platelet-rich plasma, and plasma enzyme-linked immunoassays. A thrombin receptor agonist peptide (TRAP) and adenosine diphosphate (ADP) were used as agonists. Normal individuals pretreated with aspirin served as controls. RESULTS: Clopidogrel attenuated platelet aggregation to both ADP (10 micromol/l) and TRAP (10 micromol/l) by 22% and P-selectin expression by 16% and 25%, respectively. The drug decreased the excess platelet-monocyte and platelet-neutrophil conjugates found in the blood of ACS patients (p < 0.01) and prevented their formation ex vivo with agonist stimulation. Plasma levels of soluble CD40L were reduced by 27% (p < 0.001) and of soluble P-selectin by 15% (p < 0.001). CONCLUSIONS: Clopidogrel attenuates the agonist effects of ADP and TRAP on platelet secretion, aggregation, and formation of platelet-monocyte and platelet-neutrophil conjugates in patients with ACS. These effects may all contribute to the clinical benefits of the drug in these syndromes.

ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME.

Endostatin is an endogenous inhibitor of vascular endothelium. It can inhibit endothelial cell migration, proliferation, and vascular angiogenesis and is mainly used for anticancer therapy. We have previously found that endostatin is an important node protein in the pathogenesis of sepsis. However, its impacts on sepsis have not yet been reported. We established a septic mouse model using cecal ligation and puncture (CLP) and gave the mice either endostatin or placebo (saline). The effects of endostatin on serum enzyme, Evans blue leakage, lung wet-to-dry weight ratio, and cytokine (tumor necrosis factor α, interleukin 1ß [IL-1ß], and IL-6) production were assessed. Survival rates were observed for up to 3 days. In addition, we examined the effects of endostatin on serum vascular endothelial growth factor A (VEGF-A), VEGF-C, and pathological changes and scores of lung tissues as well as the phosphorylation of JNK, p38, and ERKl/2 proteins in lung tissues of mice with sepsis. We found that endostatin can increase the survival of septic mice in a time- and dose-dependent manner probably by reducing multiorgan dysfunctions shown by serum indicators, morphologic changes, Evans blue leakage, wet-to-dry weight ratio, and inflammation of lung tissues. In addition, endostatin could reduce serum tumor necrosis factor α, IL-1ß, IL-6, and VEGF-C levels in septic mice as well as inhibit phosphorylation of p38 and ERK1/2 in lung tissues of septic mice. This is the first study demonstrating the protective effect of endostatin on sepsis and its possible underlying mechanisms from the aspects of inhibiting inflammatory responses, blocking VEGF receptor, attenuating VEGF-C expression, and reducing vascular permeability. Overall, the study revealed the potential protect role for endostatin in the treatment of sepsis.

Identification of potential biomarkers by serum proteomics analysis in rats with sepsis.

This study was aimed to find new biomarkers for diagnosis and prediction of prognosis of sepsis. Serum samples from nonsurvivor, survivor, and control groups were obtained at 12 h after the induction of sepsis and labeled with isobaric tags (iTRAQ) and then analyzed by two-dimensional liquid chromatography and tandem mass spectrometry. Protein identification and quantification were obtained using mass spectrometry and the ProteinPilot software. Bioinformatics annotation was performed by searching against the PANTHER database. Enzyme-linked immunosorbent assays were used to further confirm the protein identification and differential expression. A logistic regression was then used to screen the index set for diagnosis and prognosis of sepsis. We found that 47 proteins were preferentially elevated in septic rats (both nonsurvivors and survivors) compared with the control rats, and 28 proteins were preferentially elevated in the NS rats as compared with the S group. Several biomarkers, such as multimerin 1, ficolin 1, carboxypeptidase N (CPN2), serine protease 1, and platelet factor 4, were tightly correlated with the diagnosis of sepsis. Logistic regression analyses established multimerin 1, pro-platelet basic protein, fibrinogen-α, and fibrinogen-ß for prognosis of sepsis.

Mipu1, a novel direct target gene, is involved in hypoxia inducible factor 1-mediated cytoprotection.

Mipu1 (myocardial ischemic preconditioning up-regulated protein 1), recently identified in our lab, is a novel zinc-finger transcription factor which is up-regulated during ischemic preconditioning. However, it is not clear what transcription factor contributes to its inducible expression. In the present study, we reported that HIF-1 regulates the inducible expression of Mipu1 which is involved in the cytoprotection of HIF-1α against oxidative stress by inhibiting Bax expression. Our results showed that the inducible expression of Mipu1 was associated with the expression and activation of transcription factor HIF-1 as indicated by cobalt chloride (CoCl2) treatment, HIF-1α overexpression and knockdown assays. EMSA and luciferase reporter gene assays showed that HIF-1α bound to the hypoxia response element (HRE) within Mipu1 promoter region and promoted its transcription. Moreover, our results revealed that Mipu1 inhibited the expression of Bax, an important pro-apoptosis protein associated with the intrinsic pathway of apoptosis, elevating the cytoprotection of HIF-1 against hydrogen peroxide (H2O2)-mediated injury in H9C2 cells. Our findings implied that Bax may be a potential target gene of transcription factor Mipu1, and provided a novel insight for understanding the cytoprotection of HIF-1 and new clues for further elucidating the mechanisms by which Mipu1 protects cell against pathological stress.