Jinchao Hou

Transient Receptor Potential Melastatin 2 Protects Mice against Polymicrobial Sepsis by Enhancing Bacterial Clearance

Background:Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear. Methods:The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture–induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results:After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca2+ influx plays an important role in lipopolysaccharide or cecal ligation and puncture–induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow–derived macrophages and in cecal ligation and puncture–induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow–derived macrophages. Pretreatment of Trpm2-knockout bone marrow–derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001). Conclusion:The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.

Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis.

Background:Sepsis is characterized by an inappropriate systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Sphingosine 1-phosphate receptor 2 (S1PR2) modulates endotoxin-induced inflammation in endothelium. However, as a highly expressed S1P receptor in macrophages, its role in regulating macrophage response to bacterial infection remains unclear. Methods:Cecal ligation and puncture or intratracheal instillation of Escherichia coli was induced in wild-type or S1pr2-deficient mice. The antibacterial ability of cell-specific S1PR2 was tested in bone marrow reconstitution mice or mice with macrophage-specific deletion. Signaling molecules responsible for S1PR2-mediated phagocytosis were also measured in the bone marrow–derived macrophages. In addition, S1PR2 expression levels and its correlation with severity of sepsis were determined in critically ill patients (n = 25). Results:Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival (genetic deletion, 0% in S1pr2+/+ vs. 78.6% in S1pr2−/−, P < 0.001; pharmaceutical inhibition, 9.1% in vehicle vs. 22.2% in S1PR2 antagonist, P < 0.05). This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages (mean fluorescent intensity, 2035.2 ± 202.1 vs. 407.8 ± 71.6, P < 0.001). Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, whose signaling pathways depend on extracellular stimulators. In septic patients, increased S1PR2 levels in peripheral blood mononuclear cells were positively correlated with the severity of sepsis (r = 0.845, P < 0.001). Conclusions:This study implies that S1PR2, as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as promising therapeutic approaches for sepsis.

Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte from Apoptosis through Regulation of Myeloid Cell Leukemia-1

Background:Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. Methods:Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. Results:Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. Conclusions:TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal–regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1–mediated hyperinflammatory response in monocytes.

S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis

Rationale: Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine‐1‐phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. Objectives: To investigate the role of S1PR3 in antibacterial immunity during sepsis. Methods: Loss‐ and gain‐of‐function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. Measurements and Main Results: S1PR3 protein levels were up‐regulated in macrophages upon bacterial stimulation. S1pr3−/− mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild‐type bone marrow‐derived macrophages rescued S1pr3−/− mice from lethal sepsis. S1PR3‐overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3−/− macrophages due to impaired recruitment of vacuolar protein‐sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. Conclusions: S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

Tai Chi Exercise for Patients with Chronic Heart Failure: A Meta-analysis of Randomized Controlled Trials.

Aim This meta-analysis aimed to update and evaluate evidence from randomized controlled trials of tai chi for patients with chronic heart failure. Method Both English and Chinese databases were searched from their inception to June 2, 2016 (PubMed, EMBASE, Cochrane Central Register of Controlled Trials for English publications and China Knowledge Resource Integrated, Wanfang, and Weipu databases for Chinese publication). Titles, abstracts, and full-text articles were screened against study inclusion criteria: randomized controlled trials studying tai chi intervention for patients with chronic heart failure. The meta-analysis was conducted with Revman 5.3 or STATA 12. Result Thirteen randomized controlled trials were included. Tai chi induced significant improvement in 6-min walking distance (51.01 m; 30.49–71.53; P < 0.00). Moreover, tai chi was beneficial for quality of life (−10.37 points; −14.43 to −6.32; P = 0.00), left ventricular ejection fraction (7.72%; 3.58–11.89; P = 0.003), and B-type natriuretic peptide (−1.01; −1.82 to −0.19; P = 0.02). Conclusion Despite heterogeneity and risk of bias, this meta-analysis further confirms that tai chi may be an effective cardiac rehabilitation method for patients with chronic heart failure. Larger, well-designed randomized controlled trials are needed to exclude the risk of bias.

Pharmacist-driven antimicrobial stewardship in intensive care units in East China: A multicenter prospective cohort study

HighlightsPharmacist‐driven antimicrobial stewardship was a protect factor for mortality.The strategy had a lower rate of the emergence of multidrug‐resistant organisms.The strategy optimised antimicrobial use in ICUs in China.The strategy need a large‐scale implementation in ICUs in China. Background: Antimicrobial stewardship programs, particularly pharmacist‐driven programs, help reduce the unnecessary use of antimicrobial agents. The objective of this study was to assess the influence of pharmacist‐driven antimicrobial stewardship on antimicrobial use, multidrug resistance, and patient outcomes in adult intensive care units in China. Method: We conducted a multicenter prospective cohort study with a sample of 577 patients. A total of 353 patients were included under a pharmacist‐driven antimicrobial stewardship program, whereas the remaining 224 patients served as controls. The primary outcome was all‐cause hospital mortality. Results: The pharmacist‐driven antimicrobial stewardship program had a lower hospital mortality rate compared with the nonpharmacist program (19.3% vs 29.0%; P = .007). Furthermore, logistic regression analysis indicated that the pharmacist‐driven program independently predicted hospital mortality (odds ratio, 0.57; 95% confidence interval, 0.36‐0.91; P = .017) after adjustment. Meanwhile, this strategy had a lower rate of multidrug resistance (23.8% vs 31.7%; P = .037). Moreover, the strategy optimized antimicrobial use, such as having a shorter duration of empirical antimicrobial therapy (2.7 days; interquartile range [IQR], 1.7‐4.6 vs 3.0; IQR, 1.9‐6.2; P = .002) and accumulated duration of antimicrobial treatment (4.0; IQR, 2.0‐7.0 vs 5.0; IQR, 3.0‐9.5; P = .030). Conclusions: Pharmacist‐driven antimicrobial stewardship in an intensive care unit decreased patient mortality and the emergence of multidrug resistance, and optimized antimicrobial agent use.

Sphingosine-1-phosphate Receptor 2 Signaling Promotes Caspase-11–dependent Macrophage Pyroptosis and Worsens Escherichia coli Sepsis Outcome

What We Already Know about This TopicNo molecular-targeted treatments for sepsis have proved successful in humans. The role of sphingosine-1-phosphate receptor 2 (S1PR2) signaling in sepsis is uncertain. What This Article Tells Us That Is NewIn an in vivo mouse model of Gram-negative sepsis, deletion of the gene for sphingosine-1-phosphate receptor 2 (S1PR2) reduced pyroptosis, possibly by decreased activation of caspase-11, and increased survival. S1PR2 and caspase-11 may be testable targets in sepsis. Background: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11–dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1&bgr; secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11–dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome. Methods: A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2-/-), or nucleotide-binding oligomerization domain-like receptor protein-3–deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11). Results: Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2-/-, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 ± 3% in wild-type vs. 10 ± 3% in S1pr2-/-, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035). Conclusions: S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis.

Self-Assembling Myristoylated Human α-Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human α-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity in vitro. Mechanistically, it selectively killed Escherichia coli ( E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The in vivo results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent in vivo tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance.

Mindfulness Meditation for Primary Headache Pain: A Meta-Analysis

Background: Several studies have reported that mindfulness meditation has a potential effect in controlling headaches, such as migraine and tension-type headache; however, its role remains controversial. This review assessed the evidence regarding the effects of mindfulness meditation for primary headache pain. Methods: Only English databases (PubMed, Cochrane Central Register of Controlled Trials [the Cochrane Library], PsycINFO, Psychology and behavioral science collection, PsyArticles, Web of Science, and Scopus) were searched from their inception to November 2016 with the keywords (“meditation” or “mindfulness” or “vipassana” or “dzogchen” or “zen” or “integrative body-mind training” or “IBMT” or “mindfulness-based stress reduction” or “MBSR” or “mindfulness-based cognitive therapy” or “MBCT” and “Headache” or “Head pain” or “Cephalodynia” or “Cephalalgia” or “Hemicrania” or “Migraine”). Titles, abstracts, and full-text articles were screened against study inclusion criteria: controlled trials of structured meditation programs for adult patients with primary headache pain. The quality of studies included in the meta-analysis was assessed with the Yates Quality Rating Scale. The meta-analysis was conducted with Revman 5.3. Results: Ten randomized controlled trials and one controlled clinical trial with a combined study population of 315 patients were included in the study. When compared to control group data, mindfulness meditation induced significant improvement in pain intensity (standardized mean difference, −0.89; 95% confidence interval, −1.63 to −0.15; P = 0.02) and headache frequency (−0.67; −1.24 to −0.10; P = 0.02). In a subgroup analysis of different meditation forms, mindfulness-based stress reduction displayed a significant positive influence on pain intensity (P < 0.000). Moreover, 8-week intervention had a significant positive effect (P < 0.000). Conclusions: Mindfulness meditation may reduce pain intensity and is a promising treatment option for patients. Clinicians may consider mindfulness meditation as a viable complementary and alternative medical option for primary headache.