Integrating source apportionment and landscape patterns to capture nutrient variability across a typical urbanized watershed.

Effective integrated watershed management requires models that can characterize the sources and transport processes of pollutants at the watershed with multiple landscape patterns. However, few studies have investigated the influence of landscape spatial configuration on pollutant transport processes. In this study, the SPARROW_TN and SPARROW_TP models were constructed by combining direct pollution source data and landscape pattern data to investigate the source composition and nutrient transport processes and to reveal the influence of landscape patterns on nutrient transport in the urbanized Beiyun River Watershed. The introduction of landscape metrics significantly improved the simulation results of both models, with R2 increasing from 0.89 to 0.85 to 0.93 and 0.91, respectively. Spatial variations existed in TN and TP loads and yields, as well as the source compositions. Pollution hotspots were effectively identified. Source apportionment showed that for the entire watershed, TN came from atmospheric nitrogen deposition (35.25%), untreated sewage (28.23%), agricultural sources (22.60%), and treated sewage (13.92%). In comparison, TP came from untreated sewage (44.94%), agricultural sources (40.22%), and treated sewage (11.51%). In addition, the largest patch index of grassland correlated positively with both TN and TP, whereas the largest shape index of buildup land and interspersion and juxtaposition index of forest were negatively correlated with TN and TP, respectively. The results of this study will provide insight into effective nutrient control measures that consider spatially varying nutrient sources and associated nutrient transport processes.

CD19+CD24hiCD38hi regulatory B cells deficiency revealed severity and poor prognosis in patients with sepsis.

BACKGROUND: Sepsis still remains a major challenge in intensive care medicine with unacceptably high mortality among patients with septic shock. Due to current limitations of human CD19+CD24hiCD38hi Breg cells (Bregs) studies among sepsis, here, we tried to evaluate Bregs in severity and prognostic value in patients with sepsis. METHODS: Peripheral blood from 58 patients with sepsis and 22 healthy controls was analyzed using flow cytometry to evaluate the frequency and number of Bregs. All cases were divided into non-survived or survived group after 28 days followed up. Spearman's correlation analysis was performed on Bregs frequency and clinical indices. The area under the curve was acquired using the receiver operating characteristic analysis to assess the sensitivity and specificity of Bregs for outcome of sepsis. Survival curve analysis and binary logistic regression were applied to estimate the value of Bregs in prognosis among cases with sepsis. RESULTS: Sepsis patients had decreased proportions and number of Bregs. Sepsis patients with low frequency of Bregs were associated with an increased risk of septic shock. Bregs frequency is inversely associated with lactate, SOFA, and APACHE II and positively correlated with Tregs frequency. Low levels of Bregs closely correlated with septic outcomes. Numbers of Bregs were prediction factors for poor prognosis. CONCLUSIONS: Frequency and number of Bregs decreased, and Bregs deficiency revealed poor prognosis in patients with sepsis.

Impaired Circulating Antibody-Secreting Cells Generation Predicts the Dismal Outcome in the Elderly Septic Shock Patients.

Purpose: Sepsis is a condition that derives from a dysregulated host response to infection. Although B lymphocytes play a pivotal role in immune response, little is known about status of their terminally differentiated cells, antibody-secreting cells (ASCs) during immunosuppressive phase of sepsis, especially in elderly patients. Our aim was to extensively characterize the immune functions of ASCs in elderly septic patients. Patients and Methods: Clinical and laboratory data were collected on days 1, 3, and 7 of hospitalization. Circulating ASCs were evaluated by flow cytometry from fresh whole blood in elderly septic patients at the onset of disease. RNA sequencing analyzed ASCs gene expression profile. Receiver operating characteristic (ROC) curve analysis and logistic regression predicted the survival rate of 28-day mortality. Results: A total of 103 septic patients were enrolled. The number and proportion of ASCs among total lymphocytes dramatically increased in septic patients, and RNA sequencing analysis showed that ASCs from septic patients exhibited a different gene expression profile. Furthermore, we found these ASCs could promote the function of T cells. Logistic regression analysis showed ASCs population was an independent outcome predictor in septic shock patients. Conclusion: Our study revealed the complex nature of immune disorders in sepsis and identified circulating ASCs population as a useful biomarker for predicting mortality in elderly septic patients, which provided a novel clue to combat this severe disease.

Engineering dual catalytic nanomedicine for autophagy-augmented and ferroptosis-involved cancer nanotherapy.

Chemodynamic therapy represents a distinct anti-tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts. However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated copper peroxide nanodots (CPNs) and artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H2O2 self-supplying platform, release H2O2 and Cu2+ under acidic tumor environment and endogenously generate .OH via Fenton-like reaction (catalytic reaction I). In addition, Cu2+ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and lipid peroxide accumulation, leading to cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular iron pool through degradation of ferritin, which could promote cancer cell ferroptosis, producing the best antineoplastic effect. After accumulation into the tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing tumor growth by autophagy-augmented ferroptosis-involved cancer nanotherapy.

B cell subsets were associated with prognosis in elderly patients with community acquired pneumonia.

BACKGROUND: The role of B cell subsets remained to be elucidated in a variety of immune diseases, though which was used as an effective biomarker for anti-inflammatory or antiviral response. This study aimed to evaluate the early changes of B cell subtypes distribution in elderly patients with community acquired pneumonia (CAP), as well as the association between B cell subtypes and prognosis. METHODS: This prospective study included elderly patients with CAP, severe CAP (sCAP) and healthy elderly subjects between April 2016 and March 2018. Flow cytometry was used to detect CD3, CD20, HLA-DR, CD24, CD27, CD38, IgM, and IgD. CD20+ B cells were further divided into naïve B cells (Bn), IgM/D+ memory B cells (IgM+ Bm), switched B cells (SwB), and transitional B cells (Btr). RESULTS: A total of 22 healthy controls, 87 patients with CAP and 58 patients with sCAP were included in the study. Compared to CAP, sCAP was characterized by significantly lower absolute number of B cells, Bn and Btr, significantly lower Btr and Bn subset percentage, while percentage of IgM+ Bm was significantly higher. Heat map showed Bn and Btr on day 3 and day 7 was negatively correlated with activated partial prothrombin time (APTT), international normalized ratio (INR), sequential organ failure assessment score (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II). After 28-day follow-up, Btr percentage in survival group was significantly higher. Receiver operator characteristic (ROC) curve analysis found that Btr count showed sensitivity of 48.6% and specificity of 87.0% for predicting the 28-day survival, with an area under the ROC curves of 0.689 (p = 0.019). CONCLUSIONS: Severity and prognosis of CAP in elderly people is accompanied by changes in the B cell subsets. Btr subsets could play prognostic role for a short-term mortality of elderly CAP patients.

Bubble-assisted HIFU ablation enabled by calcium peroxide.

High intensity focused ultrasound (HIFU), as one of the most advanced and preferred cancer treatment modes, has shown great promise due to its minimal invasiveness and irradiation-free nature. However, a key limiting factor for its further clinical application is its relatively low therapeutic potency. In this study, CaO2@SiO2 NPs were developed for efficient O2 bubble-assisted HIFU surgery against tumors. After entering the tumor sites, these nanoparticles can release O2 and H2O2, achieving enhancement of US imaging signals and improved potency of HIFU surgery. In addition, local temperature increase during HIFU treatment could trigger O2 generation by the conversion of unstable H2O2 into O2 gas, further augmenting the efficacy of HIFU treatment. This work not only provides a paradigm of CaO2 for cancer management in nanomedicine, but also presents an efficient way for bubble-enhanced HIFU surgery.

Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype.

BACKGROUND: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood. METHODS: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA. RESULTS: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking EMT through TGF-ß1/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed the epithelial to mesenchymal transition (EMT) in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-ß1, TGF-ßR1, Smad2 while up-regulation of Smad7 expression. CONCLUSIONS: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS.

Lymphocyte expression of EZH2 is associated with mortality and secondary infectious complications in sepsis.

Recent studies have shown that epigenetic factors may affect immune responses. We previously reported that histone methyltransferase enhancer of zeste homolog 2 (EZH2) was involved in the innate inflammatory responses both in animal model of sepsis and in septic patients. In this study, we prospectively evaluated EZH2 expression kinetics in peripheral CD4+ and CD8+ T cells and HLA-DR expression in CD14+ cells from 48 patients with sepsis and 48 healthy controls. Results showed higher level of EZH2 in CD4+ T cells and CD8+ T cells in sepsis patients than in controls. Meanwhile, EZH2 expression was correlated with CD27 status on T cells. Mean fluorescence intensity (MFI) of EZH2 in CD8+ T cells on day 1 independently predicted death in septic patients. Also, the combination of CD8+ T cell EZH2 expression with APACHEII and SOFA score could enhance the prognostic predictive ability. Moreover, multivariate logistic regression analysis showed that increased expression (proportion and MFI) of EZH2 in CD4+ and CD8+ lymphocytes on day 3 were independently associated with nosocomial infection in septic patients. Additionally, spearman correlation analysis indicated that the levels of EZH2 in CD4+ T cells and CD8+ T cells correlated to CD14+ cells-expressing HLA-DR in patients with sepsis at each time point. Overall, these findings suggest that EZH2 in CD4+ T cells or/and CD8+ T cells may be a novel biomarker for predicting adverse outcomes (mortality and secondary infectious complications) in patients with sepsis.

Blockade of endothelial, but not epithelial, cell expression of PD-L1 following severe shock attenuates the development of indirect acute lung injury in mice.

This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post-septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1-driven pathological changes resulting from systemic stimuli such as Hem-CLP.

miR-205 Suppresses Pulmonary Fibrosis by Targeting GATA3 Through Inhibition of Endoplasmic Reticulum Stress.

OBJECTIVE: To investigate the role of miR-205 and GATA3 in Pulmonary Fibrosis (PF). METHODS: Bleomycin (BLM) was used to induce PF in SD rats and in vitro PF model was established by using TGFß1-induced RLE-6TN cells. miR-205 mimics were used for the overexpression of miR- 205. The expression of miR-205, GATA3, α-SMA, Collagen I, CHOP and GRP78 were measured using RT-qPCR or western blotting. Dual-luciferase reporter assay was used to confirm binding between GATA3 3'-UTR and miR-205. RESULTS: The expression of miR-205 was significantly down-regulated, while the expression of GATA3 was remarkably up-regulated in the model rats. GATA3 levels were remarkably decreased when miR-205 was overexpressed. When miR-205 was overexpressed, the lung injury by BLM-induced fibrosis was improved. The expression of α-SMA, Collagen I, as well as GRP78 and CHOP, was significantly up-regulated in both in vivo and in vitro PF models, and overexpression of miR-205 remarkably reversed the effects. Dual-luciferase reporter assay showed that miR-205 directly targeted and negatively regulated GATA3. CONCLUSION: miR-205 improved pulmonary fibrosis through inhibiting ER-stress by targeting GATA3.

Novel pharmacological inhibition of EZH2 attenuates septic shock by altering innate inflammatory responses to sepsis.

The function of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in sepsis remains unknown. We reported here that the expression of EZH2 and H3K27me3 was significantly upregulated in the circulation of septic patients, whereas patients who survived presented downregulated the expression of EZH2 on CD14+ monocytes. We further identified increased expression of EZH2 in the circulation, peritoneal fluid, and septic lungs from CLP mice. 3-DZNeP treated CLP mice improved mortality and protected from organ injury. EZH2 inhibition not only suppressed the activation of inflammatory cells and release of cytokines in the circulation and infectious sites, but also promoted bacteria clearance and replenished the circulating monocyte and neutrophil pool from bone marrow. Blockage of EZH2 also suppressed the progression of lung injury and alleviated inflammation by decreasing the pulmonary cell apoptosis, reducing inflammatory cells infiltration and cytokines release through inhibition of the STAT3 signaling pathway and recovery of PPARγ activation. In addition, EZH2 inhibitor blunted macrophage M1 polarization by SOCS3/STAT1 pathway. Overall, these data suggest that EZH2 could be a potential biomarker predicting clinical outcome and a new target for therapeutic interference in sepsis.

The protective role of NR4A3 in acute myocardial infarction by suppressing inflammatory responses via JAK2-STAT3/NF-κB pathway.

Inflammatory responses play a critical role in left ventricular remodeling after acute myocardial infarction (AMI). NR4A3, a member of the NR4A orphan nucleus receptor family, has recently emerged as a therapeutic target for treatment of inflammation. This aim of this study is to explore the therapeutic effect of NR4A3 in cardiac remodeling post AMI. Male C57BL/6 mice were administered with lentiviral over-expression of NR4A3 (lenti-NR4A3) or empty vector (lenti-con) 7 days before coronary artery ligation. H9c2 cardiomyocytes deprived of serum were used to mimic ischemic conditions in vivo. Lenti-NR4A3 treatment significantly repressed neutrophil infiltration in the myocardium, reduced infarct size, and attenuated the reduction of left ventricular function after AMI. Furthermore, NR4A3 over-expression inhibited the NF-κB (IκB) signaling by decreasing IκBα phosphorylation and by inhibiting the translocation of p65 to the nucleus. Meanwhile, NR4A3 over-expression also increases the activity of JAK2-STAT3 signaling in mouse hearts after AMI. The inhibitory effect of NR4A3 on NF-κB activation was almost completely abolished by the JAK2 inhibitor AG490, indicating that NR4A3 prevented serum deprivation induced NF-κB activation in a STAT3 dependent manner. These findings provide novel evidence that NR4A3 could inhibit post-AMI inflammation responses via JAK2-STAT3/NF-κB signaling and may well be a therapeutic target for cardiac remodeling after AMI.

Characteristics of circular RNA expression of pulmonary macrophages in mice with sepsis-induced acute lung injury.

Circular RNAs (circRNAs) make up a large class of non-coding RNAs and play important roles in the pathology of a variety of diseases. However, their roles in pulmonary macrophage polarization after sepsisinduced lung injury is unknown. In this study, mice were divided into two groups: Sham control group and cecal ligation and puncture (CLP)-induced ALI group. Macrophages were isolated from lung homogenates 24 hours after SCLP/CLP. We started with RNA-seq of circRNA changes in macrophages and validated by RT-PCR in the following experiments. A total of 4318 circRNAs were detected in the two groups. Of these, 11 and 126 circRNAs were found to be significantly upregulated and downregulated, respectively, compared to the control (p≤0.05, Fold Change ≥2). Differentially expressed circRNAs with a high foldchange (fold-change >4, P<0.05) were selected for validation by qRT-PCR, 10 of which were verified. Furthermore, the most differentially expressed circRNAs within all the comparisons were annotated in detail with circRNA/miRNA interaction information using miRNA target prediction software. The network of circRNA-miRNA-mRNA was illustrated by cytoscape software. Gene ontology analyses indicated the upregulated circRNAs were involved in the multiple biological functions such as regulation of mitochondrion distribution and Notch binding, while the down-regulated circRNAs mainly involved in the biological process as histone H3K27 methylation. KEGG pathway analysis revealed TGF-beta signaling pathway was related to the upregulated circRNAs. The present study provides a novel insight into the roles of circRNAs in pulmonary macrophage differentiation and polarization post septic lung injury.

Chronic and low-level particulate matter exposure can sustainably mediate lung damage and alter CD4 T cells during acute lung injury.

Particulate matter (PM)2.5 is a common air pollutant known to induce damages in the respiratory, cardiovascular, and nervous systems. Previous study has shown that acute and high-level PM insult could significantly aggravate the severity of LPS-induced acute lung injury (ALI). However, humans typically experience more chronic and low-level PM, of which the effect on ALI is yet unclear. Here, we varied the concentration of PM from low, medium, to high, which was given to mice via intratracheal instillation for a short period of time. Compared to the saline-treated mice, mice with medium or high PM treatment presented significantly higher mortality rate, weight reduction, and bronchoalveolar lavage (BAL) protein concentration during ALI, while mice with low PM treatment did not demonstrate significant differences from saline-treated mice. However, when the PM was given for an elongated period of time, PM, even at the low level, significantly aggravated ALI severity. Furthermore, the PM-mediated changes were sustained even after PM withdrawal. We also examined the CD4 T cells in saline- or PM-treated mice. We found that, although PM did not significantly change the number of lung-infiltrating CD4 T cells, it significantly altered the composition of lung-infiltrating CD4 T cells, characterized by having a higher T-bet/Foxp3 ratio in the PM-treated group compared to the saline-treated group. Additionally, the Treg-mediated suppression was reduced in PM-treated mice. The effect of PM on CD4 T cells depended on the concentration of PM and the duration of the treatment, and was independent of the PM withdrawal. Overall, these results demonstrated that chronic and low-level PM was sufficient at aggravating ALI and altering pulmonary CD4 T cells, and the effect could be sustained even after PM withdrawal.

[Blockade of programmed death-ligand 1 attenuates indirect acute lung injury in mice through targeting endothelial cells but not epithelial cells].

OBJECTIVE: To examine the expression profile of programmed death-ligand 1 (PD-L1) on lung endothelial or epithelial cells, and to determine the specific role of PD-L1 in mouse model of indirect acute lung injury (i-ALI). METHODS: Eighty male C57BL/6 mice were randomly divided into two parts (both n = 40). The effects of different administration routes on the expression of PD-L1 were observed. The mice in each part were randomly divided into sham, i-ALI, i-ALI+small interfering RNA (siRNA) random sequence control, and i-ALI+PD-L1 siRNA which could specifically inhibit PD-L1 expression groups, with 10 mice in each group. i-ALI was reproduced in a mouse model of hemorrhagic shock in combination with a subsequent cecal ligation and puncture (CLP). In sham group, only bilateral femoral arteries were ligated without catheterization or bleeding, and only cecum was separated but perforation was not ligated. Intravenous or intratracheal delivery of PD-L1 siRNA was performed 2 hours following the resuscitation to suppress the expression of PD-L1 on lung endothelial or epithelial cells. The mice in i-ALI+siRNA random sequence control group were given siRNA random sequence without inhibition effect on PD-L1 expression, and those in sham group and i-ALI group were given 100 µL phosphate buffered saline (PBS). The mice were sacrificed at 24 hours after CLP, and samples of blood, lung tissue and bronchoalveolar lavage fluid (BALF) were harvested. Expressions of PD-L1 were determined with flow cytometry. Cytokines and chemokines in plasma, lung tissue and BALF were determined by enzyme linked immunosorbent assay (ELISA). The protein concentration in plasma and BALF and the activity of myeloperoxidase (MPO) in lung tissue were quantitatively measured. The pathological changes in lung tissue were observed under light microscope. RESULTS: (1) Compared with sham group, PD-L1 expression on lung endothelial or epithelial cells were significantly elevated in i-ALI group [endothelial cells: (27.88±1.53)% vs. (19.64±1.03)%, epithelial cells: (58.70±8.21)% vs. (29.23±3.94)%, both P < 0.05]. (2) Mice received intravenous delivery of liposomal-encapsulated siRNA had significantly lower expression of PD-L1 on lung endothelial cells as compared with that of i-ALI group [(21.37±0.76)% vs. (27.88±1.53)%, P < 0.05]. Intratracheal delivery of naked PD-L1 siRNA mainly inhibited the PD-L1 expression on epithelial cell as compared with that of i-ALI group [(31.23±4.71) % vs. (58.70±8.21) %, P < 0.05]. The expression of PD-L1 in pulmonary microvascular endothelial cells or pulmonary epithelial cells of i-ALI mice was not affected by siRNA random sequence. (3) PD-L1 silencing on pulmonary endothelial cells induced by intravenous delivery of PD-L1 siRNA led to a lower protein ratio of BALF/plasma [(4.48±0.35)×10-3 vs. (6.11±0.56)×10-3, P < 0.05] and a decreased MPO activity in lung tissue (U×µg-1×min-1: 2.48±0.47 vs. 4.56±0.52, P < 0.05) as compared with that of i-ALI group. Moreover, inflammatory mediator levels such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) in lung tissue or plasma were significantly reduced following PD-L1 suppression on endothelial cells as compared with those of i-ALI group [IL-6 (ng/g): 177.4±23.2 vs. 287.9±57.3, MCP-1 (ng/g): 839.6±91.7 vs. 1 395.7±211.9, MIP-2 (ng/g): 923.7±107.3 vs. 1 700.9±240.2 in lung tissue; IL-6 (ng/L): 950.2±192.7 vs. 1 828.2±243.6, TNF-α (ng/L): 258.7±29.1 vs. 443.0±58.1, MCP-1 (ng/L): 2 583.8±302.3 vs. 4 328.1±416.4, MIP-2 (ng/L): 1 512.9±165.6 vs. 2 005.9±85.7 in plasma, all P < 0.05], however, there was no significant change in the levels of inflammatory factors in BALF. It was shown in lung tissue histology that PD-L1 silencing on pulmonary endothelial cells induced by intravenous delivery of PD-L1 siRNA led to lessened pulmonary edema and reduced immune cells emigration. Intratracheal delivery of PD-L1 siRNA for PD-L1 suppression on epithelial cells had minimal effects on protein ratio of BALF/plasma, MPO activity, inflammatory mediator expressions in lung tissue, plasma, and BALF as well as lung tissue histology. CONCLUSIONS: PD-L1 silencing on endothelial cells but not epithelial cells protected mice against hemorrhagic shock-sepsis induced i-ALI.

Lycium barbarum polysaccharide reduces hyperoxic acute lung injury in mice through Nrf2 pathway.

INTRODUCTION: The disruption of the balance between antioxidants and oxidants plays a vital role in the pathogenesis of acute lung injury (ALI). Evidence has shown that Lycium barbarum polysaccharide (LBP) has antioxidant feature. We examined the efficacy and mechanisms of LBP on hyperoxia-induced acute lung injury (ALI) in the present study. MATERIALS AND METHODS: C57BL/6 wild-type (WT) mice and nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2-/-) mice were used in the present study. LBP was fed by gavages once daily for 1 week. Then, the mice were exposed to hyperoxia or room air for 72 h. Additional dosage of LBP was given per 24 h. RESULTS: Reactive oxygen species production was increased in WT mice exposed to hyperoxia. Inflammatory cytokines including interleukin (IL)-1ß as well as IL-6, and inflammatory cells were increased infiltration in the lung after 3 days hyperoxia exposure. Hyperoxia exposure also induced pulmonary edema and histopathological changes. These hyperoxia-induced changes were improved in LBP treated group. Moreover, elevated activities of heme oxygenase-1 and glutathione peroxidase and enhanced activation of Nrf2 were observed in mice treated with LBP. However, the benefit of LBP on hyperoxic ALI was abolished in Nrf2-/- mice. Moreover, our cell study showed that the LBP-induced activation of Nrf2 was dampened in pulmonary microvascular endothelial cells when the AMPK signal was inhibited by siRNA. CONCLUSIONS: LBP improves hyperoxic ALI via Nrf2-dependent manner. The LBP-induced activation of Nrf2 is mediated, at least in part, by AMPK pathway.

The protective effect of ticagrelor on renal function in a mouse model of sepsis-induced acute kidney injury.

Platelets are traditionally considered to be essential components of primary hemostasis. Recent investigations have revealed that platelets can be activated in patients with sepsis and are implicated in the development of sepsis and sepsis-induced-acute kidney injury (SAKI). In the present study, ticagrelor was used to induce a mouse model of SAKI by cecal ligation and puncture. It was found that ticagrelor could inhibit platelet activity, decrease the levels of interleukin-1ß and serum creatinine, reduce infiltration of neutrophils in renal tissue, and attenuate cell apoptosis in the kidney. The results suggested that ticagrelor could protect renal function by inhibiting inflammation, recruitment of neutrophils into the kidney, and cell apoptosis in renal tissue. Thus, the findings might provide new strategies for preventing SAKI.

Photonic cancer nanomedicine using the near infrared-II biowindow enabled by biocompatible titanium nitride nanoplatforms.

Light-activated photoacoustic imaging (PAI) and photothermal therapy (PTT) using the second near-infrared biowindow (NIR-II, 1000-1350 nm) hold great promise for efficient tumor detection and diagnostic imaging-guided photonic nanomedicine. In this work, we report on the construction of titanium nitride (TiN) nanoparticles, with a high photothermal-conversion efficiency and desirable biocompatibility, as an alternative theranostic agent for NIR-II laser-excited photoacoustic (PA) imaging-guided photothermal tumor hyperthermia. Working within the NIR-II biowindow provides a larger maximum permissible exposure (MPE) and desirable penetration depth of the light, which then allows detection of the tumor to the full extent using PA imaging and complete tumor ablation using photothermal ablation, especially in deeper regions. After further surface polyvinyl-pyrrolidone (PVP) modification, the TiN-PVP photothermal nanoagents exhibited a high photothermal conversion efficiency of 22.8% in the NIR-II biowindow, and we further verified their high penetration depth using the NIR-II biowindow and their corresponding therapeutic effect on the viability of tumor cells in vitro. Furthermore, these TiN-PVP nanoparticles were developed as a contrast agent for NIR-II-activated PA imaging both in vitro and in vivo for the first time and realized efficient photothermal ablation of the tumor in vivo within both the NIR-I and NIR-II biowindows. This work not only provides a paradigm for TiN-PVP photothermal nanoagents working in the NIR-II biowindow both in vitro and in vivo, but also proves the feasibility of PAI and PTT cancer theranostics using NIR-II laser excitation.

Herpes Virus Entry Mediator (HVEM) Expression Promotes Inflammation/ Organ Injury in Response to Experimental Indirect-Acute Lung Injury.

Therapeutic interventions to treat acute lung injury (ALI) remain largely limited to lung-protective strategies, as a real molecular pathophysiologically driven therapeutic intervention has yet to become available. While we have previously documented the expression of herpes virus entry mediator (HVEM) on leukocytes of septic mice and critically ill patients, its functional role in shock/sepsis-induced ALI has not yet been studied. Inasmuch, a murine model of indirect ALI (iALI) was induced by hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), septic challenge and HVEM-siRNA or phosphate buffered saline was administrated by intratracheal instillation 2 h after hemorrhage to determine the role of HVEM in the development of experimental iALI. Indices of lung injury were measured. HVEM expression was significantly elevated in iALI mice. Compared with phosphate buffered saline treated iALI mice, HVEM knock-down by siRNA caused a reduction of cytokine/chemokine levels, myeloperoxidase activity, broncho-alveolar lavage fluid (BALF) cell count and protein concentration. HVEM-siRNA treatment reduced inflammation and attenuated pulmonary architecture destruction as well as provided an early (60 h post HEM-CLP) survival benefit in iALI mice. This ability of anti-HVEM treatment to prevent the development of iALI and provide a transient survival benefit implies that mitigating signaling through HVEM may be a novel target worth further investigation.

[Evaluation value of human antibacterial peptide LL-37 on the prognosis of elderly patients with sepsis].

OBJECTIVE: To evaluate the prognostic value of human antibacterial peptide LL-37 in elderly patients with sepsis. METHODS: Elderly sepsis patients over 65-year-old satisfied the diagnostic criteria for sepsis and septic shock admitted to intensive care unit of East Hospital of Tongji University from January 2016 to December 2017 were enrolled (elderly sepsis group). Aged community-acquired pneumonia (CAP) patients hospitalized during the same period were enrolled as a control group for pneumonia, and the aged health check-ups served as a healthy control group during the same period. The peripheral blood LL-37 levels of all patients on the 1st, 3rd, 7th day of admission and the results on the day of physical examination in the healthy control group and on the day of admission in aged CAP group were recorded. C-reactive protein (CRP), arterial blood lactate (Lac), procalcitonin (PCT) were monitored, and acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores were calculated based on the worst values within 24 hours. The correlation between LL-37 and various indicators was analyzed by Spearman method. According to the 28-day clinical outcome, the elderly patients with sepsis were divided into survival group and non-survival group. The differences in all parameters between the two groups were compared. The statistically significant indicators were analyzed by receiver operating characteristic (ROC) curve, and the predictive value of each indicator for prognosis was evaluated. RESULTS: (1) A total of 113 elderly patients with sepsis were enrolled in the final analysis, including 67 patients in sepsis group and 46 patients in septic shock group. Thirty-two patients were enrolled as healthy controls and 31 elderly patients with CAP as elderly pneumonia group. The PCT, CRP, Lac, APACHE II and SOFA scores of the patients in the three groups were higher than those of the healthy control group, and they were gradually increased with the severity of infection. There was no significant difference in gender or age among the groups. Compared with the healthy control group, the other three groups had higher LL-37 level after admission, the LL-37 levels in the sepsis group and the septic shock group were decreased with the prolongation of the hospitalization time, and they were lower than the pneumonia group at 7 days after admission [LL-37 (µg/L): 1 403.9±501.9, 1 517.1±676.4 vs. 1 608.4±816.2, both P > 0.05]. It was shown by correlation analysis that the LL-37 level in peripheral blood of elderly patients with sepsis was significantly negatively correlated with APACHE II score (r = -0.329, P = 0.007) and SOFA score (r = -0.344, P = 0.005), but no significant correlation with Lac was found (r = -0.128, P = 0.311). (2) The 28-day survival analysis revealed that of the 113 elderly patients with sepsis, 54 (47.8%) survived at 28 days and 59 (52.2%) died. There was no significant difference in gender, age, PCT or CRP levels at 1 day after admission between the two groups. The 1-day Lac, APACHE II and SOFA scores of the patients in the non-survival group were significantly higher than those in the survival group, they were gradually increased with the prolongation of the hospitalization time, and they were significantly higher than those in the survival group at 7 days after admission [Lac (mmol/L): 2.4 (1.4, 4.4) vs. 1.0 (0.8, 1.7), APACHE II score: 21.77±5.85 vs. 13.74±4.99, SOFA score: 9.62±4.78 vs. 3.18±2.71, all P < 0.01]. With the prolongation of admission, there was no significant change in LL-37 level of peripheral blood in the survival group. The LL-37 level in the non-survival group showed a downward tendency, and it was significantly lower than that in the survival group at 7 days after admission (µg/L: 1 277.8±642.6 vs. 1 620.6±461.6, P < 0.05). It was shown by ROC curve analysis that the LL-37 in peripheral blood, Lac, APACHE II score and SOFA score at 7-day of admission of elderly patients with sepsis had predictive value for prognosis, and LL-37 had the best predicted effect for 28-day death, the area under the ROC curve (AUC) of LL-37 was 0.670, 95% confidence interval (95%CI) = 0.513-0.757, when the optimal cut-off value was 1 283.0 µg/L, the sensitivity was 75.7%, and the specificity was 61.5%. CONCLUSIONS: The expression of LL-37 increased in the early course of the disease in elderly patients with sepsis. However, as the disease progressed and worsened, the level of LL-37 had a decline tendency and was associated with death. The dynamic monitoring of LL-37 combined with APACHE II and SOFA scores had clinical guidance value in predicting the prognosis of sepsis in the elderly.