Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity.

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.

Dexmedetomidine attenuates inflammation and organ injury partially by upregulating Nur77 in sepsis.

PURPOSE: The aim of this study was to investigate the effect of dexmedetomidine (Dex) on inflammation and organ injury in sepsis, as well as the potential relationship between Dex and nuclear receptor 77 (Nur77). METHODS: We investigated the effects of dexmedetomidine on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells and organ injury in the cecal ligation and puncture (CLP) mouse model. Additionally, we examined the relationship between dexmedetomidine and Nur77. The expression levels of Nur77 in RAW264.7 cells were analyzed under various types of stimulation using quantitative reverse transcription polymerase chain reaction and western blot analysis. Inflammatory cytokine levels in the cells were evaluated using enzyme-linked immunoassay. Organ injuries were assessed by examining tissue histology and pathology of the lung, liver, and kidney. RESULTS: Dexmedetomidine increased the expression of Nur77 and IL-10, and downregulated inflammatory cytokines (IL-1ß and TNF-α) in LPS-treated RAW264.7 cells. The effect of dexmedetomidine on inhibiting inflammation in LPS-treated RAW264.7 cells was promoted by overexpressing Nur77, while it was reversed by downregulating Nur77. Additionally, dexmedetomidine promoted the expression of Nur77 in the lung and CLP-induced pathological changes in the lung, liver, and kidney. Activation of Nur77 with the agonist Cytosporone B (CsnB) significantly suppressed the production of IL-1ß and TNF-α in LPS-treated RAW264.7 cells. In contrast, knockdown of Nur77 augmented IL-1ß and TNF-α production in LPS-treated RAW264.7 cells. CONCLUSION: Dexmedetomidine can attenuate inflammation and organ injury, at least partially, via upregulating Nur77 in sepsis.

TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis.

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

Ag-Doped Metal-Organic Frameworks' Heterostructure for Sonodynamic Therapy of Deep-Seated Cancer and Bacterial Infection.

Metal-organic frameworks (MOF) have attracted great potential in sonodynamic therapy (SDT) owing to large sonosensitizers' loading and fast reactive oxygen species' (ROS) diffusion; however, the low ligand-to-metal charge transfer efficiency sharply impairs the SDT effect. Herein, we report the design of MIL@Ag heterostructures with high electron-hole pairs separation efficiency and enhanced diverse ROS generation ability for deep-seated cancer treatment and bacterial infection. The MIL@Ag heterostructure is composed of Ti-based MOFs (named MIL), on which are in situ assembled silver nanoparticles (Ag NPs). The electrochemical experiments and density functional theory calculations verify that the introduction of Ag NPs can significantly improve the electron transfer efficiency and O2 adsorption capacity of MIL. Under ultrasound irradiation, the doped Ag NPs can trap the activated electrons from MIL to reduce surrounding O2 and produce superoxide radicals (•O2-), while the activated holes enable oxidizing H2O to produce hydroxyl radicals (•OH). Thus, they efficiently improve the therapeutic efficiency of SDT. MIL@Ag-PEG-mediated SDT implements A549 cancer cells' killing under a tissue barrier of 2 cm and eradicates the bacterial infection of Staphylococcus aureus, thus promoting wound healing. Therefore, MIL@Ag-PEG provides a promising strategy for augmenting SDT performance by rational heterostructure design of sonosensitizers.

Recent Advances in Near-Infrared-II Fluorescence Imaging for Deep-Tissue Molecular Analysis and Cancer Diagnosis.

Fluorescence imaging with high sensitivity and minimal invasiveness has received tremendous attention, which can accomplish visualized monitoring and evaluation of cancer progression. Compared with the conventional first near-infrared (NIR-I) optical window (650-950 nm), fluorescence imaging in the second NIR optical window (NIR-II, 950-1700 nm) exhibits deeper tissue penetration capability and higher temporal-spatial resolution with lower background interference for achieving deep-tissue in vivo imaging and real-time monitoring of cancer development. Encouraged by the significant preponderances, a variety of multifunctional NIR-II fluorophores have been designed and fabricated for sensitively imaging biomarkers in vivo and visualizing the treatment procedure of cancers. In this review, the differences between NIR-I and NIR-II fluorescence imaging are briefly introduced, especially the advantages of NIR-II fluorescence imaging for the real-time visualization of tumors in vivo and cancer diagnosis. An important focus is to summarize the NIR-II fluorescence imaging for deep-tissue biomarker analysis in vivo and tumor tissue visualization, and a brief introduction of NIR-II fluorescence imaging-guided cancer therapy is also presented. Finally, the significant challenges and reasonable prospects of NIR-II fluorescence imaging for cancer diagnosis in clinical applications are outlined.

ROS-Activated nanoscale coordination polymers for enhanced ultrasound-mediated therapy for the treatment of cancer.

Stimuli-responsive nanoplatforms for efficient delivery of drugs in an on-demand manner show promising potential for killing cancer cells with high accuracy and minimal invasiveness. Herein, taking advantage of the good tissue-penetrating depth of sonodynamic therapy (SDT), reactive oxygen species (ROS)-responsive nanoscale coordination polymers (NCPs) were designed through self-assembly of porphyrins (PP) and platinum, which contained ROS-cleavable thioketal (TK) linkers to enhance the release of doxorubicin (Dox) during SDT. Upon exposure to the ultrasound (US), the Dox-loaded NCPs (PTK@PEG/Dox) could generate high amounts of cytotoxic ROS and heat, which not only induced the apoptosis of MCF-7 cells but also facilitated the efficient release of Dox due to the decomposition of the ROS-sensitive TK linkers, achieving the synergistic therapy of US-induced therapy and chemotherapy. After being modified with Arg-Gly-Asp (RGD) peptide, RGD/PTK@PEG exhibited a good targeting ability to cancer cells. Importantly, using the multicellular tumor spheroids (MCTS) derived from MCF-7 cells as a model, the RGD/PTK@PEG/Dox exhibited an efficient and controlled release behavior of Dox under the US irradiation, accompanying a tremendous anti-cancer effect for inducing apoptosis in the solid tumor tissues. This work provided a potential strategy to design controllable and stimuli-responsive nanoplatforms for synergistic/enhanced US-induced cancer therapy. STATEMENT OF SIGNIFICANCE: Stimulus-responsive nanoplatforms can deliver drugs efficiently in an on-demand manner, showing the potential to kill cancer cells with high accuracy and minimal invasiveness. Taking advantage of the good penetration ability of ultrasound (US), nanoscale coordination polymers (NCP) composed of porphyrin (PP), thioketal (TK) linkers, and platinum(II) were prepared via a coordination-driven self-assembly procedure. After doxorubicin (Dox) was loaded on the NCP (PTK@PEG/Dox), the nanoplatform responded to reactive oxygen species (ROS) under the stimulation of US, and induced the on-demand release of Dox, thereby achieving the combined therapeutic effect of sonodynamic therapy (SDT) and chemotherapy for cancer. This work provides a potential strategy for the development of controllable and stimuli-responsive nanoplatforms for enhanced ultrasound-induced cancer therapy.

Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy.

The potential therapeutic effect of nitric oxide (NO) for cancers has received considerable attention as a "killer" that causes damage to mitochondria and DNA by oxidation or nitrosation. However, the fabrication of an intelligent and controllable NO release system has remained elusive in the desired location to realize selective cancer therapy. Herein, an intelligent endogenous esterase-triggered nitric oxide (NO) generator for synergetic cancer therapy is fabricated by integrating NO prodrug and doxorubicin (DOX) into a single glutathione (GSH)-responsive mesoporous silica nanoparticle (MPND). When the MPND is internalized into the cancer cell, the rupture of -S-S- bridges and the degradation of MPND occur in the tumor microenvironment with a high level of GSH, inducing the on-demand release of DOX. Importantly, the high endogenic esterase concentration can activate the prodrug to generate abundant NO, which further enhances the release performance of DOX. In vitro results verify that the release profiles of NO and DOX show the stimuli-responsive dependence of endogenic esterase and GSH, respectively, demonstrating the potential for on-demand release in the cancer cells. Consequently, MPND shows a high antitumor efficiency in MCF-7 cancer cells. Furthermore, using multicellular tumor spheroids to mimic in vivo experiment, MPND can enhance the tumor penetration and therapeutic effect for killing the deep tumor tissue at the central location. Therefore, the endogenous esterase-triggered NO nanogenerators may provide a potential alternative strategy to develop NO-relevant platforms for synergistic cancer therapy.

Role of dexmedetomidine in the treatment of delirium in critically ill patients: a systematic review and meta-analysis.

INTRODUCTION: Although dexmedetomidine has been found to prevent delirium in critically ill patients, it is uncertain whether it can treat acute delirium. This study aimed to evaluate the efficacy and safety of dexmedetomidine in treating delirium, by analyzing and reviewing data from previous studies. EVIDENCE ACQUISITION: Clinical trial data on the use of dexmedetomidine in adult critically ill patients with delirium were retrieved from four databases (PubMed, Embase, Web of Science, and the Cochrane Library) and clinicaltrials.gov, from inception to May, 2020. EVIDENCE SYNTHESIS: Ten randomized controlled trials (RCTs) and five non-RCTs met the selection criteria and data were obtained from 1017 patients. In one study, dexmedetomidine reduced the duration of delirium to a greater extent than did the placebo. In six studies, it was associated with a lower point-prevalence of delirium after treatment (OR, 0.39; 95% CI, 0.20, 0.76; P=0.006) and a shorter time to resolution of delirium (hours; MD, -23.25; 95% CI, -45.28, -1.21; P=0.04) compared with those of other drugs. In four RCTs, it was superior to haloperidol in reducing the time to resolution of delirium (hours; MD, -30.17; P=0.01). However, in seven studies, it showed a higher risk of bradycardia (OR, 3.48; 95% CI, 1.47, 8.23; P=0.004) than that of comparators. CONCLUSIONS: Dexmedetomidine promotes the resolution of delirium but also increases the incidence of bradycardia during treatment. Furthermore, it may be superior to haloperidol in treating delirium, although more studies are needed to confirm this.

Evaluation of 2 Rat Models for Sepsis Developed by Improved Cecal Ligation/Puncture or Feces Intraperitoneal-Injection.

BACKGROUND The aim of this study was to evaluate the clinical characteristics of 2 rat models of sepsis for improved cecal ligation/puncture (CLP) and feces intraperitoneal-injection (FIP), including systemic inflammation, organ dysfunction, and blood coagulation. MATERIAL AND METHODS Sixty-two male SD rats were randomly divided into 3 groups: a normal control group (NC, n=6), a CLP group (n=28), and a FIP group (n=28). Ten rats each in the CLP and FIP groups were observed for 72-h mortality rate. The remaining 18 rats in each group were divided into 3 subgroups (n=6) according to their post-operation period (6, 12, and 24 h). Abdominal arterial blood was collected to determine the lactic acid (Lac) concentration, prothrombin time (PT), active partial prothrombin time (APTT), plasmic interleukin-6 (IL-6) level, and cardiac troponin (cTnI) level. The intestines, lung, and heart were collected for pathological examination. RESULTS The 72-h mortality rates in the CLP and FIP groups were 60% and 100%, respectively. The Lac level in both groups was significantly elevated at 6, 12, and 24 h after modeling. Compared with the NC group, PT in the CLP and FIP groups was prolonged at 12 and 24 h, and APTT was significantly prolonged at 6 h. IL-6 levels in the CLP and FIP groups peaked at 6 h. The cTnI level in the FIP group was significantly higher at 12 h after modeling compared with the NC group. The intestines, lung, and heart were pathologically damaged at 6 h, and this damage worsened over time. CONCLUSIONS Both modeling methods induced sepsis in rats and closely mimicked the clinical conditions, but FIP was easier to establish and was more suitable for standardization.

[Analysis of prognostic risk factors of bloodstream infection in intensive care unit patients].

OBJECTIVE: To explore the prognostic risk factors of bloodstream infection (BSI) in intensive care unit (ICU) patients, furthermore, to provide a reliable evidence for early warning and treatment for the critical patients with BSI. METHODS: A retrospective study was performed. The clinical data of patients with blood culture-positive admitted to ICU of the Affiliated Hospital of Guizhou Medical University from January 1 to September 30, 2019 were analyzed. The data including gender, age, proportion of basic diseases, acute physiology and chronic health evaluation II (APACHE II), the duration of mechanical ventilation after being diagnosed with BSI, length of stay in ICU, aggressive operation and blood product infusion after BSI, proportion of using continuous renal replacement therapy (CRRT) and continuous vasoactive agents for more than 72 hours after being diagnosed with BSI, and site of central venous catheterization were recorded. Meantime, the worst laboratory values within 72 hours after being diagnosed with BSI, information about pathogenic microorganism categories and distributions were collected and analyzed. The patients were divided into survival and death groups based on the the 28-day prognosis, and the differences of clinical data between the two groups were compared. Logistic regression analysis was used to select the independent prognostic risk factors of BSI. RESULTS: One hundred and fifty-four patients with positive results of BSI were enrolled, and the 156 strains of bacteria were detected, including 75 Gram positive (G+) bacteria strains, 70 Gram negative (G-) bacteria strains and 11 fungi strains among those BSI patients. The top five pathogenic microorganisms were Coagulase negative staphylococcus (35.9%), Klebsiella pneumonia (12.8%), Acinetobacter baumannii (9.0%), Enterococci (9.0%), and Escherichia coli (8.3%). There were 45 strains (60.0%) of multidrug-resistant strains in G+ bacteria and 40 strains of multidrug-resistant strains (57.1%) in G- bacterial strains, but in fungi there was only 1 strain (9.1%). There were 81 cases in survival group and 73 cases in death group according to 28-day prognosis. We found that there were no significant differences between the comparators in age, lenth of stay in ICU, duration for mechanical ventilation after being diagnosed with BSI, percentage of BSI with chronic obstructive pulmonary disease (COPD), hypertension, cardiovascular disease or chronic kidney dysfunction (all P > 0.05). In death group, the proportion of male was obviously lower than that of survival group [58.9% (43/73) vs. 75.3% (61/81), P < 0.05] and APACHE II score was significantly higher than that in survival group (27.1±7.0 vs. 19.5±6.7, P < 0.05). The mean arterial pressure (MAP) of death group on first 3 days of BSI was significantly lower than that of survival group [mmHg (1 mmHg = 0.133 kPa): 72.8±13.6 vs. 79.7±12.9, P < 0.05), in the death group, the proportion of patients complicated with diabetes, cancer [28.8% (29/73) vs. 12.3% (10/81), 19.2% (14/73) vs. 7.4% (6/81)], post-BSI CRRT and blood transfusion [39.7% (29/73) vs. 16.0% (13/81), 64.4% (47/73) vs. 46.9% (38/81)], and continuous use of asoactie drugs for ≥ 72 hours [37.0% (27/73) vs. 12.3% (10/81)] were significantly higher than those in the survival group (all P < 0.05). In death group, platelet count (PLT) was significantly decreased than that of survival group [×109/L: 124.93±98.21 vs. 181.15±116.39,P < 0.05], aspartate aminotransferase (AST) level was significantly higher than that of survival group [U/L: 75.40 (38.50, 140.95) vs. 56.20 (29.20, 85.70), P < 0.05], the rest of the laboratory indexes had no statistically significant differences between the two groups (all P > 0.05). The results of Logistic regression analysis showed that the APACHE II score [odds ratio (OR) = 1.279, 95% confidence interval (95%CI) was 1.158 to 1.412, P < 0.001], CRRT after BSI (OR = 3.522, 95%CI was 1.013 to 12.245, P = 0.048) were independent risk factors affecting the prognosis of patients with BSI, and MAP is a protective factor for prognosis (OR = 0.961, 95%CI was 0.927 to 0.996, P = 0.031). CONCLUSIONS: In our ICU, G+ bacteria are still dominant in bloodstream infection, G- bacteria take the second place. Besides, APACHE II score and CRRT after being diagnosed with BSI are the independent prognostic risk factors.

[Analysis of prognosis risk factors of critically ill patients after cardiac surgery: a consecutive 5-year retrospective study].

OBJECTIVE: To explore the risk factors affecting prognosis of critically ill patients following cardiac surgery, furthermore, to assess severity and keep alarm earlier. METHODS: A retrospective study was conducted. The clinical data of critically ill patients following cardiac surgery admitted to intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from January 1st 2014 to December 31st 2018 were enrolled. The clinical characteristics, acute physiology and chronic health evaluation II (APACHE II) and the worst laboratory examination within 24 hours after ICU admission, and the duration of mechanical ventilation, length of ICU stay, using continuous renal replacement therapy (CRRT), accepting vasoactive agents such as norepinephrine, dopamine or dobutamine and blood products such as red blood cells, plasma or platelets were recorded. The patients were divided into survival group and dead group based on discharge prognosis, and the difference in clinical data between the two groups was compared. Binary multivariate Logistic regression analysis was used to screen the risk factors affecting the prognosis of critically ill patients following cardiac surgery, and the receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of these risk factors. RESULTS: In total, 97 patients after cardiac operation were admitted to ICU during the five years. Thirty-two patients were excluded owing to age less than 16 years old, no more than 24 hours of the length of ICU stay, without the outcomes of myocardium enzymes or myocardium markers within the first 24 hours or admitted only for pacemaker. Finally, 65 patients met the criteria, with 40 survived and 25 died. Compared with survival group, APACHE II scores, the level of serum uric acid, serum creatinine (SCr), cardiac troponin T (cTnT), brain natriuretic peptide (BNP), procalcitonin (PCT) and the rate of patients accepting CRRT, vasoactive agents and blood products in dead group were significantly increased with significant differences; however, there was no statistically difference in gender, age, body weight index (BMI), distribution of types of cardiac surgery, ratio of patients suffered from hypertension and diabetes, mean arterial pressure (MAP), white blood cell (WBC), coagulation, length of ICU stay, or duration of mechanical ventilation between the two groups. Binary multivariate Logistic regression analysis showed that APACHE II scores [odds ratio (OR) = 1.123, 95% confidence interval (95%CI) = 1.004-1.257, P = 0.043] and cTnT (OR = 1.496, 95%CI = 1.038-2.158, P = 0.031) were the independent risk factors for prognosis of critical ill patients following cardiac surgery. ROC curve analysis showed that APACHE II score and cTnT had predictive value for prognosis of critical ill patients following cardiac surgery, the best was exerted when APACHE II score combined with cTnT, the area under the ROC curve (AUC) was 0.839, the joint prediction probability was 0.42, the sensitivity was 80.0%, and the specificity was 64.0%. CONCLUSIONS: APACHE II score and cTnT may be one of independent risk factors for prognosis of critical ill patients following cardiac surgery, and there will be far more greater predictive value when APACHE II score combined with cTnT.

Responses of seed germination and shoot metabolic profiles of maize (Zea mays L.) to Y2O3 nanoparticle stress.

The potential risks of rare-earth nanoparticles (RENPs) to plants in the environment are attracting increasing attention due to their wide-spread application. In this regard, little is known about the effects of Y2O3 NPs as an important member of RENPs on crop plants. Seed germination is vulnerable to environmental stress, which determines the growth and yield of crops. Here, maize seeds were exposed to a Y2O3 NP suspension (0-500 mg L-1) in the dark for 6 days. It was found that the Y2O3 NPs had no significant effect on the germination rates (>93%) in all treatments, but they could reduce seed vitality, delay germination, and inhibit seedling growth in a dose-dependent manner. Further, the inhibition effect of Y2O3 NPs on root elongation was much stronger than that on shoot elongation. Meanwhile, the activities of peroxidase (POD) and catalase (CAT) in shoots were enhanced with the increase in the Y2O3 NP concentration. A high-concentration (≥300 mg L-1) of Y2O3 NPs induced a significant increase in the malondialdehyde (MDA) level in shoots compared to the control, indicating that the membrane lipid peroxidation and permeability were enhanced. 1H NMR-based analysis showed that the polar metabolic profiles were altered significantly after treatment with 0, 10, and 500 mg L-1 of Y2O3 NPs, but there was no marked alteration observed for the non-polar metabolic profiles. The polar metabolites (e.g., sugars, amino acids, and most organic acids) showed a dose-dependent increase to Y2O3 NP stress, indicating that the metabolic pathways of carbohydrate metabolism, the tricarboxylic acid cycle (TCA), and amino acid synthesis were disturbed. There were significantly positive correlations found among the metabolites related with the antioxidant response and osmotic adjustment. The simultaneous accumulation of these metabolites possibly indicated the adaptation of the seedlings to stress at the cost of retarding glycolysis, TCA, and protein synthesis. The retarded effects finally inhibited the apparent growth of the seedlings. These findings reveal the phytotoxicity of Y2O3 NPs and provide physiological and biochemical and molecular-scale perspectives on the response of seedlings to stress.