Recent progress of Lycium barbarum polysaccharides on intestinal microbiota, microbial metabolites and health: a review.

Intestinal microbiota is symbiotically associated with host health, learning about the characteristics of microbiota and the factors that modulate it could assist in developing strategies to promote human health and prevent diseases. Polysaccharides from Lycium barbarum (LBPs) are found beneficial for enhancing the activity of gut microbiota, as a potential prebiotic, which not only participates in improving body immunity, obesity, hyperlipidemia and systemic inflammation induced by oxidative stress, but also plays a magnificent role in regulating intestinal microenvironment and improving host health and target intestinal effects via its biological activities, as well as gut microbiota and metabolites. To highlight the internal relationship between intestinal microbiota and LBPs, this review focuses on the latest advances in LBPs on the intestinal microbiota, metabolites, immune regulation, intestinal barrier protection, microbiota-gut-brain axis and host health. Moreover, the preparation, structure, bioactivity and modification of LBPs were also discussed. This review may offer new perspective on LBPs improving health of gut and host via intestinal microbiota, and provide useful guidelines for the application of LBPs in the food industry.

UCHL1 regulates inflammation via MAPK and NF-κB pathways in LPS-activated macrophages.

Inflammation is a common pathophysiological process as well as a clinical threat that occurs in various diseases worldwide. It is well-documented that nuclear factor-κB (NF-κB) and mitogen-activated protein kinase pathways are involved in inflammatory reactions to microbial infections in lipopolysaccharide (LPS)-activated macrophages. The deubiquitinase ubiquitin carboxyl-terminal hydrolase-L1 (UCHL1) has been reported as an oncoprotein to promote the growth and progression of cancer cells. However, the regulatory mechanism of UCHL1 in inflammation is currently unclear. Here, we aimed to assess the effects of UCHL1 on LPS-associated inflammatory response in vitro and in vivo by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction, and western blot analysis. This study identified that inhibition or knockdown of UCHL1 decreased the amounts of the key pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α in macrophages. Additionally, inhibition of UCHL1 suppressed LPS-induced extracellular signal-regulated protein kinase 1/2 phosphorylation and NF-κB translocation by regulating the inhibitor of NF-κB. Mechanically, UCHL1 interacts with IκBα protein in THP-1. Meanwhile, inhibition of UCHL1 blocked the LPS-induced degradation of IκBα through the ubiquitin-proteasome system. Moreover, in vivo assay showed that suppression of UCHL1 notably reduced the LPS-induced animal death and release of pro-inflammatory cytokines. Overall, the current findings uncover that UCHL1 functions as a crucial regulator for inflammatory response via reversing the degradation of IκBα, representing a potential target for the treatment of inflammatory diseases.

Deubiquitinase Inhibitor Auranofin Attenuated Cardiac Hypertrophy by Blocking NF-κB Activation.

BACKGROUND/AIMS: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood. The present study investigated the role of Aur in cardiac hypertrophy both in vitro and in vivo. METHODS: Male Sprague-Dawley rats underwent abdominal aortic constriction to induce left ventricular hypertrophy. The neonatal rat primary myocardial cell hypertrophy model was induced by Ang II. Echocardiography, hematoxylin-eosin staining, Masson's trichrome staining, immunochemistry, western blot analysis, a cell viability assay, and enzyme-linked immunosorbent assay were performed. RESULTS: Aur significantly reduced the abdominal aortic constriction that led to left ventricular hypertrophy, reduced heart cavity expansion, and functional disorder, and thereby reduced fetal gene expression and attenuated cardiac fibrosis. Furthermore, Aur caused marked accumulation of ubiquitinated proteins and IκBα, as well as inactivation of NF-κB. This phenomenon was confirmed in the neonatal rat primary myocardial cell hypertrophy model. CONCLUSIONS: The present study indicated that Aur blocks the development of left ventricular hypertrophy induced by abdominal aortic constriction. This phenomenon might be attributed to inhibition of the 19S proteasome-associated deubiquitinase that can lead to aggregation of IκBα and inactivation of the NF-κB pathway. Thus, Aur could be a potential anti-cardiac hypertrophy agent.

Ubiquitin-specific protease 14 regulates LPS-induced inflammation by increasing ERK1/2 phosphorylation and NF-κB activation.

Persistent activation of nuclear factor B (NF-κB) is very important in the modulation of macrophages cellular response to microbial infections. The deubiquitinase USP14, which is critical for ubiquitin-mediated proteasomal degradation of proteins, is known to be involved in cancer, neurological diseases, and aging. However, the mechanism by which USP14 regulates inflammation remains unclear. Here, we demonstrated that decreasing the deubiquitinase activity of USP14 resulted in reduced lipopolysaccharides (LPS)-mediated tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 release in THP-1 and RAW264.7 cells. Meanwhile, USP14 knockdown by siRNA showed the same effects, with no cytotoxicity in THP-1 cells. Moreover, inhibiting the deubiquitinase activity of USP14 or USP14 knockdown resulted in decreased ERK1/2 and IκBα phosphorylation, increased amounts of the NF-κB inhibitor IκBα, and reduced NF-κB p65 transport from the cytoplasm into nucleus. These findings suggested that USP14 induces NF-κB activity and ERK1/2 phosphorylation triggered by microbial infection.

A novel Sagittaria sagittifolia L. polysaccharides mitigate DSS-induced colitis via modulation of gut microbiota and MAPK/NF-κB signaling pathways.

Sagittaria sagittifolia L. polysaccharides possess anti-inflammatory, antioxidant, and immune-modulatory properties. In this study, we identified a novel S. sagittifolia L. polysaccharide, named PSSP-1, and evaluated its potential in alleviating dextran sulfate sodium (DSS)-induced colitis in a mouse model. The results demonstrated that administration of PSSP-1 at doses of 100, 200, and 400 mg/kg·bw significantly reduced the disease activity index (DAI) and suppressed the expression of inflammatory cytokines in UC mice. Furthermore, PSSP-1 treatment upregulated the expression levels of claudin-1, occludin, and ZO-1, and promoted the diversity and abundance of beneficial gut microbiota, including Lactobacillus and Candidatus_Saccharimonas, while reducing the levels of Bacteroidetes and Verrucomicrobiota. Particularly, the Lactobacillus_johnsonii species may play a potentially significant role in modulating colitis. Subsequently, there was a significant increase in the levels of short-chain fatty acids (SCFAs). Additionally, the correlation analyses revealed positive associations between PSSP-1 supplementation and Nitrosospira and Dialister, which are implicated in gut inflammation. Mechanistically, PSSP-1 intervention inhibited the protein phosphorylation of key molecules in the MAPK and NF-κB signaling pathways. Collectively, these findings suggest that PSSP-1 mitigates colitis symptoms by repairing the intestinal barrier, promoting microbial metabolism, and regulating the gut microbiota-MAPK/NF-κB signaling pathways.

ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated (ECMO-RESCUE): study protocol for a prospective, multicentre, non-randomised cohort study.

INTRODUCTION: Severe septic cardiomyopathy (SCM) is one of the main causes of refractory septic shock (RSS), with a high mortality. The application of venoarterial extracorporeal membrane oxygenation (ECMO) to support the impaired cardiac function in patients with septic shock remains controversial. Moreover, no prospective studies have been taken to address whether venoarterial ECMO treatment could improve the outcome of patients with sepsis-induced cardiogenic shock. The objective of this study is to assess whether venoarterial ECMO treatment can improve the 30-day survival rate of patients with sepsis-induced refractory cardiogenic shock. METHODS AND ANALYSIS: ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated is a prospective, multicentre, non-randomised, cohort study on the application of ECMO in SCM. At least 64 patients with SCM and RSS will be enrolled in an estimated ratio of 1:1.5. Participants taking venoarterial ECMO during the period of study are referred to as cohort 1, and patients receiving only conventional therapy without ECMO belong to cohort 2. The primary outcome is survival in a 30-day follow-up period. Other end points include survival to intensive care unit (ICU) discharge, hospital survival, 6-month survival, quality of life for long-term survival (EQ-5D score), successful rate of ECMO weaning, long-term survivors' cardiac function, the number of days alive without continuous renal replacement therapy, mechanical ventilation and vasopressor, ICU and hospital length of stay, the rate of complications potentially related to ECMO treatment. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2020-hs-51). Participants will be screened and enrolled from ICU patients with septic shock by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. TRIAL REGISTRATION NUMBER: NCT05184296.

Solution-Processable NiOx:PMMA Hole Transport Layer for Efficient and Stable Inverted Organic Solar Cells.

For organic solar cells (OSCs), nickel oxide (NiOx) is a potential candidate as the hole transport layer (HTL) material. However, due to the interfacial wettability mismatch, developing solution-based fabrication methods of the NiOx HTL is challenging for OSCs with inverted device structures. In this work, by using N, N-dimethylformamide (DMF) to dissolve poly(methyl methacrylate) (PMMA), the polymer is successfully incorporated into the NiOx nanoparticle (NP) dispersions to modify the solution-processable HTL of the inverted OSCs. Benefiting from the improvements of electrical and surface properties, the inverted PM6:Y6 OSCs based on the PMMA-doped NiOx NP HTL achieves an enhanced power conversion efficiency of 15.11% as well as improved performance stability in ambient conditions. The results demonstrated a viable approach to realize efficient and stable inverted OSCs by tuning the solution-processable HTL.

Facile fabrication of two-dimensional iodine nanosheets for antibacterial therapy.

Herein, we report a facile approach for the preparation of two-dimensional iodine nanosheets (2D iodine NSs) with good stability and high biocompatibility via an aqueous solvent-assisted ultrasonic route. Due to the large specific surface area of the 2D morphology, iodine NSs effectively interact with bacterial membranes and destroy bacterial integrity, as well as further damaging intracellular DNA, showing prominent antibacterial activity against S. aureus in vitro and in vivo.

Association between the ß-blocker use and patients with sepsis: a cohort study.

Objective: This study aimed to assess whether ß-blockers are associated with mortality in patients with sepsis. Method: We conducted a retrospective cohort study of patients with sepsis using the Medical Information Market for Intensive Care (MIMIC)-IV and the emergency intensive care unit (eICU) databases. The primary outcome was the in-hospital mortality rate. The propensity score matching (PSM) method was adopted to reduce confounder bias. Subgroup and sensitivity analyses were performed to test the stability of the conclusions. Results: We included a total of 61,751 patients with sepsis, with an overall in-hospital mortality rate of 15.3% in MIMIC-IV and 13.6% in eICU. The inverse probability-weighting model showed that in-hospital mortality was significantly lower in the ß-blockers group than in the non-ß-blockers group [HR = 0.71, 95% CI: 0.66-0.75, p < 0.001 in MIMIC-IV, and HR = 0.48, 95% CI: 0.45-0.52, p < 0.001 in eICU]. In subgroups grouped according to sex, age, heart rate, APSIII, septic shock, and admission years, the results did not change. Conclusion: ß-blocker use is associated with lower in-hospital mortality in patients with sepsis, further randomized trials are required to confirm this association.

Slit dual-frequency ultrasound-assisted pulping of Lycium barbarum fresh fruit to improve the dissolution of polysaccharides and in situ real-time monitoring.

In this study, the slit dual-frequency ultrasound-assisted pulping of fresh Lycium barbarum fruit was optimized to improve the dissolution of polysaccharides. The microscopic mechanism of polysaccharide dissolution was explored through establishing polysaccharides dissolution kinetics model and visualizing the multi-physical fields during ultrasonic process, and an in situ real-time monitoring model was established by the relationship between the chemical value and spectral information collected by near-infrared spectroscopy. The results showed that, under optimal conditions, treatment with ultrasound (28-33 kHz, 250 W, 30 min) not only significantly promoted the dissolution rate of polysaccharides in Lycium barbarum pulp (LBPPs, increased by 43.64 %, p < 0.01), reduced its molecular weight, but also improved the arabinose molar ratio, the uniformity of polysaccharide particles, and the antioxidant activity of LBPPs. Correlation analysis indicated that ultrasonic treatment is closely related to LBPPs content, particle size and scavenging capacity against superoxide anion radicals (ptotal sugar content < 0.01, pparticle size < 0.05 and psuperoxide anion scavenging < 0.05). Moreover, the in situ real-time monitoring model for the pulping process could quantitatively predict LBPPs dissolution rate and its superoxide anion radical scavenging capacity with good calibration and prediction performance (Rc = 0.9841, RMSECV = 0.0873, Rp = 0.9772, RMSEP = 0.0530; Rc = 0.9874, RMSECV = 0.1246, Rp = 0.9868, RMSEP = 0.0665). These results indicated that slit dual-frequency ultrasound has great potential in improving the quality of Lycium barbarum pulp, which may provide theoretical support for the industrial development of intelligent systems for polysaccharides preparation.

Effects of slit dual-frequency ultrasound-assisted pulping on the structure, functional properties and antioxidant activity of Lycium barbarum proteins and in situ real-time monitoring process.

To improve the protein dissolution rate and the quality of fresh Lycium barbarum pulp (LBP), we optimized the slit dual-frequency ultrasound-assisted pulping process, explored the dissolution kinetics of Lycium barbarum protein (LBPr), and established a near-infrared spectroscopy in situ real-time monitoring model for LBPr dissolution through spectral information analysis and chemometric methods. The results showed that under optimal conditions (dual-frequency 28-33 kHz, 300 W, 31 min, 40 °C, interval ratio 5:2 s/s), ultrasonic treatment not only significantly increased LBPr dissolution rate (increased by 71.48 %, p < 0.05), improved other nutrient contents and color, but also reduced the protein particle size, changed the amino acid composition ratio and protein structure, and increased the surface hydrophobicity, zeta potential, and free sulfhydryl content of protein, as well as the antioxidant activity of LBPr. In addition, ultrasonication significantly improved the functional properties of the protein, including thermal stability, foaming, emulsification and oil absorption capacity. Furthermore, the real-time monitoring model of the dissolution process was able to quantitatively predict the dissolution rate of LBPr with good calibration and prediction performance (Rc = 0.9835, RMSECV = 2.174, Rp = 0.9841, RMSEP = 1.206). These findings indicated that dual-frequency ultrasound has great potential to improve the quality of LBP and may provide a theoretical basis for the establishment of an intelligent control system in the industrialized production of LBP and the functional development of LBPr.

The relationship between soluble CD73 and the incidence of septic shock in severe sepsis patients: a cross-sectional analysis of data from a prospective FINNAKI study.

Background: Sepsis is a leading cause of mortality worldwide. Septic shock is a subtype of sepsis in which the underlying cardiovascular and cellular/metabolic disorders are profound enough to increase mortality significantly. We sought to investigate the association between soluble cluster of differentiation-73 (sCD73) and the incidence of septic shock in severe sepsis patients. Methods: This cross-sectional study included 588 Finnish patients with severe sepsis or septic shock from the Finnish Acute Kidney Injury (FINNAKI) study. The primary exposure of interest was baseline level of sCD73. The outcome was the incidence of septic shock. Multivariable logistic regression analyses were performed to assess the independent association between sCD73 and the incidence of septic shock. Results: The average age of 588 participants was 62±16 years, and 65.14% of the patients were male. The average sCD73 was 5.11 (interquartile range, 3.30, 8.25) ng/mL. The incidence of sepsis shock was 429 (72.96%). In the multivariate logistic regression model, sCD73 was negatively associated with septic shock. After multiple adjustments (for age, gender, lactate, the Sequential Organ Failure Assessment score, systolic heart failure, emergency admission, operative admission, and acute kidney injury within 12 h), a 1 ng/mL increment in sCD73 was associated with a 5% lower incidence of septic shock [odds ratio (OR) =0.95; 95% confidence interval (CI): 0.92, 0.98; P<0.001]. Conclusions: We found that sCD73 was negatively correlated with septic shock. Higher sCD73 was associated with a lower incidence of septic shock. Keywords: Septic shock; severe sepsis; soluble cluster of differentiation-73 (sCD73); inflammation; phosphatidylinositol 3-kinase/Akt signaling (PI3K/Akt signaling).

Association between Wait Time for Transthoracic Echocardiography and 28-Day Mortality in Patients with Septic Shock: A Cohort Study.

Background: the optimal timing of Transthoracic echocardiography (TTE) performance for patients with septic shock remains unexplored. Methods: a retrospective cohort study included patients with septic shock in the MIMIC-Ⅲ database. Risk-adjusted restricted cubic splines modeled the 28-day mortality according to time elapsed from ICU admission to receive TTE. The cut point when a smooth curve inflected was selected to define early and delayed group. We applied propensity score matching (PSM) to ensure our findings were reliable. Causal mediation analysis was used to assess the intermediate effect of fluid balance within 72 h after ICU admission. Results: 3264 participants were enrolled and the risk of 28-day mortality increased until the wait time was around 10 h (Early group) and then was relatively flat afterwards (Delayed group). A beneficial effect of early TTE in terms of the 28-day mortality was observed (HRs 0.73−0.78, all p < 0.05) in the PSM. The indirect effect brought by the fluid balance on day 2 and 3 was significant (both p = 0.006). Conclusion: early TTE performance might be associated with lower risk-adjusted 28-day mortality in patients with septic shock. Better fluid balance may have mediated this effect. A wait time within 10 h after ICU may represent a threshold defining progressively increasing risk.

Modification of the SnO2 Electron Transporting Layer by Using Perylene Diimide Derivative for Efficient Organic Solar Cells.

Recently, tin oxide (SnO2) nanoparticles (NPs) have attracted considerable attention as the electron transporting layer (ETL) for organic solar cells (OSCs) due to their superior electrical properties, excellent chemical stability, and compatibility with low-temperature solution fabrication. However, the rough surface of SnO2 NPs may generate numerous defects, which limits the performance of the OSCs. In this study, we introduce a perylene diimide derivative (PDINO) that could passivate the defects between SnO2 NP ETL and the active layer. Compared with the power conversion efficiency (PCE) of the pristine SnO2 ETL-based OSCs (12.7%), the PDINO-modified device delivers a significantly increased PCE of 14.9%. Overall, this novel composite ETL exhibits lowered work function, improved electron mobility, and reduced surface defects, thus increasing charge collection efficiency and restraining defect-caused molecular recombination in the OSC. Overall, this work demonstrates a strategy of utilizing the organic-inorganic hybrid ETL that has the potential to overcome the drawbacks of SnO2 NPs, thereby developing efficient and stable OSCs.

[Relationship between "1-hour serum lactate" level and 30-day mortality in critical care patients in intensive care unit].

OBJECTIVE: To investigate the relationship between 1-hour lactate (1 h Lac) and 30-day mortality in critical care patients in intensive care unit (ICU). METHODS: A retrospective, observational cohort study was performed with adult critical patients (age ≥ 16 years old) having lactate records within 1 hour after ICU admission from Medical Information Mart for Intensive Care-III database (MIMIC-III). According to the 1 h Lac level, the patients were divided into three groups: < 2 mmol/L, 2-4 mmol/L, and > 4 mmol/L groups. The baseline characteristics were analyzed. Multivariable Logistic regression analysis was performed to assess the association between 1 h Lac and 30-day mortality. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of 1 h Lac for 30-day mortality, and Kaplan-Meier survival curve was performed according to the best cut-off value. In addition, sensitivity analysis was carried out for each classification variable. RESULTS: A total of 3 969 ICU patients were included, with 673 died in 30 days, and the total mortality was 16.95%. There were 1 664, 1 588, 717 patients in Lac < 2 mmol/L, 2-4 mmol/L and > 4 mmol/L group, respectively. There were significant differences in age, ICU duration, ICU type, heart rate, leukocyte count, hemoglobin, creatinine, sequential organ failure score (SOFA), ventilator application, vasoactive drug use and main diagnosis among the three groups. Multivariable Logistic regression analysis showed that a 1 mmol/L increment in Lac was associated with 0.24 times higher risk of 30-day mortality [odds ratio (OR) = 1.24, 95% confidence interval (95%CI) was 1.19-1.29, P < 0.000 1]. ROC curve analysis showed that the area under ROC curve (AUC) of 1 h Lac for predicting 30-day mortality of severe patients was 0.694 (95%CI was 0.669-0.718). The cut-off value was 3.35 mmol/L with sensitivity of 0.499 and specificity of 0.779, whilst positive likelihood ratio was 2.260, and negative likelihood ratio was 0.643. According to the cut-off value of 1 h Lac, the patients were divided into high lactate group (≥ 3.35 mmol/L) and low lactate group (< 3.35 mmol/L). In the two subgroups, 30-day mortality was 31.58% (336/1 064) and 11.60% (337/2 905), respectively. The Kaplan-Meier survival curve showed that the 30-day cumulative survival rate of high lactate group was significantly lower than that of low lactate group (Log-rank test: χ2 = 247.72, P < 0.000 1). Multiple Logistic regression analysis showed that the 30-day mortality rate of high lactate group was 2.34 times that the level of low lactate group (OR = 2.34, 95%CI was 1.90-2.88, P < 0.000 1), after the adjustment of age, time of admission, type of ICU, hemoglobin, leukocyte count, use of vasopressor, use of ventilator and main diagnosis of patients. Stratified analysis showed that the relationship between 1 h Lac and 30-day mortality was stable. CONCLUSIONS: 1 h Lac is associated with 30-day mortality in critical care patients. The risk of death was significantly increased in critically ill patients with 1 h Lac higher than 3.35 mmol/L.

[The interaction between soluble CD73 and 90-day mortality from patients with non-septic shock and sepsis shock: a secondary analysis from the prospective FINNAKI study].

OBJECTIVE: Fundamental researches have shown that soluble CD73 (sCD73) can inhibit inflammatory response and limit excessive tissue damage caused by continuous immune cell activation. A Finnish prospective, observational study of acute kidney injury (FINNAKI) showed no association between sCD73 and 90-day mortality in sepsis patients. Clinical data of this study was used for secondary analysis to explore whether the relationship between sCD73 and 90-day mortality was consistent in septic shock and non-septic shock patients. METHODS: The FINNAKI study was a prospective, observational cohort study conducted in 17 intensive care units (ICUs) in Finland from September 1st, 2011 to February 1st, 2012. Sepsis/septic shock was defined according to Sepsis-1 definition. Demographic characteristics, treatment, comorbidities and 90-day mortality of the patients were analyzed. To evaluate the difference (interaction test) between the relationship of sCD73 and 90-day mortality in septic shock and non-septic shock patients, likelihood ratio test was used to integrate the product term (sCD73×septic shock or non-septic shock) into multivariable Logistic regression. Sensitivity analysis was performed with the definition of Sepsis-3. The interaction between sCD73 and 90-day mortality in patients with septic shock and non-septic shock were verified by generalized additive model (GAM). RESULTS: A total of 588 patients with severe sepsis/septic shock were enrolled. 164 patients died in 90 days, and the 90-day mortality was 27.89%. Based on the Sepsis-1 definition, there were 159 non-septic shock patients and 429 septic shock patients. Compared with the non-septic shock patients, lactate (Lac) level, sequential organ failure assessment (SOFA) score, fluid balance on the first day, and ratio of mechanical ventilation, 12-hour acute kidney injury (AKI), renal replacement therapy (RRT), and postoperative ICU transition in the septic shock patients were significantly increased and the proportion of emergency admission to ICU was significantly decreased. Based on the Sepsis-3 definition, there were 383 non-septic shock patients and 205 septic shock patients; the results of clinical data analysis between the two groups were similar to those based on Sepsis-1. Based on Sepsis-1, there was no significant difference in 90-day mortality between non-septic shock and septic shock patients [23.90% (38/159) vs. 29.37% (126/429), P > 0.05]. However, based on Sepsis-3, the 90-day mortality of patients with septic shock was significantly higher than that of patients with non-septic shock [37.56% (77/205) vs. 22.72% (87/383), P < 0.01]. Multivariate Logistic regression analysis and interaction test showed that after adjusting all confounding factors (except the number of complications) in non-sepsis shock and sepsis shock patients, sCD73 and 90-day mortality were significantly different in both Sepsis-1 and Sepsis-3. The P values for interaction tests were 0.046 and 0.027, respectively. In patients with non-septic shock, sCD73 tended to be positively associated with 90-day mortality [Sepsis-1: odds ratio (OR) = 1.46, 95% confidence interval (95%CI) was 0.99-2.13, P = 0.053; Sepsis-3: OR = 1.34, 95%CI was 1.02-1.74, P = 0.034]. In septic shock patients, sCD73 tended to be negatively associated with 90-day mortality (Sepsis-1: OR = 0.91, 95%CI was 0.69-1.20, P = 0.494; Sepsis-3: OR = 0.80, 95%CI was 0.55-1.17, P = 0.249). The results of GAM model validation were consistent with the results of Logistic regression equation cross validation. CONCLUSIONS: The relationship between sCD73 and 90-day mortality is significantly different from patients with non-sepsis shock and sepsis shock. In patients with non-sepsis shock, sCD73 is trend to positively associated with 90-day mortality, and there is a negative trend between sCD73 and 90-day mortality in patients with septic shock.

Deubiquitinase Inhibitor b-AP15 Attenuated LPS-Induced Inflammation via Inhibiting ERK1/2, JNK, and NF-Kappa B.

b-AP15 is a deubiquitinase (DUB) inhibitor of 19S proteasomes, which in turn targets ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14). Nuclear factor kappa B (NF-κB) is closely linked to cellular response in macrophages when the organism is in the state of microbial infection, and it acts as a vital part in the mechanism of inflammatory reaction. However, the molecular mechanism by which DUB inhibitors, especially b-AP15, regulates inflammation remains poorly understood. This study aimed to investigate the relationship between b-AP15 and inflammation. The results showed that b-AP15 treatment significantly reduced the amounts of inflammatory indicators, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in lipopolysaccharide (LPS)-stimulated THP-1 and macrophages. Meanwhile, similar results were obtained from in vivo experiments. In addition, b-AP15 also significantly improved the survival rate of sepsis mouse via high-density LPS mediation. Furthermore, b-AP15 also inhibited the ERK1/2 and JNK phosphorylation, increased IκBα levels, and inhibited NF-κB p65 by removing them from the cytoplasm into the nucleus. All these findings suggested that b-AP15 has anti-inflammatory action and acts as a potential neoteric target drug for treating microbial infection.