Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear. OBJECTIVES: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS. METHODS: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry. RESULTS: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher. CONCLUSIONS: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

The Postharvest Application of Carvone, Abscisic Acid, Gibberellin, and Variable Temperature for Regulating the Dormancy Release and Sprouting Commencement of Mini-Tuber Potato Seeds Produced under Aeroponics.

This study investigated the efficacy of carvone, abscisic acid (ABA), gibberellin (GA3), and variable temperature in managing dormancy and sprouting in aeroponically grown mini-tuber potato (Solanum tuberosum L.) seeds. The results showed that carvone treatment effectively reduced the weight loss rate by 12.25% and decay rate by 3.33% at day 25 compared to control. ABA treatment significantly enhanced the germination rate, increasing it to 97.33%. GA3 treatment resulted in the longest sprouts of 14.24 mm and reduced the MDA content by 23.08% at day 30, indicating its potential in shortening dormancy and maintaining membrane integrity. The variable-temperature treatment demonstrated a balanced performance in reducing weight loss and maintaining a lower relative conductivity, indicating less cellular damage. The enzymatic activities of α-amylase, CAT, and SOD were modulated by the treatments, ensuring a balanced enzymatic environment for seed vitality. These results establish a solid basis for improving postharvest management strategies to optimize germination uniformity and preserve the quality of aeroponic potato seeds during extended dormancy, promising enhanced yield and productivity in potato cultivation.

Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination.

Maresin1 is a potent lipid mediator exhibiting potential anti-inflammatory activity in a variety of inflammatory diseases, however, the underlying mechanisms remain poorly understood. Excessive activation of NLRP3 inflammasome has been established in multiple inflammatory diseases. Here, we show that Maresin1 dose-dependently inhibited the NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1ß secretion. This inhibitory effect could be reversed by KH7 and H89, the inhibitors of the cAMP-PKA signaling pathway. Activation of PKA kinase induced by Maresin1 led to the K63-linked ubiquitination of NLRP3 in macrophages. Maresin1 attenuated serum IL-1ß secretion through inhibition of NLRP3 inflammasome in vivo using Nlrp3-deficient mouse models of lipopolysaccharide (LPS)-induced sepsis. Maresin1 also repressed MSU-induced peritonitis. This study suggests that Maresin1 is an inhibitor of NLRP3 inflammasome activation and can be used clinically in the treatment of NLRP3 inflammasome-driven inflammatory diseases.

Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. An excessive inflammatory response results in the progression of ALI/ARDS, and the NLRP3 inflammasome is a key participant in inflammation. Erythropoietin (EPO), which is clinically used for anemia, reportedly exerts pleiotropic effects in ALI. However, whether EPO could protect against lipopolysaccharide (LPS)-induced ALI by regulating the NLRP3 inflammasome and its underlying mechanisms remain poorly elucidated. This study aimed to explore whether the therapeutic effects of EPO rely on the suppression of the NLRP3 inflammasome and the specific mechanisms in an LPS-induced ALI mouse model. ALI was induced in C57BL/6 mice by intraperitoneal (i.p.) injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 h later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry (W/D) ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) secretion, the expression of NLRP3 inflammasome components including pro-IL-1ß, NLRP3, and cleaved caspase-1 as well as phosphorylation of nuclear factor-κB (NF-κB) p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of Janus-tyrosine kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). However, all the beneficial effects of EPO on ALI and modulation NLRP3 inflammasome were remarkably abrogated by the inhibition of EPOR/JAK2/STAT3 pathway and knockout (KO) of NLRP3 gene. Taken together, this study indicates that EPO can effectively attenuate LPS-induced lung injury in mice by suppressing the NLRP3 inflammasome, which is dependent upon activation of EPOR/JAK2/STAT3 signaling and inhibition of the NF-κB pathway.

Coagulative biomarkers on admission to the ICU predict acute kidney injury and mortality in patients with septic shock caused by intra-abdominal infection.

PURPOSE: Sepsis-associated coagulopathy (SAC) contributes to the development of multiple organ failure (MOF) and increasing mortality. The present study was conducted to investigate whether coagulative biomarkers on admission to the intensive care unit (ICU) can predict acute kidney injury (AKI) and mortality in patients with septic shock caused by intra-abdominal infection (IAI). PATIENTS AND METHODS: An observational retrospective study was conducted in the surgical ICU. We studied patients who met the criteria of septic shock (Sepsis-3) caused by IAI between January 1, 2013, and December 31, 2016. By adjusting for baseline characteristics, multivariate regression analyses were employed to identify independent risk factors for predicting AKI and mortality. RESULTS: Of the 138 enrolled patients, 65 patients developed AKI. The patients who developed AKI exhibited a dramatically higher Sequential Organ Failure Assessment (SOFA) score (median, 12), Acute Physiology and Chronic Health Evaluation (APACHE) II score (median, 27.5) and mortality rate. In both models, we found that activated partial thromboplastin time (APTT) (odds ratio (OR)=1.074, 95% confidence interval (CI) 1.030-1.120, p=0.001), prothrombin time (PT) (OR=1.162, 95% CI 1.037-1.302, p=0.010) and D-dimer level (OR=1.098, 95% CI 1.002-1.202, p=0.045) on admission to the ICU were significant risk factors for AKI. Moreover, Cox regression analysis showed that prolonged APTT (OR=1.065, 95% CI 1.025-1.107, p=0.001) was independently associated with high mortality. CONCLUSION: In patients with septic shock caused by IAI, APTT, PT and D-dimer level on admission to the ICU were significantly associated with AKI. Furthermore, APTT was an independent predictor of 30-day mortality.

Low-Copy Number Polymorphism in DEFA1/DEFA3 Is Associated with Susceptibility to Hospital-Acquired Infections in Critically Ill Patients.

DEFA1/DEFA3, genes encoding human neutrophil peptides (HNP) 1-3, display wide-ranging copy number variations (CNVs) and is functionally associated with innate immunity and infections. To identify potential associations between DEFA1/DEFA3 CNV and hospital-acquired infections (HAIs), we enrolled 106 patients with HAIs and 109 controls in the intensive care unit (ICU) and examined their DEFA1/DEFA3 CNVs. DEFA1/DEFA3 copy number ranged from 2 to 16 per diploid genome in all 215 critically ill patients, with a median of 7 copies. In HAIs, DEFA1/DEFA3 CNV varied from 2 to 12 with a median of 6, which was significantly lower than that in controls (2 to 16 with a median of 8, p = 0.017). Patients with lower DEFA1/DEFA3 copy number (CNV < 7) were far more common in HAIs than in controls (52.8% in HAIs versus 35.8% in controls; p = 0.014; OR, 2.010; 95% CI, 1.164-3.472). The area under the receiver operating characteristic (AUROC) of DEFA1/DEFA3 CNV combined with clinical characteristics to predict the incidence of HAIs was 0.763 (95% CI 0.700-0.827), showing strong predictive ability. Therefore, lower DEFA1/DEFA3 copy number contributes to higher susceptibility to HAIs in critically ill patients, and DEFA1/DEFA3 CNV is a significant hereditary factor for predicting HAIs.

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

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

A multifactor model for predicting mortality in critically ill patients: A multicenter prospective cohort study.

PURPOSE: The objective of this study was to develop a model using a combination of routine clinical variables to predict mortality in critically ill patients. METHODS: A cohort of 500 patients recruited from eight university hospital intensive care units (ICUs) was used to develop a model via logistic regression analyses. Discrimination and calibration analyses were performed to assess the model. RESULTS: The model included the lactate level (odds ratio [OR]=1.11, 95% confidence interval [CI] 1.01 to 1.22, P=0.029), neutrophil-to-lymphocyte ratio (OR=1.03, 95% CI 1.01 to 1.04, P=0.002), acute physiology score (OR=1.11, 95% CI 1.06 to 1.15, P<0.001), Charlson comorbidity index (OR=1.36, 95% CI 1.15 to 1.60, P<0.001) and surgery type (OR: selective=Ref, no surgery=8.04, 95% CI 3.74 to 17.30, P<0.001, emergency=3.66, 95% CI 1.60 to 8.36, P=0.002). The model showed good discrimination (area under receiver operating characteristic curve: 0.84, 95% CI: 0.80 to 0.87) and calibration (Hosmer-Lemeshow test P=0.137) for predicting in-hospital mortality. CONCLUSION: The developed multifactor model can be used to effectively predict mortality in critically ill patients at ICU admission.

Comparison of the Performance Between Sepsis-1 and Sepsis-3 in ICUs in China: A Retrospective Multicenter Study.

The definition of sepsis was updated to sepsis-3 in February 2016. However, the performance of the previous and new definition of sepsis remains unclear in China. This was a retrospective multicenter study in six intensive care unit (ICUs) from five university-affiliated hospitals to compare the performance between sepsis-1 and sepsis-3 in China. From May 1, 2016 to June 1, 2016, 496 patients were enrolled consecutively. Data were extracted from the electronic clinical records. We evaluated the performance of sepsis-1 and sepsis-3 by measuring the area under the receiver operating characteristic curves (AUROC) to predict 28-day mortality rates. Of 496 enrolled patients, 186 (37.5%) were diagnosed with sepsis according to sepsis-1, while 175 (35.3%) fulfilled the criteria of sepsis-3. The AUROC of systemic inflammatory response syndrome (SIRS) is significantly smaller than that of sequential organ failure assessment (SOFA) (0.55 [95% confidence interval, 0.46-0.64] vs. 0.69 (95% confidence interval, 0.61-0.77], P = 0.008) to predict 28-day mortality rates of infected patients. Moreover, 5.9% infected patients (11 patients) were diagnosed as sepsis according to sepsis-1 but not to sepsis-3. The APACHE II, SOFA scores, and mortality rate of the 11 patients were significantly lower than of patients whose sepsis was defined by both the previous and new criteria (8.6±3.5 vs. 16.3±6.2, P =  < 0.001; 1 (0-1) vs. 6 (4-8), P = <0.001; 0.0 vs. 33.1%, P = 0.019). In addition, the APACHE II, length of stay in ICU, and 28-day mortality rate of septic patients rose gradually corresponding with the raise in SOFA score (but not the SIRS score). Sepsis-3 performed better than sepsis-1 in the study samples in ICUs in China.

Expression of high mobility group protein B1 in the lungs of rats with sepsis.

BACKGROUND: Vibrio vulnificus inside the body could activate the NF-κB signaling pathway and initiate the inflammatory cascade. The lung is one of the earliest organs affected by sepsis associated with acute lung injury. High mobility group protein B1 (HMGB1) is an important late-acting pro-inflammatory cytokine involving in the pathophysiology of sepsis. It is also involved in the injury process in the lung, liver and intestine. There has been no report on the involvement of HMGB1 in Vibrio vulnificus sepsis-induced lung injury. METHODS: Sixty rats were randomly divided into a normal control group (group A, n=10) and a Vibrio vulnificus sepsis group (group B, n=50). Sepsis was induced in the rats by subcutaneous injection of Vibrio vulnificus (concentration 6×10(8) cfu/mL, volume 0.1 mL/100g)) into the left lower limbs. The rats in group B were sacrificed separately 1, 6, 12, 24, and 48 hours after the infection. Their lungs were stored as specimens, lung water content was measured, and lung pathology was observed under a light microscope. The expressions of the HMGB1 gene and protein in the lungs were detected by RT-PCR and Western blot. Data were analyzed with one-way analysis of variance (ANOVA) and the LSD method for pair-wise comparison between the two groups. P<0.05 was considered statistically significant. RESULTS: Compared to group A (0.652±0.177), HMGB1 mRNA expression in the lungs of group B was significantly higher at 0 hour (1.161±0.358, P=0.013), 24 hours (1.679±0.235, P=0.000), and 48 hours (1.258±0.274, P=0.004) (P<0.05), and peaked at 24 hours. Compared to group A (0.594±0.190), HMGB1 protein expression at 6 hours (1.408±0.567, P=0.026) after infection was significantly increased (P<0. 05), and peaked at 24 hours (2.415±1.064, P=0.000) after infection. Compared to group A (0.699±0.054), lung water content was significantly increased at 6 hours (0.759±0.030, P=0.001),12 hours (0.767±0.023, P=0.000), 24 hours (0.771±0.043, P=0.000) and 48 hours (0.789±0.137, P=0.000) after infection (P<0.05). Compared to group A, pathological changes at 12 hours in group B indicate marked pulmonary vascular congestion, interstitial edema and inflammatory infiltration. Alveolar cavity collapse and boundaries of the alveolar septum could not be clearly identified. CONCLUSION: Vibrio vulnificus sepsis can lead to injury in rat lungs, and increased HMGB1 expression in lung tissue may be one of the mechanisms for injury from Vibrio vulnificus sepsis.

[Expression of inflammatory factors in lung tissue of acute paraquat poisoned rats].

OBJECTIVE: To investigate the expression of inflammatory factors in lung tissue of acute paraquat (PQ) poisoned rats. METHODS: Fifty male SD rats were randomized divided into two groups: the normal control group (NC group, n = 10) and the PQ group (n = 40). The 1 ml saline was administered once in normal control group. The PQ group was administered with 20 mg/kg 1% PQ by intraperitoneal injection to establish the model of PQ induced lung injury. At six hours, at the first, the third and the seventh day the PQ group were sacrificed, while at the first day the normal control group was sacrificed. The level of tumor necrosis factor alpha (TNF-alpha) mRNA, interleukin 10 (IL-10) mRNA, high mobility group box 1 (HMGB-1) mRNA in lung of rats were detected. Meanwhile, pathological changes of the lung were examined under optical microscope. RESULTS: Compared with that in normal control group, TNF-alpha mRNA expression in lung tissue of PQ group reached the peak at the six hour and decreased slowly at the first day [(0.740 +/- 0.100) and (0.584 +/- 0.049) respectively]. At the six hour and the first day in PQ group it was significantly higher than that in normal control group (P < 0.05 or P < 0.01). IL-10 mRNA expression in lung tissue of PQ group was elevated at the six hour, reached the peak at the first day, at the third day [(0.551 +/- 0.016) and (0.524 +/- 0.010) respectively] and the seventh day also higher than that in normal control group. At the first and the seventh day in the PQ group it was significantly higher than that in normal control group (P < 0.01). Meanwhile, HMGB-1 mRNA expression in lung tissue of PQ group was also elevated at the six hour, reached the peak at the first day, at the third [(0.695 +/- 0.060), (0.871 +/- 0.154) and (0.819 +/- 0.188) respectively] and the seventh day also higher than that in normal control group. At six hour, the first and the third day in the PQ group it was significantly higher than that in normal control group (P < 0.01). The histological changes such as alveolar edema, hemorrhage and inflammatory cell infiltration in the PQ group were more than those in the normal control group. CONCLUSION: In rats after PQ intoxication the levels of the inflammatory factors TNF-alpha, IL-10 and HMGB-1 are higher than normal rats, and inflammatory could play an important role in lung injury of poisoned rats.