Novel cortisol trajectory sub-phenotypes in sepsis.

BACKGROUND: Sepsis is a heterogeneous syndrome. This study aimed to identify new sepsis sub-phenotypes using plasma cortisol trajectory. METHODS: This retrospective study included patients with sepsis admitted to the intensive care unit of Zhongshan Hospital Fudan University between March 2020 and July 2022. A group-based cortisol trajectory model was used to classify septic patients into different sub-phenotypes. The clinical characteristics, biomarkers, and outcomes were compared between sub-phenotypes. RESULTS: A total of 258 patients with sepsis were included, of whom 186 were male. Patients were divided into two trajectory groups: the lower-cortisol group (n = 217) exhibited consistently low and slowly declining cortisol levels, while the higher-cortisol group (n = 41) showed relatively higher levels in comparison. The 28-day mortality (65.9% vs.16.1%, P < 0.001) and 90-day mortality (65.9% vs. 19.8%, P < 0.001) of the higher-cortisol group were significantly higher than the lower-cortisol group. Multivariable Cox regression analysis showed that the trajectory sub-phenotype (HR = 5.292; 95% CI 2.218-12.626; P < 0.001), APACHE II (HR = 1.109; 95% CI 1.030-1.193; P = 0.006), SOFA (HR = 1.161; 95% CI 1.045-1.291; P = 0.006), and IL-1ß (HR = 1.001; 95% CI 1.000-1.002; P = 0.007) were independent risk factors for 28-day mortality. Besides, the trajectory sub-phenotype (HR = 4.571; 95% CI 1.980-10.551; P < 0.001), APACHE II (HR = 1.108; 95% CI 1.043-1.177; P = 0.001), SOFA (HR = 1.270; 95% CI 1.130-1.428; P < 0.001), and IL-1ß (HR = 1.001; 95% CI 1.000-1.001; P = 0.015) were also independent risk factors for 90-day mortality. CONCLUSION: This study identified two novel cortisol trajectory sub-phenotypes in patients with sepsis. The trajectories were associated with mortality, providing new insights into sepsis classification.

Response of seed germination, seedling growth and physiological characteristics to alkali stress in halophyte Suaeda liaotungensis.

Soil salinization has been considered as a major environmental threat to plant growth. Different types of salt in saline soil have different effects on germination and seedling growth. Effect of NaCl on germination and seedling establishment in Suaeda liaotungensis have been reported, but its response to alkali stress remains unclear. Our results showed that brown seeds had higher germination rate, however, black seeds had higher germination recovery percentage under alkali stress. Na2CO3 had stronger inhibitory effect on germination and seedling growth than NaHCO3. As the concentration of alkali stress increased, the ROS level of brown seeds gradually ascended, while that of black seeds decreased first and then ascended. MDA content of dimorphic seeds significantly increased under alkali stress. The trend of SOD, POD and CAT activity between dimorphic seeds was similar under the same type of alkali stress. Alkali stress enhanced proline content of dimorphic seeds, and dimorphic seeds in NaHCO3 solution had higher proline content than Na2CO3 solution. Moreover, radicle and shoot tolerance indexes of seedlings in NaHCO3 solution were significantly higher than that of Na2CO3 solution. Under strong alkali stress, seedlings in NaHCO3 solution had significantly lower ROS level and MDA content as well as higher antioxidant enzyme activity than Na2CO3 solution. This study comprehensively compared the morphological and physiological characteristics in germination and seedlings to better reveal the saline-alkali tolerance mechanisms in S. liaotungensis.

Luteimonas suaedae sp. nov., a novel bacterium isolated from rhizosphere of Suaeda aralocaspica (Bunge) Freitag & Schütze.

Light yellowish-white colonies of a bacterial strain, designated LNNU 24178T, were isolated from the rhizosphere soil of halophyte Suaeda aralocaspica (Bunge) Freitag and Schütze grown at Shihezi district, Xinjiang, PR China. Cells were Gram-stain-negative, non-flagellum-forming, rod-shaped and non-motile. The results of phylogenetic analysis based on the 16S rRNA gene sequence indicated that LNNU 24178T represented a member of the genus Luteimonas and shared the highest sequence similarity with Luteimonas yindakuii CGMCC 1.13927T (97.1 %) and lower sequence similarity (< 97.0 %) to other known species. The genomic DNA G+C content of LNNU 24178T was 68.8 %. The average nucleotide identity (ANI) values between LNNU 24178T and Luteimonas yindakuii CGMCC 1.13927T, Luteimonas mephitis DSM 12574T, Luteimonas arsenica 26-35T and Luteimonas huabeiensis HB2T were 78.7, 78.6, 78.4 and 80.0 %, respectively. The digital DNA-DNA hybridisation (dDDH) values between LNNU 24178T and L. yindakuii CGMCC 1.13927T, L. mephitis DSM 12574T, L. arsenica 26-35T and L. huabeiensis HB2T were 22.0, 22.3, 22.2 and 23.5 %, respectively. The respiratory quinone detected in LNNU 24178T was ubiquinone-8 (Q-8). The major fatty acids (> 5.0 %) of LNNU 24178T were identified as iso-C15 : 0 (33.9 %), iso-C17 : 0 (8.7 %), iso-C11 : 0 (6.2 %), iso-C16 : 0 (5.7 %), C16 : 0 (5.3 %) and summed feature 9 (iso-C17 : 1ω9c/10-methyl C16 : 0) (21.1 %). The major polar lipids of LNNU 24178T were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), one unidentified phospholipid (PL), one unidentified glycolipid (GL) and three unidentified lipids. According to the data obtained from phenotypic, chemotaxonomic and phylogenetic analyses, strain LNNU 24178T represents a novel species of the genus Luteimonas, for which the name Luteimonas suaedae sp. nov. is proposed, with LNNU 24178T (= CGMCC 1.17331T= KCTC 62251T) as the type strain.

Effect of environmental factors on seed germination and seedling emergence of Viola prionantha, a cleistogamous plant.

Environmental conditions during seed development and maturation can affect seed traits and germination behavior, yet systematic research on the effects of seed maturation time on seed traits, germination behavior and seedling emergence of cleistogamy plants is lacking. Here, we determined the difference in phenotypic characteristics of CH and CL (namely CL1, CL2 and CL3 based on maturation time, respectively) fruits/seeds that were collected from Viola prionantha Bunge, a cleistogamous perennial plant, and evaluated the effects of various environmental factors on seed germination and seedling emergence. The fruit mass, width, seed number per fruit and mean seed mass of CL1 and CL3 were greater than that of CH and CL2, while seed setting of CH was lower than that of CL1, CL2 and CL3. Germination of CH, CL1, CL2, and CL3 seeds was < 10% in the dark at 15/5 and 20/10 â„ƒ, whereas germination (0%-99.2%) of CH, CL1, CL2, and CL3 seeds changed significantly under light conditions. In contrast, more than 71% (from 71.7 to 94.2%) germination of both CH, CL1, CL2 and CL3 seeds occurred under both light/dark conditions and continuous darkness at 30/20 â„ƒ. Germination of CH, CL1, CL2 and CL3 seeds was sensitive to osmotic potential, but CL1 seeds were more resistant to osmotic stress, compared with CH, CL2 and CL3. Seedling emergence of CH seeds was more than 67% (from 67.8 to 73.3%) at a burial depth of 0 cm-2 cm, while all types of CL seeds were below 15% at a burial depth of 2 cm. Information gathered from this study indicates that CH and CL seeds of V. prionantha were different in fruit size, seed mass, thermoperiod and photoperiod sensitivity, osmotic potential tolerance and seedling emergence, especially, maturation time significantly affect phenotypic characteristics and germination behavior of CL seeds matured at different periods. These results indicate that V. prionantha adapts to unpredictable environmental conditions by developing a variety of adaptation strategies, and ensures the survival and reproduction of the populations.

Contrast-Enhanced Ultrasonography Value for Early Prediction of Delayed Graft Function in Renal Transplantation Patients.

OBJECTIVES: Delayed graft function (DGF) is a common early complication after kidney transplantation. The aim of the present study was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the early prediction of DGF after kidney transplantation. METHODS: A total of 89 renal transplant recipients were retrospectively enrolled and divided into DGF group or normal graft function (NGF) group according to the allograft function. Conventional Doppler ultrasound and CEUS examination data on the first postoperative day were collected and analyzed. RESULTS: The resistive indices of segmental and interlobar artery in the DGF group were significantly higher than those in the NGF group (0.71 ± 0.17 versus 0.63 ± 0.08, P = .006; 0.70 ± 0.16 versus 0.62 ± 0.08, P = .004, respectively). The patients experiencing DGF had significantly lower PI-c (14.7 dB ± 6.1 dB versus 18.5 dB ± 3.3 dB, P = .001) and smaller AUC-c (779.8 ± 375.8 dB·seconds versus 991.0 ± 211.7 dB·seconds, P = .003), as well as significantly lower PI-m (12.6 dB ± 5.9 dB versus 15.9 dB ± 3.9 dB, P = .006), shorter MTT-m (30.7 ± 9.4 seconds versus 36.3 ± 7.1 seconds, P = .01), and smaller AUC-m (P = .007). Multivariate analysis demonstrated that PI-c, AUC-c, and MTT-m were independent risk factors for DGF. The area under the receiver operating characteristic curve values of the combined predicted value (PI-c + MTT-m, PI-c + AUC-c + MTT-m) of DGF incidence were bigger than that of PI-c, AUC-c, or MTT-m. CONCLUSIONS: CEUS parameters of the cortex and medulla have a good value for an early prediction of DGF after renal transplantation.

Feasibility and discriminatory value of tissue motion annular displacement in sepsis-induced cardiomyopathy: a single-center retrospective observational study.

BACKGROUND: There is no formal diagnostic criterion for sepsis-induced cardiomyopathy (SICM), but left ventricular ejection fraction (LVEF) < 50% was the most commonly used standard. Tissue motion annular displacement (TMAD) is a novel speckle tracking indicator to quickly assess LV longitudinal systolic function. This study aimed to evaluate the feasibility and discriminatory value of TMAD for predicting SICM, as well as prognostic value of TMAD for mortality. METHODS: We conducted a single-center retrospective observational study in patients with sepsis or septic shock who underwent echocardiography examination within the first 24 h after admission. Basic clinical information and conventional echocardiographic data, including mitral annular plane systolic excursion (MAPSE), were collected. Based on speckle tracking echocardiography (STE), global longitudinal strain (GLS) and TMAD were, respectively, performed offline. The parameters acquisition rate, inter- and intra-observer reliability, time consumed for measurement were assessed for the feasibility analysis. Areas under the receiver operating characteristic curves (AUROC) values were calculated to assess the discriminatory value of TMAD/GLS/MAPSE for predicting SICM, defined as LVEF < 50%. Kaplan-Meier survival curve analysis was performed according to the cutoff values in predicting SICM. Cox proportional hazards model was performed to determine the risk factors for 28d and in-hospital mortality. RESULTS: A total of 143 patients were enrolled in this study. Compared with LVEF, GLS or MAPSE, TMAD exhibited the highest parameter acquisition rate, intra- and inter-observer reliability. The mean time for offline analyses with TMAD was significantly shorter than that with LVEF or GLS (p < 0.05). According to the AUROC analysis, TMADMid presented an excellent discriminatory value for predicting SICM (AUROC > 0.9). Patients with lower TMADMid (< 9.75 mm) had significantly higher 28d and in-hospital mortality (both p < 0.05). The multivariate Cox proportional hazards model revealed that BMI and SOFA were the independent risk factors for 28d and in-hospital mortality in sepsis cases, but TMAD was not. CONCLUSION: STE-based TMAD is a novel and feasible technology with promising discriminatory value for predicting SICM with LVEF < 50%.

Prone positioning improves ventilation-perfusion matching assessed by electrical impedance tomography in patients with ARDS: a prospective physiological study.

BACKGROUND: The physiological effects of prone ventilation in ARDS patients have been discussed for a long time but have not been fully elucidated. Electrical impedance tomography (EIT) has emerged as a tool for bedside monitoring of pulmonary ventilation and perfusion, allowing the opportunity to obtain data. This study aimed to investigate the effect of prone positioning (PP) on ventilation-perfusion matching by contrast-enhanced EIT in patients with ARDS. DESIGN: Monocenter prospective physiologic study. SETTING: University medical ICU. PATIENTS: Ten mechanically ventilated ARDS patients who underwent PP. INTERVENTIONS: We performed EIT evaluation at the initiation of PP, 3 h after PP initiation and the end of PP during the first PP session. MEASUREMENTS AND MAIN RESULTS: The regional distribution of ventilation and perfusion was analyzed based on EIT images and compared to the clinical variables regarding respiratory and hemodynamic status. Prolonged prone ventilation improved oxygenation in the ARDS patients. Based on EIT measurements, the distribution of ventilation was homogenized and dorsal lung ventilation was significantly improved by PP administration, while the effect of PP on lung perfusion was relatively mild, with increased dorsal lung perfusion observed. The ventilation-perfusion matched region was found to increase and correlate with the increased PaO2/FiO2 by PP, which was attributed mainly to reduced shunt in the lung. CONCLUSIONS: Prolonged prone ventilation increased dorsal ventilation and perfusion, which resulted in improved ventilation-perfusion matching and oxygenation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04725227. Registered on 25 January 2021.

Transcriptome Analysis Reveals Genes and Pathways Associated with Salt Tolerance during Seed Germination in Suaeda liaotungensis.

Seed germination is susceptible to external environmental factors, especially salt stress. Suaeda liaotungensis is a halophyte with strong salt tolerance, and the germination rate of brown seeds under 1000 mM NaCl treatment still reached 28.9%. To explore the mechanism of salt stress response during brown seed germination in Suaeda liaotungensis, we conducted transcriptomic analysis on the dry seeds (SlD), germinated seeds under the control condition (SlG_C), and salt treatment (SlG_N). Transcriptome analysis revealed that 13314 and 755 differentially expressed genes (DEGs) from SlD vs. SlG_C and SlG_C vs. SlG_N were detected, respectively. Most DEGs were enriched in pathways related to transcription regulation and hormone signal transduction, ROS metabolism, cell wall organization or biogenesis, and carbohydrate metabolic process in two contrasting groups. Compared with the control condition, POD and CAT activity, H2O2, soluble sugar, and proline contents were increased during germinated seeds under salt stress. Furthermore, functional analysis demonstrated that overexpression of SlNAC2 significantly enhanced salt tolerance during the germination stage in Arabidopsis. These results not only revealed the tolerant mechanism of brown seed germination in response to salinity stress but also promoted the exploration and application of salt-tolerant gene resources of Suaeda liaotungensis.

A Transcription Factor SlNAC10 Gene of Suaeda liaotungensis Regulates Proline Synthesis and Enhances Salt and Drought Tolerance.

The NAC (NAM, ATAF1/2, and CUC2) transcription factors are one of the largest families of transcription factors in plants and play an important role in plant development and the response to adversity. In this study, we cloned a new NAC gene, SlNAC10, from the halophyte Suaeda liaotungensis K. The gene has a total length of 1584 bp including a complete ORF of 1107 bp that encodes 369 amino acids. The SlNAC10-GFP fusion protein is located in the nucleus and SlNAC10 has a transcription activation structural domain at the C-terminus. We studied the expression characteristics of SlNAC10 and found that it was highest in the leaves of S. liaotungensis and induced by drought, salt, cold, and abscisic acid (ABA). To analyze the function of SlNAC10 in plants, we obtained SlNAC10 transgenic Arabidopsis. The growth characteristics and physiological indicators of transgenic Arabidopsis were measured under salt and drought stress. The transgenic Arabidopsis showed obvious advantages in the root length and survival rate; chlorophyll fluorescence levels; and the antioxidant enzyme superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities, and the proline content was higher than that of the wild-type (WT) Arabidopsis, whereas the relative electrolyte leakage and malondialdehyde (MDA) content were lower than those of the wild-type Arabidopsis. We explored the regulatory role of SlNAC10 on proline synthesis-related enzyme genes and found that SlNAC10 binds to the AtP5CS1, AtP5CS2, and AtP5CR promoters and regulates their downstream gene transcription. To sum up, SlNAC10 as a transcription factor improves salt and drought tolerance in plants possibly by regulating proline synthesis.

Ruania rhizosphaerae sp. nov., a novel actinobacterium isolated from rhizosphere of Suaeda aralocaspica.

A Gram-stain-positive, non-motile and short rod-shaped actinobacterium, designated strain LNNU 22110T, was isolated from the rhizosphere soil of the halophyte Suaeda aralocaspica (Bunge) Freitag and Schütze, which collected in Xinjiang, north-west China. Growth occurred at 10-45 °C, pH 6.0-10.0 and in the presence of 0-11 % NaCl (w/v). Based on the results of 16S rRNA gene sequence phylogenetic analyses, strain LNNU 22110T belonged to the genus Ruania and had 97.5 and 95.5 % sequence similarity to Ruania alba KCTC 19413T and Ruania albidiflava CGMCC 4.3142T, respectively. The digital DNA-DNA hybridization relatedness values between strain LNNU 22110T and R. alba KCTC 19413T and R. albidiflava CGMCC 4.3142T were 23.2 and 19.9 %, respectively. The highest average nucleotide identity value between strain LNNU 22110T and its closest related strain (R. alba KCTC 19413T) was 80.2 %, much lower than the species delineation threshold of 95-96 %. The genome of strain LNNU 22110T was 4.4 Mb, with a genomic DNA G+C content of 68.4 mol%. The diagnostic diamino acids in the peptidoglycan layer of strain LNNU 22110T were lysine, alanine, glycine, glutamic acid and aspartic acid. The predominant menaquinone was MK-8(H4). The major fatty acid (>10 %) was anteiso-C15 : 0. The polar lipid profile of strain LNNU 22110T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, diacylated phosphatidyl dimannoside, one unidentified glycolipid and two unidentified phospholipids. According to the phenotypic, phylogenetic and chemotaxonomic results, strain LNNU 22110T is considered to represent a novel species of the genus Ruania, for which the name Ruania rhizosphaerae sp. nov. is proposed. The type strain is LNNU 22110T (=KCTC 39807T=CGMCC 1.17105T).

Hoyosella suaedae sp. nov., a novel bacterium isolated from rhizosphere soil of Suaeda aralocaspica (Bunge) Freitag & Schütze.

A Gram-stain-positive, non-motile and coccus-shaped bacterium, designated strain LNNU 331112T, was isolated from the composite rhizosphere soil of the halophyte Suaeda aralocaspica (Bunge) Freitag and Schütze, which was collected in Xinjiang, north-west China. Growth occurred at 10-45 °C, pH 6.0-11.0 and in the presence of 0-10 % NaCl (w/v). Phylogenetic analysis based on the 16S rRNA gene sequence suggested that strain LNNU 331112T belonged to the genus Hoyosella and showed 95.6, 95.5 and 95.4 % sequence similarities to Hoyosella altamirensis DSM 45258T, Hoyosella subflava CGMCC 4.3532T and Hoyosella rhizosphaerae CGMCC 1.15478T, respectively. The estimated digital DNA-DNA hybridization relatedness values between strain LNNU 331112T and the type strains of H. altamirensis DSM 45258T, H. subflava CGMCC 4.3532T and H. rhizosphaerae CGMCC 1.15478T were 18.9, 19.3 and 18.3 %, respectively. The average nucleotide identity values between strain LNNU 331112T and H. altamirensis DSM 45258T, H. subflava CGMCC 4.3532T and H. rhizosphaerae CGMCC 1.15478T were 72.6, 72.7 and 72.3 %, respectively. The genome sequence of strain LNNU 331112T showed 69.0-72.3 % average amino acid identity values in comparison with the related genome sequences of three validly published Hoyosella species. The genome of strain LNNU 331112T was 3.47 Mb, with a DNA G+C content of 68.4 mol%. A total of 3182 genes were identified as protein-coding in strain LNNU 331112T. Genomic analysis revealed that a number of genes involved in osmotic pressure regulation, intracellular pH homeostasis and potassium (K+) uptake protein were found in strain LNNU 331112T. The predominant menaquinones were MK-8 (44.6 %) and MK-7 (55.4 %), which differentiated strain LNNU 331112T from other three recognized Hoyosella species. Major fatty acids (>10 %) were C17 : 1 ω8c (33.8 %), C16 : 0 (23.3 %), C17 : 0 (12.8 %) and summed feature 3 (12.9 %), which also clearly separated strain LNNU 331112T from three recognized Hoyosella species. The polar lipid profile of strain LNNU 331112T included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, one unidentified glycolipid, one unidentified phospholipid and two unidentified lipids. According to the results of phenotypic, chemotaxonomic and phylogenetic analyses, strain LNNU 331112T is considered to represent a novel species of the genus Hoyosella, for which the name Hoyosella suaedae sp. nov. is proposed. The type strain is LNNU 331112T (=KCTC 39808T=CGMCC 1.17107T=DSM 103463T).

High flow nasal cannula versus conventional oxygen therapy in postoperative patients at high risk for pulmonary complications: A systematic review and meta-analysis.

BACKGROUND: The effects of high flow nasal cannula (HFNC) on postoperative patients at high risk for pulmonary complications(PC) are controversial. We aimed to further determine the effectiveness of HFNC in postoperative patients at high risk for PC by comparison to conventional oxygen therapy (COT). METHODS: We performed a comprehensive search that compared HFNC with COT in postoperative patients at high risk for PC. The main outcomes were length of hospital stay (hospital LOS) and respiratory complications. RESULTS: Six trials with a total of 733 patients were pooled in our final studies. Except for Hospital LOS (I2  = 53%, χ2  = 8.51, P = .07) and rate of intubation or non-invasive ventilation (NIV) for respiratory failure (RF) (I2  = 49%, χ2  = 1.97, P = .16) between HFNC and COT, no significant heterogeneity was found in outcome measures. Compared with COT, HFNC was associated with a lower rate of intubation or NIV for RF (RR 0.23, 95% CI 0.08-0.66, P = .006) and rate of hypercapnia (RR 0.37, 95% CI 0.20-0.68, P = .002). As for the Hospital LOS, ICU LOS, rate of requirement of O2 after discontinuous and hypoxemia, HFNC did not show any advantage over COT. Trial Sequential Analysis (TSA) for Hospital LOS showed that monitoring boundaries were finally not surpassed and required information size (RIS) was not met. CONCLUSIONS: The available randomised controlled trials (RCTs) suggest that, among the postoperative patients at high risk for PC, HFNC therapy compared with the COT significantly reduces rate of incubation or NIV for RF and rate of hypercapnia, meanwhile is safely administered. Further large-scale, multicenter, randomised and controlled studies are needed to confirm our results.

The SMO1 Family of Sterol 4α-Methyl Oxidases Is Essential for Auxin- and Cytokinin-Regulated Embryogenesis.

In the plant sterol biosynthetic pathway, sterol 4α-methyl oxidase1 (SMO1) and SMO2 enzymes are involved in the removal of the first and second methyl groups at the C-4 position, respectively. SMO2s have been found to be essential for embryonic and postembryonic development, but the roles of SMO1s remain unclear. Here, we found that the three Arabidopsis (Arabidopsis thaliana) SMO1 genes displayed different expression patterns. Single smo1 mutants and smo1-1 smo1-3 double mutants showed no obvious phenotype, but the smo1-1 smo1-2 double mutant was embryo lethal. The smo1-1 smo1-2 embryos exhibited severe defects, including no cotyledon or shoot apical meristem formation, abnormal division of suspensor cells, and twin embryos. These defects were associated with enhanced and ectopic expression of auxin biosynthesis and response reporters. Consistently, the expression pattern and polar localization of PIN FORMED1, PIN FORMED7, and AUXIN RESISTANT1 auxin transporters were dramatically altered in smo1-1 smo1-2 embryos. Moreover, cytokinin biosynthesis and response were reduced in smo1-1 smo1-2 embryos. Tissue culture experiments further demonstrated that homeostasis between auxin and cytokinin was altered in smo1-1 smo1-2 heterozygous mutants. This disturbed balance of auxin and cytokinin in smo1-1 smo1-2 embryos was accompanied by unrestricted expression of the quiescent center marker WUSCHEL-RELATED HOMEOBOX5 Accordingly, exogenous application of either auxin biosynthesis inhibitor or cytokinin partially rescued the embryo lethality of smo1-1 smo1-2 Sterol analyses revealed that 4,4-dimethylsterols dramatically accumulated in smo1-1 smo1-2 heterozygous mutants. Together, these data demonstrate that SMO1s function through maintaining correct sterol composition to balance auxin and cytokinin activities during embryogenesis.

Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice.

BACKGROUND: Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1-phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis. METHODS: Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow-derived macrophages were prepared from C57BL/6J wild-type, Casp1, Nlrp3 and SphK1 mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan's blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured. RESULTS: SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1ß mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/FIO2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543-treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543-treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan's blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1ß release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1ß-evoked Src-mediated phosphorylation of vascular endothelial cadherin. CONCLUSIONS: SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis.

Heterozygous SOD2 deletion deteriorated chronic intermittent hypoxia-induced lung inflammation and vascular remodeling through mtROS-NLRP3 signaling pathway.

Oxidative stress caused by chronic intermittent hypoxia (CIH) is the hallmark of obstructive sleep apnea (OSA). Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (SOD2). In this study, wild-type (WT) and SOD2-heterozygous knockout (SOD2+/-) mice were exposed to CIH or normoxic (Nor) conditions. After 4 weeks, pulmonary artery pressure was measured, and the mice were processed to harvest either serum for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that heterozygous deletion of SOD2 markedly deteriorated pulmonary remodeling and increased the oxidative stress, especially promoted the infiltration of macrophages in the lungs of CIH mouse. Moreover, in the intermittent hypoxia (IH)-treated RAW264.7 cells, SOD2 knockdown increased the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation accompanied with the IL-1ß elevation and caspase-1 activity. Additionally, mitochondrial ROS (mtROS) scavenger mito-TEMPO abolished NLRP3 inflammasome activation in IH-treated RAW264.7 cells. Collectively, our results supported that SOD2 contributed to the pathogenesis of CIH-induced lung remodeling. Meanwhile, SOD2 knockdown exacerbates oxidative damage through assembly and activation of NLRP3 inflammasome in macrophages. SOD2 may be a novel therapeutic target for CIH-induced pulmonary inflammation and arteriole remodeling.

2-Methoxyestradiol attenuates chronic-intermittent-hypoxia-induced pulmonary hypertension through regulating microRNA-223.

Pulmonary hypertension (PH) is prevalent in patients with obstructive sleep apnea (OSA) syndrome, and coexistence of PH and OSA indicates a worse prognosis and higher mortality. Chronic intermittent hypoxia (CIH) is the key pathogenesis of OSA. Also, microRNA-223 (miR-223) plays a role in the regulation of CIH-induced PH process. However, the detailed mechanism of CIH inducing PH is still unclear. This study aimed to investigate the pathological process of CIH associated PH and explore the potential therapeutic methods. In this study, adult Sprague-Dawley rats were exposed to CIH or normoxic (N) conditions with 2-methoxyestradiol (2-Me) or vehicle treatment for 6 weeks. The results showed that 2-Me treatment reduced the progression of pulmonary angiogenesis in CIH rats, and alleviated proliferation, cellular migration, and reactive oxygen species formation was induced by CIH in pulmonary artery smooth muscle cells (PASMCs). CIH decreased the expression of miR-223, whereas 2-Me reversed the downregulation of miR-223 both in vivo and in vitro. Furthermore, the antiangiogenic effect of 2-Me observed in PASMCs was abrogated by miR-223 inhibitor, while enhanced by miR-223 mimic. These findings suggested that miR-223 played an important role in the process of CIH inducing PH, and 2-Me might reverse CIH-induced PH via upregulating miR-223.

Epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection: a case report and literature review.

Vibrio vulnificus is a Gram-negative bacterium that belongs to the Vibrionaceae family. It represents a deadly opportunistic human pathogen which grows in water with the proper temperature and salinity, and is mostly acquired from seafood eating or direct contact. In susceptible individuals, a traumatic infection could be fatal, causing severe wound infection and even septic shock, and may require amputation. Global warming plays an important role in the geographical area expanding of Vibrio disease. The pathogenesis of Vibrio vulnificus-associated sepsis is very complex, including iron intake, cell injury, and adhesion-related protein and virulence regulation. Vibrio vulnificus infection mainly manifests clinical subtypes such as primary sepsis, traumatic infection, and gastroenteritis, with rapid symptom progression and signs of multiple organ dysfunction syndrome (MODS). It is important to assess these pathogenetic mechanisms in order to select more appropriate measures to prevent and treat Vibrio vulnificus infections, including antibiotic usage and surgical intervention. In this work, we report a typical case of successful treatment of necrotizing fasciitis caused by Vibrio vulnificus, and review the epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection.

Sodium Arsenite Inhibits Lung Fibroblast Differentiation and Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality and poor prognosis. Transforming growth factor (TGF)-ß plays crucial roles in the pathogenesis of IPF. To investigate the role of sodium arsenite (SA) on fibroblast differentiation and pulmonary fibrosis, we checked the effects of SA on TGF-ß-induced normal human lung fibroblasts (NHLFs) differentiation, and the anti-fibrotic effect of SA on bleomycin (BLM)-induced pulmonary fibrosis in mouse. SA treatment significantly inhibits α-smooth muscle actin and fibronectin (FN) expression in TGF-ß treated NHLFs; and SA also inhibits TGF-ß stimulated expression of NADPH oxidase 4 and accumulation of intracellular reactive oxygen species. TGF-ß-induced the phosphorylation of ERK and Smad3 were also blocked by SA. The administration of SA (IP) suppressed BLM-induced lung fibrosis characterized as the inhibition of collagen deposition, TGF-ß accumulation in bronchoalveolar lavage fluid, and the expression of FN and collagen 1a2 in lung tissue. This study revealed that SA inhibits TGF-ß-induced lung fibroblast differentiation and BLM-induced pulmonary fibrosis in mice, suggesting that SA could be a potential therapeutic approach to IPF.

An LC-MS/MS method for quantification of HR011303, a novel highly selective urate transporter 1 inhibitor in beagle dogs and the application to a pharmacokinetic study.

HR011303 is a novel and highly selective urate transporter 1 (URAT1) inhibitor. In this study, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantification of HR011303 in beagle dog plasma. Plasma samples were pretreated with protein-precipitation extraction by acetonitrile and added with a trifluoromethyl substituted analog of HR011303 as internal standard. The chromatographic separation was performed on a Shiseido C18 column (100 × 4.6 mm, i.d., 5 µm) by mobile phases consisting of 5 mm ammonium-formic acid (100:0.1) and acetonitrile-formic acid (100:0.1) solutions in gradient elution. The MS detection was conducted in electrospray positive ionization with multiple reactions monitoring at m/z 338 → 240 for HR011303 and m/z 328 → 230 for the internal standard using 25 eV argon gas collision induced dissociation. The established LC-MS/MS method showed good selectivity, sensitivity, precision and accuracy. The plasma pharmacokinetics of HR011303 in beagle dogs following both oral and intravenous administration were then successfully evaluated using this LC-MS/MS method.