Development and external validation of a nomogram for the early prediction of acute kidney injury in septic patients: a multicenter retrospective clinical study.

Background and purpose: Acute kidney injury (AKI) is a common serious complication in sepsis patients with a high mortality rate. This study aimed to develop and validate a predictive model for sepsis associated acute kidney injury (SA-AKI). Methods: In our study, we retrospectively constructed a development cohort comprising 733 septic patients admitted to eight Grade-A tertiary hospitals in Shanghai from January 2021 to October 2022. Additionally, we established an external validation cohort consisting of 336 septic patients admitted to our hospital from January 2017 to December 2019. Risk predictors were selected by LASSO regression, and a corresponding nomogram was constructed. We evaluated the model's discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curves (CIC) in both internal and external validation. Results: AKI incidence was 53.2% in the development cohort and 48.2% in the external validation cohort. The model included five independent indicators: chronic kidney disease stages 1 to 3, blood urea nitrogen, procalcitonin, D-dimer and creatine kinase isoenzyme. The AUC of the model in the development and validation cohorts was 0.914 (95% CI, 0.894-0.934) and 0.923 (95% CI, 0.895-0.952), respectively. The calibration plot, DCA, and CIC demonstrated the model's favorable clinical applicability. Conclusion: We developed and validated a robust nomogram model, which might identify patients at risk of SA-AKI and promising for clinical applications.

Septic macrophages induce T cells immunosuppression in a cell-cell contact manner with the involvement of CR3.

Background: In addition to excessive inflammation, immunosuppression has been recognized as a contributing factor to poor prognosis of sepsis. Although it has been reported that T cells can become functionally impaired during sepsis, the underlying mechanisms responsible for this phenomenon remain unclear. This study aims to elucidate the mechanisms by which macrophages induce immunosuppression in T cells. Methods: In an in vivo setting, C57BL-6J mice were subjected to cecal ligation and puncture (CLP) with or without depletion of macrophages, and the functions of T cells were assessed. In vitro experiments involved direct co-culture or separate culture of T cells and septic macrophages using a transwell system, followed by analysis of T cell immunity. Additionally, a siRNA targeting CD18 on macrophages was utilized to investigate the role of complement receptor 3 (CR3). Results: Both macrophages and T cells exhibited immunosuppression during sepsis. In the in vivo experiments, the absence of macrophages partially alleviated T cell immunosuppression, as evidenced by restored vitality, increased production of TNF-α and IFN-γ, elevated CD8+ T cell levels, and decreased CD25+ T cell levels. In the in vitro experiments, direct co-culture of T cells with septic macrophages resulted in diminished T cell immunity, which was improved when T cells and macrophages were separated by a chamber wall. The expression of CR3 (CD11b/CD18) was upregulated on septic macrophages, and silencing of CD18 led to decreased TNF-α production by T cells, reduced CD4+ T cell numbers, and increased CD25+ T cell numbers. Conclusion: In sepsis, macrophages induce immunosuppression in T cells through direct cell-cell contact, with the involvement of CR3.

A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Prediction of post-transplant graft survival by different definitions of early allograft dysfunction.

BACKGROUND: The efficacy of early allograft dysfunction (EAD) definitions in predicting post-transplant graft survival in a Chinese population is still unclear. METHODS: A total of 607 orthotopic liver transplants (OLT) have been included in the current study. Model accuracy was evaluated using receiver operating characteristic (ROC) analysis. Risk factors for EAD was evaluated using univariable analysis and multivariable logistic regression model. RESULTS: The 3-, 6-, and 12-month patient/graft survival were 91.6%/91.4%, 91.1%/90%, and 87.5%/87.3%, respectively. MELDPOD5 had a superior discrimination of 3-month graft survival (C statistic, 0.83), compared with MEAF (C statistic, 0.77) and Olthoff criteria (C statistic, 0.72). Multivariate analysis of risk factors for EAD defined by MELDPOD5, showed that donor body mass index (P=0.001), donor risk index (P=0.006), intraoperative use of packed red blood cells (P=0.001), hypertension of recipient (P=0.004), and preoperative total bilirubin (P<0.001) were independent risk factors. CONCLUSIONS: The results suggest that MLEDPOD5 is a better criterion of EAD for the Chinese population, which might serve as a surrogate end-point for graft survival in clinical study.

Association of DYNC1H1 gene SNP/CNV with disease susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients.

BACKGROUND: Systemic lupus erythematosus is a heterogeneous autoimmune disease characterized by multi-system injuries and overproduction of autoantibodies. There are many genetic studies on SLE, but no report has considered the relationship between cytoplasmic dynein and SLE susceptibility. OBJECTIVES: Our study intends to investigate whether DYNC1H1 gene SNP/CNV is related to SLE susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients. METHODS: A total of 502 cases and 544 healthy controls were recruited into the case-control study, and 472 subjects from the case group were followed up for 12 weeks to evaluate GCs efficacy, HRQOL, anxiety, and depression. Multiplex SNaPshot technique was applied to genotype the seven SNPs of DYNC1H1, and AccuCopyTM method was conducted to quantify the copy number of DYNC1H1. Anxiety and depression were evaluated using HAMA and HAMD-24 scales, respectively. The SF-36 scale was used to assess HRQOL. RESULTS: The significant association between SNP rs1190606 and SLE susceptibility was displayed in the dominant model (PBH = 0.004) as well as its allele model (PBH = 0.004). We also found that SNP rs2273440 was related to photosensitization symptom in SLE patients (PBH = 0.032). In the follow-up study, SNP rs11160668 was connected with the improvement of BP in male patients (PBH = 0.011). However, no association of DYNC1H1 gene with GCs efficacy, anxiety, and depression was found. No CNV in DYNC1H1 was detected. CONCLUSIONS: The study suggests that DYNC1H1 gene polymorphisms may have an effect on SLE susceptibility and BP improvement of HRQOL in Chinese SLE patients.

Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution.

Ischemia-reperfusion injury (IRI) remains the major reason for impaired donor graft function and increased mortality post-liver transplantation. The mechanism of IRI involves multiple pathophysiological processes and numerous types of cells. However, a systematic and comprehensive single-cell transcriptional profile of intrahepatic cells during liver transplantation is still unclear. We performed a single-cell transcriptome analysis of 14,313 cells from liver tissues collected from pre-procurement, at the end of preservation and 2 h post-reperfusion. We made detailed annotations of mononuclear phagocyte, endothelial cell, NK/T, B and plasma cell clusters, and we described the dynamic changes of the transcriptome of these clusters during IRI and the interaction between mononuclear phagocyte clusters and other cell clusters. In addition, we found that TNFAIP3 interacting protein 3 (TNIP3), specifically and highly expressed in Kupffer cell clusters post-reperfusion, may have a protective effect on IRI. In summary, our study provides the first dynamic transcriptome map of intrahepatic cell clusters during liver transplantation at single-cell resolution.

Associations of BNIP3 and DAPK1 gene polymorphisms with disease susceptibility, clinicopathologic features, anxiety, and depression in gastric cancer patients.

The purpose of this study is to explore the associations of BNIP3 and DAPK1 polymorphisms with disease susceptibility, clinicopathologic characteristics, depression, and anxiety in gastric cancer (GC) patients. In this study, 150 GC patients and 100 healthy controls were recruited. 1000 Genomes database and Haploview 4.0 software were used to select tag SNPs. Improved multiplex ligase detection reaction was used for genotyping. Data were analyzed using Chi-square test (χ2 test) and univariate and multivariate logistic regression. The results demonstrated that the rs10781582 of BNIP3 in the dominant model was associated with a reduced risk of GC in the younger group (P BH = 0.015), and the minor allele G of rs1329600 at DAPK1 was associated with reduced risk of GC (P BH = 0.018). In the stratified analysis, the rs3793742 and rs10781582 of BNIP3 in the dominant model were associated with gender and age of GC patients, respectively (rs3793742: P BH = 0.033; rs10781582: P BH = 0.030). The rs10781582 of BNIP3 in the dominant model was correlated with depression in GC patients (P BH = 0.003). However, no association was found between BNIP3 and DAPK1 polymorphisms and differentiation degree, TNM stage, lymph node metastases, visceral metastasis, and anxiety. In summary, polymorphisms of BNIP3 and DAPK1 were associated with a protective effect against GC. So far, this is the first study to explore the association between BNIP3 and DAPK1 gene polymorphism and GC risk, which may provide new insight about biologic mechanisms of GC pathogenesis.

The Warburg Effect Promotes Mitochondrial Injury Regulated by Uncoupling Protein-2 in Septic Acute Kidney Injury.

BACKGROUND: Evidence implying that metabolism reprogramming plays an important role in the regulation of sepsis is increasing; however, whether it has a similar role in septic organ dysfunction remains unclear. Here, we provide evidence to support a new role of uncoupling protein-2 (UCP2)-regulated Warburg effect, i.e., aerobic glycolysis, in promoting mitochondrial injury in the kidney. METHODS: To imitate sepsis condition, male C57BL/6 mice were operated by the cecal ligation puncture in vivo, whereas a normal human kidney cell line (HK-2) was treated with lipopolysaccharide in vitro. UCP2 small interfering RNA pretreatment was performed to knock down UCP2 expression in vitro. The glycolysis metabolite was detected by liquid chromatography/tandem mass spectrometry in vivo and detected by commercial kits in vitro. Oxidative phosphorylation level and glycolysis level were monitored by measuring the oxygen consumption rate (indicative of respiration) and extracellular acidification rate (indicative of glycolysis) in vitro. Exogenous lactate was supplied to stimulate HK-2 cells and indicators of mitochondrial dysfunction were also assessed. RESULTS: Aerobic glycolysis is enhanced in septic tubular epithelial cells, and the glycolysis inhibitor 2-deoxyglucose can partially restore mitochondrial membrane potential and decrease the reactive oxygen species production. With the knockdown of UCP2, the aerobic glycolysis level upregulates, and mitochondrial injury increases. CONCLUSIONS: These results provide insights on a new mechanism of metabolic regulation of mitochondrial injury and the importance of targeting aerobic glycolysis for the treatment of septic acute kidney injury.

Associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in systemic lupus erythematosus patients.

OBJECTIVES: To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. METHODS: All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case-control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. RESULTS: rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. CONCLUSIONS: FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients. Key Points • FKBP5 gene polymorphisms were associated with depression of SLE patients. • FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients. • FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients. • FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

Identification of Significant Genes and Pathways in Acute Pancreatitis via Bioinformatical Analysis.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is one of the common acute abdominal diseases with complicated pathogenesis. The purpose of this study is to identify the differentially expressed genes (DEGs) in the pancreas and underlying mechanisms. METHODS: Gene expression profiles of GSE109227 and GSE65146 were available from GEO database. Then, an integrated analysis of these genes was performed, including gene ontology (GO) and KEGG pathway enrichment analysis, protein-protein interaction (PPI) network construction, core gene correlation analysis, transcription factors (TFs) prediction, and expression level evaluation in human organs. RESULTS: A total number of 92 differential expressed genes were screened from the datasets, including 81 up-regulated genes and 11 down-regulated genes. The up-regulated genes were mainly enriched in the biological process, such as sarcomere organization, actin cytoskeleton organization, tumor necrosis factor biosynthetic process, response to cytokine, cell-cell adhesion, and the cell migration, and also involved in some signaling pathways, including leukocyte transendothelial migration, proteoglycans in cancer, thyroid cancer, cell adhesion, tight junction, bladder cancer, amoebiasis, glycerolipid metabolism, and VEGF signaling pathway, while down-regulated genes were significantly enriched in the endoplasmic reticulum unfolded protein response, the oxidation-reduction, and no significant signaling pathways. CDH1 and CLDN4 were identified as core genes by PPI network analysis with MCODE plug-in, as well as GO and KEGG re-enrichment. For validation in Gene Expression Profiling Interactive Analysis (GEPIA), CDH1 and CLDN4 were interacting with each other and regulated by the predictive common TFs FOXP3 or USF2. The two core genes and USF2 were expressed in varied human organs including the pancreas, while FOXP3 was not detected in the normal human pancreatic tissues. CONCLUSIONS: This study implied that core gene CDH1 and CLDN4, which might be regulated by FOXP3 or USF2, played a significant role in acute pancreatitis. They could be potential diagnostic and therapeutic targets for AP patients.

Seasonal variation and trends in the Internet searches for losing weight: An infodemiological study.

OBJECTIVES: This study sought to examine the variation trends and seasonality of losing weight by using the data from Google Trends tool. METHODS: According to the search term of [lose weight+weight loss], Google Trends data were obtained. Search activity was conducted within the USA, the UK, Canada, Ireland, Australia, and New Zealand from January 01, 2004, to December 31, 2018, utilizing the health category. RESULTS: Dynamic series analysis and the plot of seasonal decomposition of time series show that relative search volume of [lose weight+weight loss] increased from 2004 to 2018 at both national and hemispherical levels. Statistically significant seasonal variations in relative search volume for the term [lose weight+weight loss] were observed using cosinor analyses in the USA (p<0.001), the UK (p<0.001), Canada (p<0.001), Ireland (p<0.001), Australia (p<0.001), and New Zealand (p<0.001), peaking in the spring months and reaching the lowest level in the autumn months. The highest level in spring and the lowest level in autumn were reversed by 6 months in both hemisphere countries, consistent with a seasonal pattern. CONCLUSION: Our results indicate that Internet search queries for losing weight increased within the timeframe of 2004 to 2018, likely reflecting the rising global public interest. In addition, the present research provided preliminary evidence that there is a seasonality of losing weight with a peak in the spring months.

Hsp70 Gene Polymorphisms Are Associated With Disease Susceptibility and HRQOL Improvement in Chinese Han Population With Systemic Lupus Erythematosus.

OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China.

BACKGROUND: Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents' characteristics and cases outcomes. METHODS: A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. RESULTS: Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025-.529). CONCLUSIONS: When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

TUDCA Ameliorates Liver Injury Via Activation of SIRT1-FXR Signaling in a Rat Hemorrhagic Shock Model.

OBJECTIVE: The aim of this study was to investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)-FXR (farnesoid X receptor) signaling. METHODS: A Sprague-Dawley (SD) rat HS model was established, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used. RESULTS: Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1-FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro. CONCLUSION: TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1-FXR signaling.

Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4/NF-κB pathway.

PURPOSE: It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. MATERIALS AND METHODS: The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. RESULTS: Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. CONCLUSION: Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

Copy number variations and polymorphisms in HSP90AB1 and risk of systemic lupus erythematosus and efficacy of glucocorticoids.

The aim of our study was to assess the associations of HSP90AB1 copy number variations (CNVs) with systemic lupus erythematosus (SLE) risk and glucocorticoids (GCs) efficacy, as well as the relationship between HSP90AB1 single-nucleotide polymorphisms (SNPs) and GCs efficacy. HSP90AB1 CNVs and SLE risk were analysed in 519 patients and 538 controls. Patients treated with GCs were followed up for 12 weeks and were divided into sensitive and insensitive groups to investigate the effects of CNVs (419 patients) and SNPs (457 patients) on the efficacy of GCs. Health-related quality of life (HRQoL) was also measured by SF-36 at baseline and week 12 to explore the relationship between CNVs/SNPs and HRQoL improvements in Chinese SLE patients. Our results indicated a statistically significant association between HSP90AB1 CNVs and SLE (PBH  = 0.039), and this association was more pronounced in the female subgroup (PBH  = 0.039). However, we did not detect association of HSP90AB1 CNVs/SNPs with efficacy of GCs. But we found a marginal association between SNP rs13296 and improvement in Role-emotional, while this association was not strong enough to survive in the multiple testing corrections. Collectively, our findings suggest that the copy number of HSP90AB1 is associated with SLE susceptibility. But copy number and polymorphisms of HSP90AB1 may not be associated with efficacy of GCs.

Fluid resuscitation via the rectum ameliorates hemodynamic disorders through adjusting aquaporin expression in an experimental severe acute pancreatitis model.

Acute pancreatitis is an acute abdominal disease, with 10-20% of the cases deteriorating rapidly, accompanied by persistent organ failure and further development into severe acute pancreatitis (SAP). The aim of the present study was to investigate the mechanism of fluid resuscitation via the rectum in the early stages of SAP and the role of aquaporins (AQPs). An SAP model was constructed by injection of 5% sterile sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats, and the mean arterial pressure (MAP) was continuously monitored via femoral artery catheterization. At 30 min after the construction of the SAP model, the rats in the fluid resuscitation groups were resuscitated with normal saline at a rate of 4 ml/kg/h through the venous or the rectal route. The AQP and Na+-K+-ATPase levels, and the correlation of the MAP and colon AQPs at the early stages of SAP were analyzed. The results demonstrated that the mRNA level of AQP-3 and AQP-4 in the distal colon decreased significantly in the group subjected to fluid resuscitation via the rectum, while no significant differences were identified in the Na+-K+-ATPase levels of the colon in that group. Furthermore, a negative correlation was identified between the expression of AQPs and the MAP (P<0.01). Thus, fluid resuscitation via the rectum appears to ameliorate hemodynamic disorders through adjusting the expression of AQP-3 and AQP-4 in the distal colon in an experimental SAP model.

DC-SIGN Expression in Intestinal Epithelial Cells Regulates Sepsis-Associated Acute Intestinal Injury Via Activating ERK1/2-NF-κB/P65 Signaling.

OBJECTIVE: The aim of the study was to investigate the role of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in intestinal epithelial cells (IECs) in regulating sepsis-induced acute intestinal injury and systemic inflammatory response. METHODS: To induce sepsis condition, Male C57BL/6 mice were exposed to cecal ligation and puncture (CLP) in vivo, whereas a normal human IECs line (FHs74Int) was stimulated with lipopolysaccharide (LPS) in vitro. DC-SIGN siRNA pretreatment was used to knock down DC-SIGN expression both in vivo and in vitro. The expression of DC-SIGN was detected by western blot and immunohistochemistry. The expression of total and phosphorylation of ERK1/2 and NF-κB/p65 was examined by western blot. The levels of cytokines in serum and culture supernatant were measured by ELISA. The survival rate and organ injures of septic mice were also assessed. RESULTS: In vivo, DC-SIGN expression in mouse IECs was time-dependently upregulated by CLP. CLP-induced phosphorylation of ERK1/2 and NF-κB/p65 was effectively inhibited by DC-SIGN siRNA pretreatment, leading to the decrease of systemic inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10, and IFN-γ), which alleviated multiple organ injuries and increased the survival rate of septic mice. In vitro, DC-SIGN expression in FHs74Int was significantly upregulated by LPS stimulation in a time- and dose-dependent manner. DC-SIGN knockdown abolished LPS-induced ERK1/2 and NF-κB/p65 phosphorylation, resulting in the decrease of cytokines release by FHs74Int. CONCLUSIONS: Sepsis-induced DC-SIGN expression in IECs plays a significant role in regulating acute intestinal injury and systemic inflammatory response. The inhibition of DC-SIGN exhibited protective effects on sepsis-associated organ injury and systemic inflammation.

Mycophenolate Mofetil Protects Septic Mice via the Dual Inhibition of Inflammatory Cytokines and PD-1.

Due to the imbalance between hyper-inflammation and hypo-inflammation, which are characterized by excessive cytokine productions and programmed death 1 (PD-1) upregulation, respectively, sepsis remains a highly lethal inflammatory syndrome with limited effective therapies. Mycophenolate mofetil (MMF), an immunosuppressant, has been reported to attenuate various inflammatory diseases. However, the role of MMF in sepsis therapy remains to be elucidated. C57BL-6J mice underwent cecal ligation and puncture (CLP) and were treated either with or without MMF. Survival rate and organ injuries were compared. Cytokine levels, bacteria clearance, apoptosis of spleen and peritoneal macrophages, and PD-1 expression were assessed. At the beginning of CLP, 60 mg/kg MMF administered by gavage significantly protected septic mice, which was evidenced by improved survival and attenuated organ injuries, decreased cytokines, lower bacterial loads, and alleviated immune cell apoptosis. In addition, immune cells in the MMF mice showed lower PD-1 expression and improved immune response to pathogeny stimuli. MMF protects septic mice via the dual inhibition of cytokine releasing and PD-1 expression.