Protective effects of Dioscin against sepsis-induced cardiomyopathy via regulation of toll-like receptor 4/MyD88/p65 signal pathway.

BACKGROUND: Dioscin has many pharmacological effects; however, its role in sepsis-induced cardiomyopathy (SIC) is unknown. Accordingly, we concentrate on elucidating the mechanism of Dioscin in SIC rat model. METHODS: The SIC rat and H9c2 cell models were established by lipopolysaccharide (LPS) induction. The heart rate (HR), left ventricle ejection fraction (LVEF), mean arterial blood pressure (MAP), and heart weight index (HWI) of rats were evaluated. The myocardial tissue was observed by hematoxylin and eosin staining. 4-Hydroxy-2-nonenal (4-HNE) level in myocardial tissue was detected by immunohistochemistry. Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in serum samples of rats and H9c2 cells were determined by colorimetric assay. Bax, B-cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated-p65 (p-p65), and p65 levels in myocardial tissues of rats and treated H9c2 cells were measured by quantitative real-time PCR and Western blot. Viability and reactive oxygen species (ROS) accumulation of treated H9c2 cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and dihydroethidium staining assays. RESULTS: Dioscin decreased HR and HWI, increased LVEF and MAP, alleviated the myocardial tissue damage, and reduced 4-HNE level in SIC rats. Dioscin reversed LPS-induced reduction on SOD, CAT, GSH, and Bcl-2 levels, and increment on Bax and TLR4 levels in rats and H9c2 cells. Overexpressed TLR4 attenuated the effects of Dioscin on promoting viability, as well as dwindling TLR4, ROS and MyD88 levels, and p-p65/p65 value in LPS-induced H9c2 cells. CONCLUSION: Protective effects of Dioscin against LPS-induced SIC are achieved via regulation of TLR4/MyD88/p65 signal pathway.

COMPARISON AMONG PRESEPSIN, PROCALCITONIN, AND C-REACTIVE PROTEIN IN PREDICTING BLOOD CULTURE POSITIVITY AND PATHOGEN IN SEPSIS PATIENTS.

ABSTRACT: Background: Sepsis is caused by the invasion of the bloodstream by microorganisms from local sites of infection, leading to high mortality. This study aimed to compare the predictive ability of the biomarkers presepsin, procalcitonin (PCT), and C-reactive protein for bacteraemia. Methods: In this retrospective, multicentre study, a dataset of patients with sepsis who were prospectively enrolled between November 2017 and June 2021 was analyzed. The performances of the biomarkers for predicting positive blood cultures and infection with specific pathogens were assessed by the areas under the receiver operating characteristic curves (AUCs). The independent effects of the pathogen and foci of infection on presepsin and PCT levels were assessed by linear logistic regression models. Results: A total of 577 patients with 170 positive blood cultures (29.5%) were enrolled. The AUC achieved using PCT levels (0.856) was significantly higher than that achieved using presepsin (0.786, P = 0.0200) and C-reactive protein (0.550, P < 0.0001) levels in predicting bacteraemia. The combined analysis of PCT and presepsin levels led to a significantly higher AUC than the analysis of PCT levels alone for predicting blood culture positivity (0.877 vs. 0.856, P = 0.0344) and gram-negative bacteraemia (0.900 vs. 0.875, P = 0.0216). In a linear regression model, the elevated concentrations of presepsin and PCT were both independently related to Escherichia coli , Klebsiella species, Pseudomonas species, and Streptococcus species infections and Sequential Organ Failure Assessment score. Presepsin levels were also associated with Acinetobacter species and abdominal infection, and PCT levels were positively associated with other Enterobacteriaceae and negatively associated with respiratory infection. Combined analysis of presepsin and PCT levels provided a high sensitivity and specificity in identifying E. coli or Klebsiella species infection. Conclusions: Presepsin and PCT were promising markers for predicting bacteraemia and common pathogens at the time of sepsis onset with a synergistic effect.

Epidemiology of sepsis in Beijing from 2012 to 2018: analysis of hospital homepage databases derived from the Beijing Public Health System.

BACKGROUND: We aimed to evaluate the epidemiology of sepsis in secondary and tertiary hospitals in Beijing, China between 2012 and 2018 using information derived from the Beijing Public Health System. METHODS: The Beijing Public Health System accessed hospital homepage databases and identify patients who diagnosed sepsis or associated condition according to the International Classification of Diseases, 10th Edition, Clinical Modification codes. There are 125 hospitals involved in this study, including 61 secondary hospitals, accounting for 49.2%, and 63 tertiary hospitals, accounting for 50.8%. Patients were stratified by age as minors (0-17 years old), adults (18-64 years old), seniors (65-84 years old), and the elderly (≥ 85 years old). Patient's demographic information, treatments, outcomes, and all-cause hospitalization cost were evaluated. RESULTS: This study involved 8,597 patients. Patients treated in tertiary hospitals or received blood transfusion decreased with age, while patients who were male, received ventilation, or took Traditional Chinese Medicine, and in-hospital mortality and hospitalization cost, increased with age. There were 2,729 (31.7%) deaths in this study. A slight increase in in-hospital mortality occurred from 2012 to 2018. Median hospitalization cost for all patients was ¥29,453 (15,011, 65,237). Hospitalization cost showed no significant change from 2012 to 2016, but increased in 2017 and 2018. CONCLUSION: Sepsis is associated with high mortality and cost. From 2012 to 2018, in-hospital mortality and hospitalization cost of sepsis in Beijing increased significantly with age, and slightly by year.

Effects of Albumin Supplements on In-Hospital Mortality in Patients with Sepsis or Septic Shock: A Systemic Review and Meta-Analysis.

Objective: To explore the clinical effects of albumin supplements on the basis of crystalloid solution in patients with sepsis or septic shock. Methods: The online databases including PubMed, Web of Science, Cochrane Library, and EMBASE were comprehensively searched from inception to June 28, 2021, with the keywords including "albumin," "sepsis," or "septic shock." Retrospective cohort (RC) and randomized controlled trials (RCT) were included for analysis. Two authors independently searched and analyzed the literature. The in-hospital mortality at 7 days and 28 days, duration of mechanical ventilation, renal replacement therapy, length of ICU stay, and length of hospital stay were compared between patients with albumin supplements and crystalloid solution and those with crystalloid alone. Results: A total of 10 studies with 6463 patients were eventually included for meta-analysis. The in-hospital mortality of patients at 7 days (OR = 1.00, 95% CI: 0.81-1.23) and 28 days (OR = 1.02, 95% CI: 0.91-1.13) did not show a significant difference between the two groups of patients. Also, the pooled results demonstrated no significant differences in duration of mechanical ventilation (OR = 0.29, 95% CI: -0.05-0.63), renal replacement therapy (WMD = 1.15, 95% CI: 0.98-1.35), length of ICU stay (WMD = -0.07, 95% CI: -0.62-0.48), and length of hospital stay (WMD = -0.09, 95% CI: -0.70-0.52) between patients receiving albumin plus crystalloid solution and those with crystalloid solution alone. Conclusion: Albumin supplements on the basis of crystalloid solution did not improve the 7-day and 28-dayin-hospital mortality in patients with sepsis or septic shock compared with those with crystalloid solution alone.

miR-181a-5p Inhibits Pyroptosis in Sepsis-Induced Acute Kidney Injury through Downregulation of NEK7.

Sepsis is a life-threatening organ dysfunction caused by the uncontrolled inflammation, easily affecting the kidney. Sepsis-induced acute kidney injury (S-AKI) has high morbidity and mortality, of which the pathophysiological mechanisms have not been completely illuminated, leading to nonspecific therapies. Specific microRNAs were related with the pathogenesis of AKI. However, only limited studies focused on the pyroptosis in the context of S-AKI. The in vitro LPS-induced HK-2 cell model and in vivo CLP-induced mouse model were established. qRT-PCR, Western blot, ELISA, and RNA pulldown were used for expression examination. Multiple biological databases were used for miRNA screening. H&E staining and IHC staining were performed. The LPS-induced HK-2 cells showed significantly increased (P < 0.01) fluorescence intensity of N-GSDMD and ASC compared with the HK-2 cells. The expression of NLRP3, NEK7, ASC, active caspase-1, and N-GSDMD was significantly enhanced (P < 0.05) and the inflammatory factors including IL-18, IL-1ß, and THF-α were all increased in LPS-induced HK-2 cells and CLP-induced mice. Renal edema, serum Cr and BUN, and expression of KIM-1 and NGAL were significantly higher (P < 0.05) in CLP-induced S-AKI mice than the sham group. miR-101-3p, miR-144-3p, miR-181a-5p, miR-4262, and miR-513b-5p could inhibit NEK7. NEK7 is an interacting protein of miRNA-181a-5p. miR-181a-5p inhibits pyroptosis of the LPS-induced HK-2 cells through downregulation of NEK7. Pyroptosis of HK-2 cells promotes inflammation. miR-181a-5p inhibits pyroptosis through downregulation of NEK7 in LPS-induced HK-2 cells and CLP-induced mice. Our study indicated miR-181a-5p as a new potential therapeutic target for S-AKI therapy.

Role of HMGB1-PTEN Signaling in T Lymphocytes and Monocytes Upon Sepsis.

BACKGROUND: The aim of the study was to evaluate the role of high-mobility group box 1 (HMGB1)-phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling in T lymphocytes and monocytes upon sepsis. METHODS: Thirty C57BL/6 male mice aged 8 - 10 weeks old were randomly divided into sham, model, and inhibitor groups (n = 10). The model of sepsis was established through cecal ligation and perforation. Sham group was only subjected to cecum exposure, and then the wound was sutured without cecal ligation. After the operation, the inhibitor group was intraperitoneally injected with HMGB1-specific inhibitor glycyrrhizic acid (dose: 10 mg/kg) every 6 hours for 4 consecutive times, while sham and model groups were intraperitoneally injected with an equal dose of normal saline. The histopathological changes, cell apoptosis in spleen and thymus tissues, proliferative activity and apoptosis of T lymphocytes, chemotactic activity of monocytes, expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-10, and expressions of HMGB1 and PTEN in mice were detected using hematoxylineosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, MTT assay, flow cytometry, transwell chemotaxis assay, enzyme-linked immunosorbent assay, and western blotting, respectively. RESULTS: The cell apoptosis rate in spleen and thymus tissues, proliferative activity and apoptosis rate of T lymphocytes, chemotactic activity of monocytes, protein expressions of TNF-α, IL-6 and IL-10, and expressions of HMGB1 and PTEN significantly increased in the model group compared with those in the sham group (p < 0.05). However, the cell apoptosis rate in spleen and thymus tissues, T lymphocyte apoptosis rate, protein expressions of TNF-α and IL-6, and expressions of HMGB1 and PTEN were significantly lower, while the proliferative activity of T lymphocytes, chemotactic activity of monocytes and protein expression of IL-10 were significantly higher in the inhibitor group than those in the model group (p < 0.05). CONCLUSIONS: Repressing HMGB1-PTEN signaling can effectively reduce the apoptosis rate of T cells, increase the proliferative activity of T cells, and enhance the function of monocytes in the case of sepsis.

Potential Value of Presepsin Guidance in Shortening Antibiotic Therapy in Septic Patients: a Multicenter, Prospective Cohort Trial.

INTRODUCTION: Long-term use of antibiotics for septic patients leads to bacterial resistance, increased mortality, and hospital stay. In this study, we investigated an emerging biomarker presepsin-guided strategy, which can be used to evaluate the shortening of antibiotic treatment in patients with sepsis without risking a worse outcome. METHODS: In this multicenter prospective cohort trial, patients were assigned to the presepsin or control groups. In the presepsin group, antibiotics were ceased based on predefined cut-off ranges of presepsin concentrations. The control group stopped antibiotics according to international guidelines. The primary endpoints were the number of days without antibiotics within 28 days and mortality at 28 and 90 days. Secondary endpoints were the percentage of patients with a recurrent infection, length of stay in ICU and hospital, hospitalization costs, days of first episode of antibiotic treatment, percentage of antibiotic administration and multidrug-resistant bacteria, and SOFA score. RESULTS: Overall, 656 out of an initial 708 patients were eligible and assigned to the presepsin group (n = 327) or the control group (n = 329). Patients in the presepsin group had significantly more days without antibiotics than those in the control group (14.54 days [SD 9.01] vs. 11.01 days [SD 7.73]; P < 0.001). Mortality in the presepsin group showed no difference to that in the control group at days 28 (17.7% vs. 18.2%; P = 0.868) and 90 (19.9% vs. 19.5%; P = 0.891). Patients in the presepsin group had a significantly shorter mean length of stay in the hospital and lower hospitalization costs than control subjects. There were no differences in the rate of recurrent infection and multidrug-resistant bacteria and the SOFA score tendency between the two groups. CONCLUSIONS: Presepsin guidance has potential to shorten the duration of antibiotic treatment in patients with sepsis without risking worse outcomes of death, recurrent infection, and aggravation of organ failure. TRIAL REGISTRATION: ChiCTR, ChiCTR1900024391. Registered 9 July 2019-Retrospectively registered, http://www.chictr.org.cn.

Establishment and validation of the predictive model for the in-hospital death in patients with sepsis.

BACKGROUND: Identifying sepsis patients with risk of in-hospital death early can improve the prognosis of patients. This study aimed to develop a model to predict in-hospital death of sepsis patients based on the Medical Information Mart for Intensive Care-Ⅲ (MIMIC-Ⅲ) database, and use clinical data to externally validate the model. METHODS: A total of 1,839 sepsis patients were used for model development, and 125 clinical cases were used for external validation. The discriminatory ability of the model was determined by calculating the area under the curve (AUC) with 95% confidence intervals (CI). RESULTS: The AUC of the random forest model and logistic regression model was 0.754 (95%CI, 0.732-0.776) and 0.703 (95%CI, 0.680-0.727), respectively, and the random forest model had higher AUC (Z = 3.070, P = .002). External validation showed that the AUC of the random forest model was 0.539 (95%CI, 0.440-0.628). Further validation was carried out according to gender and SOFA score. The AUC of the model in males and females was 0.648 and 0.412, respectively. In addition, the AUC of the model in the population with SOFA scores of 3-8, 9-12, and 13-15 were 0.705, 0.495, and 0.769, respectively. CONCLUSIONS: The random forest model had a better predictive ability and a good applicability to external populations with SOFA score of 13-15.

Risk predictive role of hypernatremia for occurrence of sepsis-induced acute kidney injury.

BACKGROUND: Septic acute kidney injury (AKI), identified when sepsis and AKI present concurrently, is a syndrome of acute function impairment and organ damage, which accounts for ~50% AKI in the intensive care unit (ICU). METHODS: This study retrospectively reviewed 591 patients who were diagnosed with sepsis and admitted to the ICU of Beijing Friendship Hospital from January 2009 to December 2014. According to the concentration of serum sodium, the 591 patients were further divided into 3 groups: normal group, hyponatremia group, and hypernatremia group. RESULTS: The arterial partial pressure of carbon dioxide (PaCO2, P=0.014), concentration of sodium (Na+, P<0.001), and chloride ion (Cl-, P<0.001), blood urea nitrogen (BUN, P<0.001), acute physiology and chronic health evaluation (APACHE) score (P<0.001), sequential organ failure assessment (SOFA) score (P<0.001), and Glasgow score (P<0.001) showed significant differences. The SOFA score [P=0.040; odds ratio (OR) =1.261], body mass index (BMI, P=0.041; OR =1.229), P content (P=0.032; OR =7.180) and creatine kinase myocardial band (CK-MB, P=0.006; OR =1.168) may be risk factors for occurrence of AKI in patients with hypernatremia. The AKI (P<0.001; OR =6.850) and P content (P=0.027; OR =3.676) may be risk factors for death in patients with hypernatremia. The Na+ suggested a predictive ability for AKI (P<0.001; area under the curve (AUC): 0.586) but not for death (P=0.104). CONCLUSIONS: Hypernatremia is independently associated with an increased risk and has a predictive ability of AKI in patients with sepsis.

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2.

OBJECTIVE: To explore the effects of wedelolactone (WEL) on sepsis-induced renal injury in the human renal proximal tubular epithelial cell line HK-2. METHODS: HK-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) to trigger renal injury in vitro. HK-2 cells were pretreated with or without WEL (0.1, 1 and 10 µM) before LPS stimulation. Protein and mRNA analyses were performed using enzyme-linked immunosorbent assays, Western blot analysis and quantitative reverse transcription-polymerase chain reaction. The MTT assay and flow cytometry were used to measure cell viability and the rate of cell apoptosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) knockdown was induced by the transection of HK-2 cells with short hairpin RNA. RESULTS: Cell viability was significantly increased in a dose-dependent manner by WEL in LPS-induced HK-2 cells. WEL also decreased the levels of four inflammatory cytokines and cell apoptosis in LPS-induced HK-2 cells. The level of PTPN2 was increased after WEL treatment. PTPN2 knockdown partly abolished the inhibitory effects of WEL on cell apoptosis, the levels of inflammatory cytokines and on p38 mitogen-activated protein kinase/nuclear factor-kappaB signalling in LPS-induced HK-2 cells. CONCLUSION: WEL improved renal injury by suppressing inflammation and cell apoptosis through upregulating PTPN2 in HK-2 cells. PTPN2 might be used as a potential therapeutic target for LPS-induced sepsis.

Risk factors for 28-day mortality in patients with sepsis-related myocardial injury in intensive care units.

OBJECTIVE: This study aimed to identify the risk factors for death in patients with sepsis-related myocardial injury. METHODS: A retrospective study was conducted in 158 patients with sepsis-related myocardial injury in a mixed medical intensive care unit from January 2009 to March 2020. The patients were divided into those who survived and those who died on the basis of whether they survived after 28 days. Demographic and clinical parameters were collected. Multivariate logistic regression was performed. RESULTS: Sixty-nine (43.7%) patients died within 28 days after admission to the intensive care unit. Multivariate logistic regression analysis showed that the oxygenation index (odds ratio [OR]: 0.979, 95% confidence interval [CI]: 0.970-0.989), acute kidney injury (OR: 4.787, 95% CI: 1.674-13.693), norepinephrine dose (OR: 1.706, 95% CI: 1.375-2.117), and abdominopelvic cavity infection (OR: 0.257, 95% CI: 0.076-0.866) were significantly associated with mortality within 28 days after admission in patients with sepsis-related myocardial injury. CONCLUSIONS: Patients with sepsis-related myocardial injury have a high mortality rate. A high oxygenation index, occurrence of acute kidney injury, high norepinephrine dose, and occurrence of abdominopelvic cavity infection are independent risk factors for 28-day mortality in patients with sepsis-related myocardial injury.

GPR120 Ameliorates Apoptosis and Inhibits the Production of Inflammatory Cytokines in Renal Tubular Epithelial Cells.

Acute kidney injury (AKI) is the most common complication of sepsis with a high mortality rate. In this study, we focus on the renal injury caused by the immune response of renal tubular epithelial cells and inflammation-induced renal tubular epithelial cell apoptosis. We studied the role of GRP120 in the inflammation and apoptosis of human renal cell line HK-2 and mouse primary renal tubular epithelial cells. GPR120 agonist GW9508 activated the GPR120 pathway. Inflammatory factors were detected using quantitative real-time PCR and enzyme-linked immunosorbent assay. Cell apoptosis experiments included the annexin V and PI double-staining method combined with flow cytometry, TUNEL method, and Western blot. The level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS was significantly decreased (P < 0.05) in HK-2 and TECs after the activation of the GPR120 pathway. Besides, the cell apoptosis of both cells increased. Overexpressed GPR120 and shGPR120 were established. Treatment with lipopolysaccharide (LPS) increased the level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS in HK-2 cell and TECs. Compared with control-LPS and negative control (NC)-LPS, the overexpression of GPR120 and shGPR120 could decrease and increase the level of secreted cytokines significantly (P < 0.05), respectively, after LPS-induced apoptosis. After H2O2- and LPS-induced apoptosis, respectively, compared with the control and NC groups, overexpressed GPR120 and shGPR120 could reduce and increase the expression of caspase-3, respectively. GPR120 could suppress the cellular immune response and apoptosis in renal tubular epithelial cells, thereby possibly protecting the kidney and relieving sepsis-induced AKI.

Acute Kidney Injury in Critically Ill Patients with Sepsis: Clinical Characteristics and Outcomes.

Objective: The objectives of this study were to examine the clinical profile of critically ill patients with septic acute kidney injury (AKI) and to investigate clinical characteristics associated with the outcome of patients. Methods: Data from 582 critically ill patients were collected and retrospectively reviewed. Patients were divided into two groups: without AKI development and with AKI development. Baseline characteristics, laboratory, and other clinical data were compared between these two groups, and correlations between the characteristics and AKI development were examined. Patients with AKI development were further divided into two groups according to the survival outcome, and variables associated with the outcome were determined. Results: AKI was developed in 54.12% (n = 315) of patients, and these patients had blood pressure, SOFA score, APACHE II score, GCS, and various blood chemistry and hematology characteristics significantly different from the patients without AKI. Demographic characteristics (e.g. age and weight) were comparable between the two groups of patients. Among the 315 patients with AKI, 136 of them died during the study period. Multivariate logistic regression analysis revealed that the outcome of patients was associated with lung infection, coagulation system dysfunction, staphylococcus aureus infection, and use of various treatments (epinephrine, norepinephrine, and the use of mechanical ventilation) after AKI development. Conclusion: AKI occurred in approximately half of the critically ill patients admitted to ICU. The site and type of infections, as well as the use of vasopressor agents, were associated with the outcome.