Levosimendan protects from sepsis-inducing cardiac dysfunction by suppressing inflammation, oxidative stress and regulating cardiac mitophagy via the PINK-1-Parkin pathway in mice.

Background: Sepsis is a leading cause of death in China, the mortality rate of which is elevated when cardiac dysfunction is induced. Levosimendan is used for the treatment of decompensated cardiac failure. In this study, we sought to investigate the role of levosimendan in the inflammation, oxidative stress, and mitophagic response of the septic heart. Methods: A lipopolysaccharide (LPS)-induced septic myocardial dysfunction mouse model was established. To study the relationship between levosimendan and inflammation, oxidative stress, and mitophagy response, mice were pretreated with mdivi-1 (an inhibitor of mitophagy) prior to LPS administration. Levosimendan was given (24 µg/kg) via intraperitoneal injection 3 h after LPS had been administered. At 6 h after LPS injection, echocardiographic analysis, enzyme-linked immunosorbent assay (ELISA), oxidative stress index, myocardial pathological changes, transmission electron microscopy (TEM), immunofluorescence, and western blot were used to investigate the protective effects of levosimendan against LPS-induced myocardial dysfunction. Results: In the sepsis model, levosimendan markedly ameliorated myocardial dysfunction, decreased the release of myocardial enzymes and inflammatory cytokines, improved oxidative stress index and myocardial pathological changes, reduced mitochondrial division, and activated mitophagy. To confirm whether the protection of levosimendan was mediated by mitophagy, a mitophagy inhibitor-mdivi-1 was used in this study. It significantly impaired the protective effects of levosimendan. In addition, our studies further confirmed the protection of levosimendan against LPS-induced myocardial injury and the mechanisms involving PINK-1-Parkin mediated mitophagy signaling. Conclusions: Levosimendan was able to rescue the LPS-induced cardiac dysfunction mice, supporting its mechanism of action by suppressing inflammation, oxidative stress, and directly targeting the PINK-1-Parkin pathway.

Long non-coding RNA AK006774 inhibits cardiac ischemia-reperfusion injury via sponging miR-448.

In recent years, the incidence and mortality of myocardial infarction (MI) have been increasing throughout the world, threatening public health. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play critical roles in the progression of MI. The present study aimed to investigate the role of lncRNA AK006774 in the progression of myocardial infarction and find out novel therapeutic or diagnostic target of myocardial infarction. A mouse ischemia/reperfusion (I/R) model and 2,3,5-Triphenyte-trazoliumchloride (TTC) staining were performed to evaluate the effects of AK006774 on I/R injury in vivo. Hypoxia/reoxygenation (H/R) models using primary cardiomyocytes have been established. Flow cytometry and Terminal Deoxynucleotide Transferase dUTP Nick End Labeling (TUNEL) assays were performed to evaluate the effects of AK006774 on cardiomyocyte apoptosis. Luciferase and RNA pull-down assays were performed to verify the interaction between miR-448 and its targets. Western blotting and quantitative PCR were performed to determine protein and gene expression, respectively. We first found that AK006774 overexpression reduced I/R-induced infarct area and cardiomyocyte apoptosis in vivo. Accordingly, AK006774 inhibited apoptosis and oxidative stress in cardiomyocytes subjected to H/R treatment in vitro. Mechanistically, AK006774 modulated the expression of bcl-2 by sponging miR-448. Overexpression of miR-448 antagonized the effects of AK006774 on cardiomyocyte apoptosis. The AK006774/miR-448/bcl-2 signaling axis acts as a key regulator of I/R injury and may be a potential therapeutic or diagnostic target for the treatment of MI.

Combined predictive performance of age and neutrophilic percentage on admission for severe novel coronavirus disease 2019.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) poses a huge threat to the global public health. This study aimed to identify predictive indicators of severe COVID-19. METHODS: We retrospectively collected clinical data on hospital admission of all patients with severe COVID-19 and a control cohort (1:1) of gender- and hospital-matched patients with mild disease from 13 designated hospitals in the Hebei Province between 22 January and 15 April 2020. RESULTS: A total of 104 patients (52 with severe COVID-19 and 52 with mild disease) were included. Only age, fever, duration from symptom onset to confirmation, respiratory rate, percutaneous oxygen saturation (SpO2 ) and neutrophilic percentage were independent predictors of severe COVID-19. Age and neutrophilic percentage performed best in predicting severe COVID-19, followed by SpO2 . 'Age + neutrophilic percentage' (the sum of age and neutrophilic percentage) (area under the curve [AUC] 0.900, 95% confidence interval [CI] 0.825-0.950, P < .001) and 'age and neutrophilic percentage' (the prediction probability of age and neutrophilic percentage for severe type obtained by logistic regression analysis) (AUC 0.899, 95% CI 0.824-0.949, P < .001) had excellent predictive performance for severe type. The optimal cut-off for 'age + neutrophilic percentage' was >119.1 (sensitivity, 86.5%; specificity, 84.6%; Youden index, 0.712). CONCLUSION: The combination of age and neutrophil percentage could effectively predict severe COVID-19. The sum of age and neutrophil percentage was recommended for clinical application because of its excellent predictive value and practicability. TRAIL REGISTRATION: China Clinical Trial Registry, number ChiCTR2000030226. Registered 26 February 2020-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=49855.

Clinical characteristics and treatment of critically ill patients with COVID-19 in Hebei.

BACKGROUND: In December, 2019, a novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, China. We aimed to clarify the epidemiology, laboratory examinations, imaging findings, and treatment of critically ill patients with COVID-19 in Hebei province, China. METHODS: In this retrospective study, the demographic, laboratory and imaging, and treatment data of patients with severe COVID-19 treated in 13 designated hospitals in Hebei were collected and analyzed. RESULTS: A total of 319 severe COVID-19 patients were treated at the 13 designated hospitals between 22 January, 2020 and 25 March, 2020. Eventually, 51 critically ill (31 severe cases and 20 critically severe cases) patients were included in the analysis. The patients had an average age of 58.9±13.7 years, and 27 (52.9%) were men. Twenty-one (41.2%) were familial cluster, and 33 (64.7%) had chronic illnesses. The patients in critically severe group had longer duration from symptom to confirmation, more severe infections, more severe lung injury, and a lower percentage of lymphocytes. All 51 patients received antiviral drugs, 47 (92.2%) received antibacterial agents, 49 (96.1%) received traditional Chinese drugs, and 46 (90.2%) received methylprednisolone. The critically severe patients received more fluid and more diuretic treatment; 14 (70.0%) required invasive mechanical ventilation, and 13 (65.0%) developed extrapulmonary complications. CONCLUSIONS: COVID-19 patients who had underlying diseases and longer confirmation times were more likely to progress to critically severe COVID-19. These patients also presented with a higher risk of respiratory depression, circulatory collapse, extrapulmonary complications, and infection.

[Diagnostic accuracy of bedside ultrasound measurement of limb skeletal muscle thickness for intensive care unit-acquired weakness].

OBJECTIVE: To explore the diagnostic accuracy of bedside ultrasound measurement of limb skeletal muscle thickness for intensive care unit-acquired weakness (ICU-AW) in patients receiving mechanical ventilation. METHODS: A prospective observational study was conducted. Patients receiving mechanical ventilation admitted to the emergency ICU of Cangzhou Central Hospital from June 2018 to March 2020 were enrolled. The demographic data were collected. Medical Research Council (MRC) score was used to assess muscle strength and to determine the presence of ICU-AW once the patients were awake. The thicknesses of biceps brachii (BB), flexor carpi radialis (FCR), rectus femoris (RF) and tibialis anterior (TA) were measured by bedside ultrasound. The difference of each index was compared between the patients in ICU-AW group and in non-ICU-AW group. Receiver operator characteristic (ROC) curves were plotted to examine the values of the thicknesses of these four muscles in diagnosing ICU-AW. RESULTS: Forty-one patients receiving mechanical ventilation (15 patients with ICU-AW, 26 patients without ICU-AW) were recruited. Compared with the non-ICU-AW group, the MRC score, the thicknesses of FCR, RF and TA were lower in the ICU-AW group [MRC score: 36 (30, 40) vs. 60 (56, 60), FCR (cm): 1.09±0.19 vs. 1.30±0.28, RF (cm): 1.57±0.58 vs. 2.23±0.58, TA (cm): 1.76±0.33 vs. 2.21±0.43, all P < 0.05], and the length of ICU stay was longer [days: 15 (9, 26) vs. 10 (4, 12), P < 0.05]. Although the thickness of BB was also lower in the ICU-AW group, there was no statistical difference between the two groups (cm: 2.45±0.57 vs. 2.70±0.61, P = 0.205). ROC curve showed that the thicknesses of FCR, RF and TA had diagnostic values for ICU-AW [area under ROC curve (AUC) and 95% confidence interval (95%CI) was 0.742 (0.582-0.866), 0.787 (0.631-0.899), 0.817 (0.665-0.920), respectively, all P < 0.01]. The thicknesses of BB couldn't diagnose ICU-AW (AUC = 0.597, 95%CI was 0.433-0.747, P = 0.296). CONCLUSIONS: The thicknesses of FCR, RF and TA measured by bedside ultrasound in patients with mechanical ventilation had diagnostic values for ICU-AW, while the thickness of BB could not diagnose ICU-AW.

[Renal echography and cystatin C for prediction of acute kidney injury: very different in patients with cardiac failure or sepsis].

OBJECTIVE: To explore the predicting performance of renal resistive index (RRI), semi quantitative power Doppler ultrasound (PDU) score and serum cystatin C (Cys C) for acute kidney injury (AKI) in patients with cardiac failure or sepsis. METHODS: A prospective, observational study was conducted. Critically ill patients with acute cardiac failure or sepsis admitted to the emergency intensive care unit (ICU) of Cangzhou Central Hospital from January 1st to December 31st in 2018 were enrolled. In addition to the demographic data, serum Cys C, RRI, and PDU score were measured within 6 hours after admission to ICU. Renal function was assessed on day 5 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patients who proceeded to AKI stage 2 or 3 within 5 days from admission were defined as the AKI 2-3 group; other patients were classified into the AKI 0-1 group. The differences of each index were compared in all patients, cardiac failure patients and sepsis patients between the two groups. Multivariate binary Logistic regression was carried out to identify the independent risk predictors of AKI 2-3. Receiver operator characteristic (ROC) curves were plotted to examine the values of Cys C, RRI, PDU score, and RRI+PDU in predicting AKI 2-3. RESULTS: Thirty-seven patients with cardiac failure (11 with no AKI, 10 with AKI stage 1, 3 with AKI stage 2, and 13 with AKI stage 3) and 26 patients with sepsis (8 with no AKI, 2 with AKI stage 1, 7 with AKI stage 2, and 9 with AKI stage 3) were recruited. In all patients as well as the subgroup of cardiac failure, compared with the AKI 0-1 group, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, rate of continuous renal replacement therapy (CRRT), 28-day mortality, serum creatinine (SCr), Cys C and RRI were higher in AKI 2-3 group, and urine output, PDU score were lower; in the subgroup of sepsis, rate of CRRT, SCr, and Cys C were higher in AKI 2-3 group, and urine output was lower. Multivariate Logistic regression analysis found that Cys C and PDU score were independent risk factors for AKI 2-3 in all patients [Cys C: odds ratio (OR) = 11.294, 95% confidence interval (95%CI) was 2.801-45.541, P = 0.001; PDU score: OR = 0.187, 95%CI was 0.056-0.627, P = 0.007]; RRI and PDU score were independent risk factors for AKI 2-3 in patients with cardiac failure [RRI (×10): OR = 6.172, 95%CI was 0.883-43.153, P = 0.067; PDU score: OR = 0.063, 95%CI was 0.007-0.584, P = 0.015]; Cys C was the independent risk factor for AKI 2-3 in patients with sepsis (OR = 22.830, 95%CI was 1.345-387.623, P = 0.030). It was shown by ROC curve analysis that: in the subgroup of cardiac failure, the predictive values of RRI, PDU score and Cys C were well [area under the curve (AUC) and 95%CI was 0.839 (0.673-0.942), 0.894 (0.749-0.971), 0.777 (0.610-0.897), all P < 0.01]. RRI+PDU performed best in predicting AKI (AUC = 0.956, 95%CI was 0.825-0.997, P < 0.01), and the predictive value was higher than Cys C [AUC (95%CI): 0.956 (0.825-0.997) vs. 0.777 (0.610-0.897), P = 0.034]. In the subgroup of sepsis, the predictive value of Cys C was well (AUC = 0.913, 95%CI was 0.735-0.987, P < 0.01), however, the predictive value of RRI, PDU, RRI+PDU were poor. CONCLUSIONS: RRI and PDU score effectively predict AKI stage 2 or 3 in cardiac failure patients, but not in patients with sepsis. The predictive values of Cys C for AKI are similar in patients with cardiac failure or sepsis.

Inhibiting role of rosiglitazone in the regulation of inflammatory response and protective effects for severe acute pancreatitis in mice.

OBJECTIVES: Our study aimed to probe the effects of rosiglitazone treatment on a severe acute pancreatitis (SAP) model induced by caerulein and investigate the underlying mechanism. METHODS: Differentially expressed messenger RNAs (mRNAs) in the mice of a SAP group were screened out by microarray analysis. The inflammatory response pathway was obtained from the online website DAVID Bioinformatics Resources 6.8. The interactions of caerulein and its target proteins were shown by search tool for interactions of chemicals (STITCH). Functional interactions of the genes associated with pancreatitis and the target proteins of caerulein were obtained with search tool for interactions of chemicals (STRING). SAP mice were established by hourly intraperitoneal injection of caerulein. Rosiglitazone was used as treatment drug, and pancreatic inflammation was assessed. The expression of Socs3 was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of interleukin (IL)-6, IL-1b, and Egr1 were studied by RT-PCR and Western blot analysis. RESULTS: The GSE77983 data were analyzed, and the results showed that Socs3 was overexpressed in SAP tissues. The inflammation response pathway in pancreas was selected by DAVID, STITCH, and STRING. After injection of rosiglitazone in mice, the serum levels of amylase and lipase were decreased. Furthermore, the mRNA and protein levels of Socs3 and inflammatory cytokines in pancreatic tissues were downregulated. CONCLUSIONS: Rosiglitazone could protect mice with SAP from injury by downregulating Socs3 and inhibiting the inflammatory response pathway.