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The nonpeptide AVE0991 is an agonist of the angiotensin-(1–7) (Ang-(1–7)) Mas receptor and is expected to be a putative new drug for treatment of cardiovascular disease. However, the mechanisms involved in the antiproliferative effects of AVE0991 are not fully understood. We saw that the compound attenuated proliferation in an angiotensin II-induced rat vascular smooth muscle cells (VSMC) proliferation model. Moreover, treatment with AVE0991 (10−5 mol/L or 10−7 mol/L) significantly attenuated reactive oxygen species (ROS) production, phosphorylation of p38 MAPK, and dose-dependently (10−8 to 10−5 mol/L) inhibited Ang II-induced VSMC proliferation. Meanwhile, heme oxygenase-1 (HO-1) expression increased in the AVE0991 + Ang II group (10−5 mol/L or 10−6 mol/L). However, the beneficial effects of AVE0991 were completely abolished when the VSMC were pretreated with A-779 (10−6 mol/L). Furthermore, treatment with the HO-1 inhibitor ZnPPIX attenuated the inhibitory effect of AVE0991 on Ang II-induced p38MAPK phosphorylation. These results suggest that AVE0991 attenuates Ang II-induced VSMC proliferation in a dose-dependent fashion and that this effect is associated with the Mas/HO-1/p38 MAPK signaling pathway.

The role of CD3+CD56+ natural killer T (NKT) cells and its co-signaling molecules in patients with sepsis-associated encephalopathy (SAE) is unknown. In this prospective observational cohort study, we initially recruited 260 septic patients and eventually analyzed 90 patients, of whom 57 were in the SAE group and 37 were in the non-SAE group. Compared to the non-SAE group, 28-day mortality was significantly increased in the SAE group (33.3% vs. 12.1%, p = 0.026), while the mean fluorescence intensity (MFI) of CD86 in CD3+CD56+ NKT cells was significantly lower (2065.8 (1625.5 ~ 3198.8) vs. 3117.8 (2278.1 ~ 5349), p = 0.007). Multivariate analysis showed that MFI of CD86 in NKT cells, APACHE II score, and serum albumin were independent risk factors for SAE. Furthermore, the Kaplan–Meier survival analysis indicated that the mortality rate was significantly higher in the high-risk group than in the low-risk group (χ2 = 14.779, p < 0.001). This study showed that the decreased expression of CD86 in CD3+CD56+ NKT cells is an independent risk factor of SAE; thus, a prediction model including MFI of CD86 in NKT cells, APACHE II score, and serum albumin can be constructed for diagnosing SAE and predicting prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to explore whether the antibrain edema of hypertonic saline (HS) is associated with alleviating ischemic blood‐brain barrier (BBB) permeability by downregulating astrocyte‐derived vascular endothelial growth factor (VEGF), which is mediated by microglia‐derived NOD‐like receptor protein 3 (NLRP3) inflammasome. Methods: The infarct volume and BBB permeability were detected. The protein expression level of VEGF in astrocytes in a transient focal brain ischemia model of rats was evaluated after 10% HS treatment. Changes in the NLRP3 inflammasome, IL‐1β protein expression, and the interleukin‐1 receptor (IL1R1)/pNF‐кBp65/VEGF signaling pathway were determined in astrocytes. Results: HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulates IL‐1β expression by inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulates VEGF expression by inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes. Conclusions: HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulated IL‐1β expression via inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulated VEGF expression through inhibiting the phosphorylation of NF‐кBp65 mediated by IL‐1β in astrocytes. [ABSTRACT FROM AUTHOR]

Background: Around the globe, moderate cases account for the largest proportion of all coronavirus disease 2019 (COVID-19) patients, and deteriorated moderate patients contribute the most in mortality. However, published articles failed to address the deterioration details of moderate cases, especially on when and how they deteriorated. Methods: All moderate COVID-19 patients hospitalized in Guangdong Province from January 14 to March 16, 2020, were included in this multicenter retrospective cohort study and were divided into deteriorated and non-deteriorated groups according to clinical status. Symptoms and demographic, therapeutic, and laboratory test result characteristics were collected to explore the features of disease deterioration. Results: Of 1,168 moderate patients included, 148 (13%) deteriorated to severe (130 cases) or critical (18 cases) status. Over 20% of the older subgroup (>50 years old) showed deterioration. The median time for deterioration was 11 days after onset [interquartile range (IQR) 9-14 days]. In addition, 12.2% severe cases could further develop to critical status after 3 days (IQR 2-6.5 days) of having a severe condition. Respiratory dysfunction and hypoxia were the major manifestations as disease deterioration, while 76 cases (52.1%) showed respiratory rate >30 breaths/min, 119 cases (80.4%) showed SaO 2 <93%, 100 cases (67.5%) had 201 < PaO 2 /FiO 2 < 300, and 27 cases (18.9%) had blood lactic acid >2.0 mmol/L. In view of multiple organ dysfunction, 87.8% of acute respiratory distress syndrome (ARDS), 20.2% of acute kidney injury (AKI), 6.8% of coagulopathy, 4% of acute heart failure (AHF), 3.4% of acute hepatic injury (AHI), and 5.4% of shock occurred in deteriorated patients, while organ injury occurred in the following sequence: ARDS, AKI, AHF, coagulopathy, AHI, and shock. Conclusions: The deteriorated pattern of moderate COVID-19 patients is characterized as the 11th day from onset (IQR 9-14 days) being an important time point of disease deterioration with further exacerbation to critical condition in 3 days (IQR 2-6.5 days), A RDS followed by AKI being the typical modes of sequential organ damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Chen, Feng, Xu, Huang, Sun, Zhou, He, Song, Wang, Li and Fang.)

Background: Blood-brain barrier (BBB) impairment plays a significant role in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the molecular mechanisms are poorly understood. In the present study, we aimed to investigate the regulatory relationship between the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, microRNA (miR)-181b and its target genes in sepsis in vivo and in vitro ., Methods: Four rat models (sham, sepsis, sepsis plus STAT3 inhibitor (Stattic), and sepsis plus miR-181b inhibitor [sepsis + anta-miR-181b]) were established. For the in vitro experiments, rat brain microvascular endothelial cells (rBMECs) and rat brain astrocytes (rAstrocytes) were cultured with 10% serum harvested from sham, sepsis, and sepsis + anta-miR-181b rats. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-QPCR) analysis was carried out to detect the binding and enrichment of the JAK/STAT3 signal core transcription complex in the miR-181b promoter region. Dual-luciferase reporter gene assay was conducted to test miR-181b and its target genes. The cell adhesion rate of rBMECs was also measured., Results: During our investigations, the expression levels of miR-181b, p-JAK2, p-STAT3, and C/EBPβ were found to be significantly increased in the septic rats compared with the sham rats. STAT3 inhibitor halted BBB damage by downregulating the expression of miR-181b. In addition, miR-181b targeted sphingosine-1-phosphate receptor 1 ( S1PR1 ) and neurocalcin delta ( NCALD ). The up-regulated miR-181b significantly decreased the cell adhesion rate of rBMECs. The administration of miR-181b inhibitor reduced damage to the BBB through increasing the expression of S1PR1 and NCALD , which again proved that miR-181b negatively regulates SIPR1 and NCALD to induce BBB damage., Conclusions: Our study demonstrated that JAK2/STAT3 signaling pathway induced expression of miR-181b, which promoted BBB impairment in rats with sepsis by downregulating S1PR1 and decreasing BBB cell adhesion. These findings strongly suggest JAK2/STAT3/miR-181b axis as therapeutic target in protecting against sepsis-induced BBB damage., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7024). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Short-term recurrence of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) polymerase chain reaction (PCR) in discharged coronavirus disease 2019 (COVID-19) patients attracts the public's concern. This study aimed to determine the clinical and epidemiological results of such patients., Methods: This retrospective study was conducted on 32 designated hospitals for COVID-19 patients discharged from January 14 to March 10, 2020. After 28-day followed-up, patients who tested positive again for SARS-CoV-2 RNA and confirmed by reverse-transcriptase polymerase chain reaction were re-admitted to hospital for further treatments. All of the close contacts of patients who tested positive again were asked to self-segregate for 14 days. Data of epidemiology, symptoms, laboratory tests, and treatments were analyzed in those patients, and their close contacts were investigated., Results: Of 1282 discharged patients, 189 (14.74%) tested positive again for SARS-CoV-2 RNA during 28-day follow-up. The median time from discharge to the next positive test was 8 days (interquartile range [IQR], 5-13). Patients in the group that tested positive again were younger (34 vs 45 years, P < .001) with a higher proportion of moderate symptoms (95.77% vs 84.35%, P < .001) in the first hospitalization than in the negative group. During the second hospitalization, all patients who tested positive again showed normal peripheral white blood cells and lymphocytes and no new symptoms of COVID-19; 78.31% further improved on chest computed tomography scan compared with the first discharge, yet 25.93% accepted antiviral therapy. The median time of re-positive to negative test was 8 days (IQR, 4-15). None of the close contacts developed COVID-19., Conclusions: Our data suggest that the short-term recurrence of positive SARS-CoV-2 RNA in discharged patients is not a relapse of COVID-19, and the risk of onward transmission is very low. This provides important information for managing COVID-19 patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The total survival rate in patients with acute aortic dissection (AAD) has been greatly improved because of surgical technique advances. However, the pre-operative mortality rate remained high. In this study, we sought to evaluate the effects of dexmedetomidine (DEX) on heart rate control and preoperative outcome in AAD., Methods: Retrospectively enrolled 461 patients who were diagnosed with AAD during the first 7-day after admission and divided into two groups according to the use of intravenous DEX: DEX group (91 patients) and Control group (370 patients). The heart rate and systolic blood pressure (SBP) level in both groups were recorded, and the incidence of aortic dissection rupture and pre-operative survival rates within 7 days were considered as the primary clinical outcomes., Results: Compared to the Control group, heart rate of DEX group in the early 3 hours was significantly higher (P=0.009), and the 24-hour heart rate fluctuation was smaller (P=0.012). There was no difference in the systolic blood pressure (SBP) between the two groups, but the 24-hour fluctuation of SBP in DEX group was less (P=0.003). We performed a propensity-matched analysis to minimize selection bias and found that there were 7 (7.9%) patients in the DEX group occurred acute pulmonary edema, 17 (19.1%) patients in the Control group (P=0.047). And the pre-operative survival rates within 7 days were significantly improved in DEX group (P=0.004). And the pre-operative survival rates within 7 days were significantly improved in DEX group (P=0.004)., Conclusions: DEX can be beneficial to facilitate heart rate control, keep SBP more steady, and reduce the incidence of pre-operative aortic rupture in patients with AAD.

1. Previously, we showed that long-term treatment of rats after myocardial infarction (MI) with B-type natriuretic peptide (BNP) prevented ventricular remodelling. However, it is unclear whether long-term BNP treatment affects cardiac hypertrophy and, if so, its mechanism of action. In the present study, we investigated the effects of long-term BNP treatment on cardiac hypertrophy and the molecular mechanisms involved. 2. Cardiac hypertrophy was established in rats by ligation of the left anterior descending coronary artery. After treatment with BNP (5 or 15 microg/kg per day) for 8 weeks, indices of cardiac hypertrophy were determined. In separate in vitro experiments, cardiomyocyte hypertrophy was induced by treatment of cardiomyocytes with 10(-6) mol/L angiotensin (Ang) II for 48 h and cell surface area and [(3)H] incorporation were measured. Transforming growth factor (TGF)-beta1 and smad7 mRNA and protein expression in vivo and in vitro were detected using reverse transcription-polymerase chain reaction and western blotting. 3. Long-term BNP treatment dose-dependently attenuated cardiac hypertrophy and improved cardiac function in rats after MI. Furthermore, BNP attenuated the upregulation of TGF-beta1 and downregulation of smad7 mRNA and protein expression. The in vitro experiments further proved that BNP inhibited cardiac hypertrophy and changes in the TGF-beta1/smad7 pathway, which were completely blocked by the cyclic GMP-dependent protein kinase (PKG) inhibitor, KT5823 (cells were treated with 10(-6) mol/L KT5823 for 48 h). 4. The results of the present study demonstrate that long-term treatment of rats with BNP dose-dependently attenuates cardiac hypertrophy and that this is associated with downregulation of TGF-beta1 and upregulation of smad7 via PKG signalling. Long-term BNP treatment may be a new therapeutic strategy to prevent cardiac hypertrophy and progression to heart failure.