Publications by authors named "Shaoqing Lei"

47 Publications

Course of illness and outcomes in older COVID-19 patients treated with HFNC: a retrospective analysis.

Aging (Albany NY) 2021 06 28;13(12):15801-15814. Epub 2021 Jun 28.

Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.

Coronavirus disease-2019 (COVID-19) has rapidly spread worldwide and causes high mortality of elderly patients. High-flow nasal cannula therapy (HFNC) is an oxygen delivery method for severely ill patients. We retrospectively analyzed the course of illness and outcomes in 110 elderly COVID-19 patients (≥65 years) treated with HFNC from 6 hospitals. 38 patients received HFNC (200 mmHg < PaO/FiO ≤ 300 mmHg, early HFNC group), and 72 patients received HFNC (100 mmHg < PaO/FiO ≤ 200 mmHg, late HFNC group). There were no significant differences of sequential organ failure assessment (SOFA) scores and APECH II scores between early and late HFNC group on admission. Compared with the late HFNC group, patients in the early HFNC group had a lower likelihood of developing severe acute respiratory distress syndrome (ARDS), longer time from illness onset to severe ARDS and shorter duration of viral shedding after illness onset, as well as shorter lengths of ICU and hospital stay. 24 patients died during hospitalization, of whom 22 deaths (30.6%) were in the late HFNC group and 2 (5.3%) in the early HFNC group. The present study suggested that the outcomes were better in severely ill elderly patients with COVID-19 receiving early compared to late HFNC.
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http://dx.doi.org/10.18632/aging.203224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266360PMC
June 2021

Selective inhibition of PKCβ2 improves Caveolin-3/eNOS signaling and attenuates lipopolysaccharide-induced injury by inhibiting autophagy in H9C2 cardiomyocytes.

J Mol Histol 2021 Jun 8. Epub 2021 Jun 8.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Lipopolysaccharide (LPS)-induced autophagy is involved in sepsis-associated myocardial injury with increased PKCβ2 activation. We previously found hyperglycemia-induced PKCβ2 activation impaired the expression of caveolin-3 (Cav-3), the dominant isoform to form cardiomyocytes caveolae which modulate eNOS signaling to confer cardioprotection in diabetes. However, little is known about the roles of PKCβ2 in autophagy and Cav-3/eNOS signaling in cardiomyocytes during LPS exposure. We hypothesize LPS-induced PKCβ2 activation promotes autophagy and impairs Cav-3/eNOS signaling in LPS-treated cardiomyocytes. H9C2 cardiomyocytes were treated with LPS (10 µg/mL) in the presence or absence of PKCβ2 inhibitor CGP53353 (CGP, 1 µM) or autophagy inhibitor 3-methyladenine (3-MA, 10 µM). LPS stimulation induced cytotoxicity overtime in H9C2 cardiomyocytes, accompanied with excessive PKCβ2 activation. Selective inhibition of PKCβ2 with CGP significantly reduced LPS-induced cytotoxicity and autophagy (measured by LC-3II, Beclin-1, p62 and autophagic flux). In addition, CGP significantly attenuated LPS-induced oxidative injury, and improved Cav-3 expression and eNOS activation, similar effects were shown by the treatment of autophagy inhibitor 3-MA. LPS-induced myocardial injury is associated with excessive PKCβ2 activation, which contributes to elevated autophagy and impaired Cav-3/eNOS signaling. Selective inhibition of PKCβ2 improves Cav-3/eNOS signaling and attenuates LPS-induced injury through inhibiting autophagy in H9C2 cardiomyocytes.
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http://dx.doi.org/10.1007/s10735-021-09990-0DOI Listing
June 2021

The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats.

Cardiovasc Drugs Ther 2021 Feb 23. Epub 2021 Feb 23.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.

Purpose: Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats.

Methods And Results: Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy.

Conclusion: Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.
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http://dx.doi.org/10.1007/s10557-021-07159-1DOI Listing
February 2021

Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury.

Cell Death Dis 2021 01 7;12(1):43. Epub 2021 Jan 7.

Department of Anesthesiology, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei, China.

The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.
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http://dx.doi.org/10.1038/s41419-020-03295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791027PMC
January 2021

Effect of phenotypic detection of circulating tumor cells marked by epithelial-mesenchymal transformation on the prognosis of lung cancer: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Oct;99(44):e22960

Department of laboratory medicine, Yingcheng City People's Hospital, Hubei Province, Hubei, China.

Background: To explore the significance of phenotype detection of circulating tumor cells (CTCs) based on epithelial-mesenchymal transition (EMT) labeling to evaluate the prognosis of lung cancer.

Methods: Database was retrieved from China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database, PubMed, and EMBASE. Based on EMT on overall survival (OS) and disease-free survival (DFS), hazard ratios (HRs) and its 95% of confidence intervals (CIs) were applied to assess the prognostic effect of CTCs. RevMan 5.3 and STATA 16.0 software were adopted to perform the meta-analysis.

Results: Based on EMT in terms of the prognosis of patients suffering from lung cancer, this study comprehensively reviewed and evaluated the available evidence of phenotype detection of CTCs.

Conclusion: Based on EMT in the prognosis of patients who developed with lung cancer, our findings proved the effect of phenotype detection of CTCs. Such studies may reveal a new prognostic marker for lung cancer patients and help clinicians and health professionals make clinical decisions.

Osf Registration Number: DOI 10.17605/OSF.IO/E7KAZ.
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http://dx.doi.org/10.1097/MD.0000000000022960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598871PMC
October 2020

Sex differences in clinical characteristics and risk factors for mortality among severe patients with COVID-19: a retrospective study.

Aging (Albany NY) 2020 Oct 13;12(19):18833-18843. Epub 2020 Oct 13.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

The coronavirus disease 2019 (COVID-19) became a global pandemic. Males, compared to females, seem to be more susceptible to COVID-19, but related evidence is scarce, especially in severe patients. We explored sex differences in clinical characteristics and potential risk factors for mortality in severe COVID-19 patients. In this retrospective cohort study, we included all severe COVID-19 patients admitted to Eastern Renmin Hospital of Wuhan University, Wuhan, China, with a definitive clinical outcome as of Apr 10, 2020. Of the included 651 patients, 332 were male, and 319 were female. Males and females did not differ in age and underlying comorbidities. Males were more likely than females to report fever and develop serious complications, including acute respiratory distress syndrome, secondary infection, acute cardiac injury, coagulopathy, acute kidney injury and arrhythmia. Further, males had much higher mortality relative to females. Multivariable regression showed neutrophilia (odds ratio 6.845, 95% CI 1.227-38.192, =0.028), thrombocytopenia (19.488, 3.030-25.335, =0.002), hypersensitive troponin I greater than 0.04 pg/mL (6.058, 1.545-23.755, =0.010), and procalcitonin greater than 0.1 ng/mL (6.350, 1.396-28.882, =0.017) on admission were associated with in-hospital death. With either of these risk factors, the cumulative survival rate was relatively lower in males than in females. In conclusion, males are more likely than females to develop serious complications and progress to death. The potential risk factors of neutrophilia, thrombocytopenia, hypersensitive troponin I greater than 0.04 pg/mL and procalcitonin more than 0.1 ng/mL may help clinicians to identify patients with poor outcomes at an early stage, especially in males.
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http://dx.doi.org/10.18632/aging.103793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732274PMC
October 2020

Meta-analysis of coagulation parameters associated with disease severity and poor prognosis of COVID-19.

Int J Infect Dis 2020 Nov 15;100:441-448. Epub 2020 Sep 15.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address:

Background: To determine whether abnormal coagulation parameters are associated with disease severity and poor prognosis in patients with 2019 Corona Virus Disease (COVID-19).

Methods: A systematic literature search was conducted using the databases PubMed, Embase, and Web of sciences until April 25, 2020. We included a total of 15 studies with 2277 patients. Platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer (D-D), and fibrinogen (FIB) were collected and analyzed. The statistical results were expressed as the effect measured by mean difference (MD) with the related 95% confidence interval (CI).

Results: The PLT level of severe cases was lower than that of mild cases, while the levels of PT, D-D, and FIB were higher than those of mild cases (P < 0.05). The level of APTT had no statistical difference between two groups (P > 0.05). PT of ICU patients was significantly longer (P < 0.05) than that of non-ICU patients. In non-survivors, PT and D-D were higher, yet PLT was lower than that of survivors (P < 0.05). There was no significant difference in APTT between survivors and non-survivors (P > 0.05). The funnel plot and Egger's regression test demonstrated that there was no publication bias.

Conclusions: Our data support the notion that coagulopathy could be considered as a risk factor for disease severity and mortality of COVID-19, which may help clinicians to identify the incidence of poor outcomes in COVID-19 patients.
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http://dx.doi.org/10.1016/j.ijid.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490635PMC
November 2020

Sleep Disturbance and Psychological Profiles of Medical Staff and Non-Medical Staff During the Early Outbreak of COVID-19 in Hubei Province, China.

Front Psychiatry 2020 22;11:733. Epub 2020 Jul 22.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Objective: The outbreak of coronavirus disease 2019 (COVID-19) has considerably burdened the healthcare system in the Hubei Province, the most severely affected region in China. The aim of our study was to assess the psychological effects of COVID-19 epidemic on the healthcare workers in Hubei.

Methods: A total of 2737 healthcare workers were sampled using a two-dimensional code shared online between Mar 4 and Mar 9, 2020. The questionnaires consisted of three elements: baseline characteristics, Pittsburgh Sleep Quality Index (PSQI), and Hospital Anxiety and Depression Scale (HADS). The primary outcome variables were PQSI, anxiety and depression scores of non-medical staff, non-frontline medical staff and frontline medical staff. Binary logistical regression analyses were used to compare between respondents with and without sleep disturbance.

Results: About 61.6% of the respondents reported sleep problems, 22.6% experienced anxiety, and 35% exhibited depressive symptoms. The prevalence of sleep disorders was higher among the frontline healthcare workers compared to the non-frontline and non-medical staff, while anxiety and depression were prevalent in the entire cohort. Logistic regression analysis identified medical occupation, family burden, bereavement, anxiety, and depression as significantly predictive of poor sleep quality.

Conclusions: Frontline medical staff are more vulnerable to sleep disturbances. Psychosocial interventions are needed to help allied healthcare personnel to better respond to COVID-19 and future outbreaks.
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http://dx.doi.org/10.3389/fpsyt.2020.00733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387679PMC
July 2020

Author's reply.

EClinicalMedicine 2020 Jun 18;23:100386. Epub 2020 May 18.

Department of anesthesiology, the University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1016/j.eclinm.2020.100386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231726PMC
June 2020

Selective Inhibition of PKC2 Restores Ischemic Postconditioning-Mediated Cardioprotection by Modulating Autophagy in Diabetic Rats.

J Diabetes Res 2020 3;2020:2408240. Epub 2020 Apr 3.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Diabetic hearts are more susceptible to myocardial ischemia/reperfusion (I/R) injury and less sensitive to ischemic postconditioning (IPostC), but the underlying mechanisms remain unclear. PKC2 is preferentially overactivated in diabetic myocardium, in which autophagy status is abnormal. This study determined whether hyperglycemia-induced PKC2 activation resulted in autophagy abnormality and compromised IPostC cardioprotection in diabetes. We found that diabetic rats showed higher cardiac PKC2 activation and lower autophagy than control at baseline. However, myocardial I/R further increased PKC2 activation and promoted autophagy status in diabetic rats. IPostC significantly attenuated postischemic infarct size and CK-MB, accompanied with decreased PKC2 activation and autophagy in control but not in diabetic rats. Pretreatment with CGP53353, a selective inhibitor of PKC2, attenuated myocardial I/R-induced infarction and autophagy and restored IPostC-mediated cardioprotection in diabetes. Similarly, CGP53353 could restore hypoxic postconditioning (HPostC) protection against hypoxia reoxygenation- (HR-) induced injury evidenced by decreased LDH release and JC-1 monomeric cells and increased cell viability. These beneficial effects of CGP53353 were reversed by autophagy inducer rapamycin, but could be mimicked by autophagy inhibitor 3-MA. It is concluded that selective inhibition of PKC2 could attenuate myocardial I/R injury and restore IPostC-mediated cardioprotection possibly through modulating autophagy in diabetes.
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http://dx.doi.org/10.1155/2020/2408240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157806PMC
February 2021

Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection.

EClinicalMedicine 2020 Apr 5;21:100331. Epub 2020 Apr 5.

State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong, China.

Background: The outbreak of 2019 novel coronavirus disease (COVID-19) in Wuhan, China, has spread rapidly worldwide. In the early stage, we encountered a small but meaningful number of patients who were unintentionally scheduled for elective surgeries during the incubation period of COVID-19. We intended to describe their clinical characteristics and outcomes.

Methods: We retrospectively analyzed the clinical data of 34 patients underwent elective surgeries during the incubation period of COVID-19 at Renmin Hospital, Zhongnan Hospital, Tongji Hospital and Central Hospital in Wuhan, from January 1 to February 5, 2020.

Findings: Of the 34 operative patients, the median age was 55 years (IQR, 43-63), and 20 (58·8%) patients were women. All patients developed COVID-19 pneumonia shortly after surgery with abnormal findings on chest computed tomographic scans. Common symptoms included fever (31 [91·2%]), fatigue (25 [73·5%]) and dry cough (18 [52·9%]). 15 (44·1%) patients required admission to intensive care unit (ICU) during disease progression, and 7 patients (20·5%) died after admission to ICU. Compared with non-ICU patients, ICU patients were older, were more likely to have underlying comorbidities, underwent more difficult surgeries, as well as more severe laboratory abnormalities (eg, hyperleukocytemia, lymphopenia). The most common complications in non-survivors included ARDS, shock, arrhythmia and acute cardiac injury.

Interpretation: In this retrospective cohort study of 34 operative patients with confirmed COVID-19, 15 (44·1%) patients needed ICU care, and the mortality rate was 20·5%.

Funding: National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/j.eclinm.2020.100331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128617PMC
April 2020

Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling.

Oxid Med Cell Longev 2019 5;2019:9836302. Epub 2019 Sep 5.

Department of Anesthesiology, University of Hong Kong, Hong Kong SAR, China.

Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O , and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl--cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl--cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.
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http://dx.doi.org/10.1155/2019/9836302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748204PMC
March 2020

Dexmedetomidine attenuates oxidative/nitrative stress in lung tissues of septic mice partly via activating heme oxygenase-1.

Exp Ther Med 2019 Oct 16;18(4):3071-3077. Epub 2019 Aug 16.

Department of Anesthesiology, The Central Hospital of Enshi Autonomous Perfecture, Enshi, Hubei 445000, P.R. China.

Excessive reactive oxygen/nitrogen species are considered to be one of the primary events that cause lung injury during sepsis. The present study aimed to determine whether dexmedetomidine (Dex) exhibits antioxidative and antinitrative effects on sepsis-induced lung injury and its effect on heme oxygenase-1 (HO-1) activation. The cecal ligation and puncture (CLP) mouse model was used, where male C57BL/6J mice were randomized into groups: Sham, CLP, Dex and Dex + zinc protoporphyrin (ZnPP). Following CLP or sham operation, intraperitoneal injections of 40 µg/kg Dex or saline were administered in the Dex + ZnPP group, intraperitoneal injections of ZnPP (40 mg/kg) were administered 1 h prior to the CLP operation. Subsequently, histopathological examination of the lungs and measurement of HO-1 activity in the lung, as well as oxidative and nitrative stress were determined 24 h following CLP. Dex significantly decreased the levels of oxidative and nitrative stress, as demonstrated by the decreased levels of malondialdehyde and nitrotyrosine, and the protein expression of inducible nitric oxide synthase, as well as increased superoxide dismutase in lung tissues. Also Dex inhibited the elevation of serum interleukin-6 and tumor necrosis factor-α and increased lung HO-1 activity. Furthermore, the effects of Dex were partially reverted by the HO-1 inhibitor ZnPP. In conclusion, Dex inhibited oxidative/nitrative stress in sepsis and attenuated sepsis-induced acute lung injury partially by increasing HO-1 activity.
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http://dx.doi.org/10.3892/etm.2019.7911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755463PMC
October 2019

Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes.

J Diabetes Res 2019 17;2019:8151836. Epub 2019 Feb 17.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.

Diabetes aggravates myocardial ischemia-reperfusion (I/R) injury because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. Studies have indicated that myocardial I/R may coincide and interact with sepsis and inflammation. However, the role of LPS in hypoxia/reoxygenation (H/R) injury in cardiomyocytes under high glucose conditions is still unclear. Our objective was to examine whether lipopolysaccharide (LPS) could aggravate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by upregulating ROS production to activate NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. H9C2 cardiomyocytes were exposed to HG (30 mM) condition with or without LPS, along with caspase-1 inhibitor (Ac-YVAD-CMK), inflammasome inhibitor (BAY11-7082), ROS scavenger N-acetylcysteine (NAC), or not for 24 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). The cell viability, lactate dehydrogenase (LDH) release, caspase-1 activity, and intracellular ROS production were detected by using assay kits. The incidence of pyroptosis was detected by calcein-AM/propidium iodide (PI) double staining kit. The concentrations of IL-1 and IL-18 in the supernatants were assessed by ELISA. The mRNA levels of NLRP3, ASC, and caspase-1 were detected by qRT-PCR. The protein levels of NF-B p65, NLRP3, ASC, cleaved caspase-1 (p10), IL-1, and IL-18 were detected by western blot. The results indicated that pretreatment LPS with 1 g/ml not 0.1 g/ml could efficiently aggravate HG and H/R injury by activating NLRP3 inflammasome to mediate pyroptosis in H9C2 cells, as evidenced by increased LDH release and decreased cell viability in the cells, and increased expression of NLRP3, ASC, cleaved caspase-1 (p10), IL-1, and IL-18. Meanwhile, Ac-YVAD-CMK, BAY11-7082, or NAC attenuated HG- and H/R-induced H9C2 cell injury with LPS stimulated by reversing the activation of NLRP3 inflammasome-mediated pyroptosis. In conclusion, LPS could increase the sensitivity of H9C2 cells to HG and H/R and aggravated HG- and H/R-induced H9C2 cell injury by promoting ROS production to induce NLRP3 inflammasome-mediated pyroptosis.
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http://dx.doi.org/10.1155/2019/8151836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398034PMC
July 2019

Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway.

Biosci Rep 2019 01 15;39(1). Epub 2019 Jan 15.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.
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http://dx.doi.org/10.1042/BSR20181614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331666PMC
January 2019

Remifentanil attenuates lipopolysaccharide-induced oxidative injury by downregulating PKCβ2 activation and inhibiting autophagy in H9C2 cardiomyocytes.

Life Sci 2018 Nov 21;213:109-115. Epub 2018 Oct 21.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address:

Aim: Lipopolysaccharide (LPS)-induced myocardial injury is a leading cause of death in patients with sepsis, which is associated with excessive activation of PKCβ (especially PKCβ2) and autophagy. Remifentanil, a μ-opioid receptor agonist, is well demonstrated to have beneficial effects during sepsis, but the underlying mechanisms are still unknown. The present study was designed to investigate the roles of remifentanil in PKCβ2 and autophagy in LPS-treated cardiomyocytes.

Main Methods: H9C2 cardiomyocytes were treated with or without remifentanil (2.5 μM), PKCβ2 inhibitor CGP53353 (CGP, 1 μM) or autophagy inhibitor 3-methyladenine (3-MA, 10 μM) in the presence or absence of LPS (10 μg/mL).

Key Findings: LPS exposure for 24 h led to a significant increase in cell death, LDH release and MDA production in H9C2 cardiomyocytes, accompanied with decreased SOD activity and excessive PKCβ2 activation and autophagy indicated by enhanced Beclin-1 and LC-3II expression and decreased p62 expression. All these changes were attenuated by remifentanil intervention. In addition, inhibition of LPS-induced PKCβ2 activation by CGP or autophagy inhibitor 3-MA has similar effects to remifentanil.

Significance: Remifentanil protects H9C2 cardiomyocytes against LPS-induced oxidative injury, as a result of downregulating PKCβ2 activation and inhibiting autophagy, partially.
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http://dx.doi.org/10.1016/j.lfs.2018.10.041DOI Listing
November 2018

Inhibition of HDAC6 Activity Alleviates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Potential Role of Peroxiredoxin 1 Acetylation and Redox Regulation.

Oxid Med Cell Longev 2018 25;2018:9494052. Epub 2018 Jun 25.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei Province, China.

Patients with diabetes are more vulnerable to myocardial ischemia/reperfusion (MI/R) injury, which is associated with excessive reactive oxygen species (ROS) generation and decreased antioxidant defense. Histone deacetylase 6 (HDAC6), a regulator of the antioxidant protein peroxiredoxin 1 (Prdx1), is associated with several pathological conditions in the cardiovascular system. This study investigated whether tubastatin A (TubA), a highly selective HDAC6 inhibitor, could confer a protective effect by modulating Prdx1 acetylation in a rat model of MI/R and an model of hypoxia/reoxygenation (H/R). Here, we found that diabetic hearts with excessive HDAC6 activity and decreased acetylated-Prdx1 levels were more vulnerable to MI/R injury. TubA treatment robustly improved cardiac function, reduced cardiac infarction, attenuated ROS generation, and increased acetylated-Prdx1 levels in diabetic MI/R rats. These results were further confirmed by an study using H9c2 cells. Furthermore, a study using Prdx1 acetyl-silencing mutants (K197R) showed that TubA only slightly attenuated H/R-induced cell death and ROS generation in K197R-transfected H9c2 cells exposed to high glucose (HG), but these differences were not statistically significant. Taken together, these findings suggest that HDAC6 inhibition reduces ROS generation and confers a protective effect against MI/R or H/R injury by modulating Prdx1 acetylation at K197.
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http://dx.doi.org/10.1155/2018/9494052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036837PMC
October 2018

Diosgenin inhibited the expression of TAZ in hepatocellular carcinoma.

Biochem Biophys Res Commun 2018 09 11;503(3):1181-1185. Epub 2018 Jul 11.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.

Emerging evidence has supported that TAZ (transcriptional co-activator with PDZ binding motif), one transcription co-activator in Hippo signaling pathway, plays an oncogenic role in liver carcinogenesis. Targeting TAZ could be a potential therapeutic approach for liver cancer patients. In the current study, we aim to determine whether diosgenin could be an inhibitor of TAZ in liver cancer cells. We found that diosgenin inhibited the expression of TAZ in liver cancer cells. Moreover, we found that diosgenin inhibited cell growth, induced apoptosis, suppressed cell migration and invasion in part via inhibition of TAZ in liver cancer cells. Our study provides the evidence to support that diosgenin could be a potential agent for treating human liver cancer.
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http://dx.doi.org/10.1016/j.bbrc.2018.07.022DOI Listing
September 2018

Glycine Protects H9C2 Cardiomyocytes from High Glucose- and Hypoxia/Reoxygenation-Induced Injury via Inhibiting PKC2 Activation and Improving Mitochondrial Quality.

J Diabetes Res 2018 4;2018:9502895. Epub 2018 Apr 4.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Background: Patients with diabetes are more vulnerable to myocardial ischemia reperfusion injury (IRI), which is involved in PKC2 activation and mitochondrial dysfunction. Glycine has been documented as a cytoprotective agent to attenuate diabetes-related abnormalities and reduce myocardial IRI, but the underlying mechanisms are still unclear. We determined whether glycine could attenuate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by inhibiting PKC2 activation and improving mitochondrial quality in cultured H9C2 cells.

Methods: H9C2 cells were either exposed to low glucose (LG) or HG conditions with or without treatment of glycine or CGP53353 (a selective inhibitor of PKC2) for 48 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). Cell viability, lactate dehydrogenase (LDH) release, mitochondrial membrane potential (MMP), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) concentration were detected using corresponding commercial kits. Mitochondrial quality control-related proteins (LC-3II, Mfn-2, and Cyt-C) and PKC2 activation were detected by Western blot.

Results: HG stimulation significantly decreased cell viability and SOD activity and increased LDH release, MDA production, and PKC2 activation as compared to LG group, all of which changes were further increased by H/R insult. Glycine or CGP53353 treatment significantly reduced the increase of LDH release, MDA production, PKC2 activation, and Cyt-C expression and the decrease of cell viability, SOD activity, MMP, Mfn-2 expression, and LC-3II/LC-3I ratio induced by HG and H/R stimulation.

Conclusions: Supplementary glycine protects H9C2 cells from HG- and H/R-induced cellular injury by suppressing PKC2 activation and improving mitochondria quality.
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http://dx.doi.org/10.1155/2018/9502895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904807PMC
October 2018

The Roles of Autophagy in Acute Lung Injury Induced by Myocardial Ischemia Reperfusion in Diabetic Rats.

J Diabetes Res 2018 3;2018:5047526. Epub 2018 Apr 3.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Patients with diabetes are vulnerable to myocardial ischemia reperfusion (IR) injury, which may also induce acute lung injury (ALI) due to overaccumulation of reactive oxygen species (ROS) and inflammation cytokine in circulation. Despite autophagy plays a significant role in diabetes and pulmonary IR injury, the role of autophagy in ALI secondary to myocardial IR in diabetes remains largely elusive. We aimed to investigate pulmonary autophagy status and its roles in oxidative stress and inflammation reaction in lung tissues from diabetic rats subjected to myocardial IR. Control or diabetic rats were either treated with or without autophagy inducer rapamycin (Rap) or autophagy inhibitor 3-methyladenine (3-MA) before myocardial IR, which was achieved by occluding the left anterior descending coronary artery for 30 min and followed by reperfusion for 120 min. Diabetic rats subjected to myocardial IR showed more serious ALI with higher lung injury score and WET/DRY ratio and lower PaO as compared with control rats, accompanied with impaired autophagy indicated by reduced LC-3II/LC-3I ratio and Beclin-1 expression, decreased superoxide dismutase (SOD) activity, and increased 15-F2t-Isoprostane formation in lung tissues, as well as increased levels of leukocyte count and proinflammatory cytokines in BAL fluid. Improving autophagy with Rap significantly attenuated all these changes, but the autophagy inhibitor 3-MA exhibited adverse or opposite effects as Rap. In conclusion, diabetic lungs are more vulnerable to myocardial IR, which are involved in impaired autophagy. Improving autophagy could attenuate ALI induced by myocardial IR in diabetic rats, possibly through inhibiting inflammatory reaction and oxidative stress.
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http://dx.doi.org/10.1155/2018/5047526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903337PMC
October 2018

MiR-34a-5p mediates sevoflurane preconditioning induced inhibition of hypoxia/reoxygenation injury through STX1A in cardiomyocytes.

Biomed Pharmacother 2018 Jun 22;102:153-159. Epub 2018 Mar 22.

Department of Anesthesia, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.

Anesthetic preconditioning is a cellular protective approach whereby exposure to a volatile anesthetic renders cardio injury. Sevoflurane preconditioning has been shown to exhibit cardio protective effect on hypoxia/reoxygenation (H/R) injury, but the underlying mechanism is unclear. Syntaxin 1A (STX1A), an important regulator in cardio disease, was predicted to be the target gene of microRNA-34a-5p (miR-34a-5p). The current research was designed to delineate the role of miR-34a-5p in regulating sevoflurane preconditioning in cardiomyocytes injury. In this study, the results demonstrated that the expression of STX1A was significantly increased, while miR-34a-5p was dramatically decreased in sev-preconditioning H9c2 cells as compared with cells only under H/R stimulation. Moreover, miR-34a-5p regulated the protective effect of sev-preconditioning in injured H9c2 cells by mediating cell proliferation and cell apoptosis. Additionally, the luciferase report confirmed the targeting reaction between STX1A and miR-34a-5p. Taken together, our study suggested that miR-34a-5p regulated sev-preconditioning induced inhibition of hypoxia/reoxygenation injury through mediating STX1A, provided a potential therapeutic target for anesthetic protection in cardio disease.
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http://dx.doi.org/10.1016/j.biopha.2018.03.002DOI Listing
June 2018

NLRP3 Inflammasome Activation-Mediated Pyroptosis Aggravates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats.

Oxid Med Cell Longev 2017 14;2017:9743280. Epub 2017 Sep 14.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.

The reactive oxygen species- (ROS-) induced nod-like receptor protein-3 (NLRP3) inflammasome triggers sterile inflammatory responses and pyroptosis, which is a proinflammatory form of programmed cell death initiated by the activation of inflammatory caspases. NLRP3 inflammasome activation plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Our present study investigated whether diabetes aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. Type 1 diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg/kg). MI/R was induced by ligating the left anterior descending artery (LAD) for 30 minutes followed by 2 h reperfusion. H9C2 cardiomyocytes were exposed to high glucose (HG, 30 mM) conditions and hypoxia/reoxygenation (H/R) stimulation. The myocardial infarct size, CK-MB, and LDH release in the diabetic rats subjected to MI/R were significantly higher than those in the nondiabetic rats, accompanied with increased NLRP3 inflammasome activation and increased pyroptosis. Inhibition of inflammasome activation with BAY11-7082 significantly decreased the MI/R injury. studies showed similar effects, as BAY11-7082 or the ROS scavenger N-acetylcysteine, attenuated HG and H/R-induced H9C2 cell injury. In conclusion, hyperglycaemia-induced NLRP3 inflammasome activation may be a ROS-dependent process in pyroptotic cell death, and NLRP3 inflammasome-induced pyroptosis aggravates MI/R injury in diabetic rats.
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http://dx.doi.org/10.1155/2017/9743280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618779PMC
July 2018

Suppression of microRNA-142-5p attenuates hypoxia-induced apoptosis through targeting SIRT7.

Biomed Pharmacother 2017 Oct 1;94:394-401. Epub 2017 Aug 1.

Department of Cardiology, People's Hospital of Xuyi, Xuyi, Jiangsu 211700, China. Electronic address:

Increasing study has suggested that microRNAs (miRNAs) are pivotal regulators in regulating hypoxia-induced injury. miR-142-5p has been suggested as a critical regulator for cellular survival. However, the role of miR-142-5p in regulating hypoxia-induced injury remains unknown. In this study, we aimed to investigate the mechanistic roles of miR-142-5p in regulating cell survival during hypoxia treatment using H9C2 cardiomyoblasts and primary cardiomyocytes. We showed that miR-142-5p expression level was significantly repressed by hypoxia treatment. Overexpression of miR-142-5p during hypoxia induced extensive cell injury and apoptosis whereas suppression of miR-142-5p significantly promoted cell viability and attenuated cell apoptosis with hypoxia treatment. Sirtuin7 (SIRT7) was identified as a direct target gene of miR-142-5p by bioinformatics analysis and dual-luciferase reporter assays. Overexpression of miR-142-5p significantly decreased SIRT7 expression, while suppression of miR-142-5p increased SIRT7 expression. Furthermore, overexpression of SIRT7 protected H9C2 cardiomyoblasts and primary cardiomyocytes against hypoxia-induced injury and apoptosis. The silencing of SIRT7 markedly abrogated the protective effect induced by miR-142-5p suppression. Taken together, these results suggest that downregulation of miR-142-5p alleviates hypoxia-induced injury through upregulation of SIRT7. Our study suggests miR-142-5p/SIRT7 as potential therapeutic targets for ischemic heart disease.
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http://dx.doi.org/10.1016/j.biopha.2017.07.083DOI Listing
October 2017

Lung-Protective Ventilation Strategies for Relief from Ventilator-Associated Lung Injury in Patients Undergoing Craniotomy: A Bicenter Randomized, Parallel, and Controlled Trial.

Oxid Med Cell Longev 2017 5;2017:6501248. Epub 2017 Jul 5.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Current evidence indicates that conventional mechanical ventilation often leads to lung inflammatory response and oxidative stress, while lung-protective ventilation (LPV) minimizes the risk of ventilator-associated lung injury (VALI). This study evaluated the effects of LPV on relief of pulmonary injury, inflammatory response, and oxidative stress among patients undergoing craniotomy. Sixty patients undergoing craniotomy received either conventional mechanical (12 mL/kg tidal volume [V] and 0 cm HO positive end-expiratory pressure [PEEP]; CV group) or protective lung (6 mL/kg V and 10 cm HO PEEP; PV group) ventilation. Hemodynamic variables, lung function indexes, and inflammatory and oxidative stress markers were assessed. The PV group exhibited greater dynamic lung compliance and lower respiratory index than the CV group during surgery ( < 0.05). The PV group exhibited higher plasma interleukin- (IL-) 10 levels and lower plasma malondialdehyde and nitric oxide and bronchoalveolar lavage fluid, IL-6, IL-8, tumor necrosis factor-, IL-10, malondialdehyde, nitric oxide, and superoxide dismutase levels ( < 0.05) than the CV group. There were no significant differences in hemodynamic variables, blood loss, liquid input, urine output, or duration of mechanical ventilation between the two groups ( > 0.05). Patients receiving LPV during craniotomy exhibited low perioperative inflammatory response, oxidative stress, and VALI.
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http://dx.doi.org/10.1155/2017/6501248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516714PMC
April 2018

Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the P38-MAPK/TXNIP signaling activation in streptozotocin induced diabetic rats.

Acta Cir Bras 2017 Jun;32(6):429-439

Full Professor, Department of Anesthesiology, Renmin Hospital, Wuhan University, China. Design and supervised all phases of the study, critical revision.

Purpose: : To determine whether dexmedetomidine (DEX) could attenuate acute kidney injury (AKI) induced by ischemia/reperfusion (I/R) in streptozotocin (STZ)-induced diabetic rats.

Methods: : Four groups each containing six rats were created (sham control(S), diabetes-sham (DS), diabetes I/R (DI/R), and diabetes-I/R-dexmedetomidine (DI/R-DEX). In diabetes groups, single-dose (65 mg/kg) STZ was administered intraperitoneally (i.p.). In Group DI/R, ischemia reperfusion was produced via 25 min of bilateral renal pedicle clamping followed by 48 h of reperfusion. In Group DI/R-DEX, 50 μg/kg dexmedetomidine was administered intraperitoneally 30 minutes before ischemia. Renal function, histology, apoptosis, the levels of TNF-α, IL-1β, and oxidative stress in diabetic kidney were determined. Moreover, expression of P38 mitogen-activated protein kinase (P38-MAPK), phosphorylated-P38-MAPK(p-P38-MAPK) and thioredoxin-interacting protein (TXNIP) were assessed.

Results: : The degree of renal I/R injury was significantly increased in DI/R group compared with S group and DS group. The levels of TNF-α, IL-1β, oxidative stress and apoptosis were found significantly higher in DI/R Group when compared with S Group and DS Group. The protein expression of p-P38-MAPK and TXNIP were significantly increased after I/R. All these changes were reversed by DEX treatment.

Conclusion: : The renoprotective effects of DEX-pretreatment which attenuates I/R-induced AKI were partly through inhibition of P38-MAPK activation and expression of TXINP in diabetic kidney.
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http://dx.doi.org/10.1590/s0102-865020170060000003DOI Listing
June 2017

DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy.

Clin Sci (Lond) 2017 Jun 22;131(11):1161-1178. Epub 2017 May 22.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China

IPO (ischaemic post-conditioning) is a promising method of alleviating myocardial IR (ischaemia-reperfusion) injury; however, IPO-mediated cardioprotection is lost in diabetic hearts via mechanisms that remain largely unclear. We hypothesized that decreased cardiac expression of DJ-1, a positive modulator of autophagy, compromises the effectiveness of IPO-induced cardioprotection in diabetic rats. Diabetic rats subjected to myocardial IR (30 min of coronary artery occlusion followed by 120 min of reperfusion) exhibited more severe myocardial injury, less cardiac autophagy, lower DJ-1 expression and AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway activity than non-diabetic rats. IPO significantly attenuated myocardial injury and up-regulated cardiac DJ-1 expression, AMPK/mTOR activity and autophagy in non-diabetic rats but not in diabetic rats. AAV9 (adeno-associated virus 9)-mediated cardiac DJ-1 overexpression as well as pretreatment with the autophagy inducer rapamycin restored IPO-induced cardioprotection in diabetic rats, an effect accompanied by AMPK/mTOR activation and autophagy up-regulation. Combining HPO (hypoxic post-conditioning) with DJ-1 overexpression markedly attenuated HR (hypoxia-reoxygenation) injury in H9c2 cells with high glucose (HG, 30 mM) exposure, accompanied by AMPK/mTOR signalling activation and autophagy up-regulation. The DJ-1 overexpression-mediated preservation of HPO-induced cardioprotection was completely inhibited by the AMPK inhibitor compound C (CC) and the autophagy inhibitor 3-MA (3-methyladenine). Thus, decreased cardiac DJ-1 expression, which results in impaired AMPK/mTOR signalling and decreased autophagy, could be a major mechanism underlying the loss of IPO-induced cardioprotection in diabetes.
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http://dx.doi.org/10.1042/CS20170052DOI Listing
June 2017

N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats.

Cardiovasc Diabetol 2016 10 12;15(1):146. Epub 2016 Oct 12.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Background: Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes.

Methods: Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R).

Results: NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA.

Conclusions: Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.
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http://dx.doi.org/10.1186/s12933-016-0460-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062884PMC
October 2016

Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: role of the PI3K/Akt and JAK2/STAT3 pathways.

Clin Sci (Lond) 2016 Mar 14;130(5):377-92. Epub 2015 Dec 14.

Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China Department of Anesthesiology, University of Hong Kong, Hong Kong, China.

Patients with diabetes are vulnerable to MI/R (myocardial ischaemia/reperfusion) injury, but are not responsive to IPostC (ischaemic post-conditioning) which activates PI3K (phosphoinositide 3-kinase)/Akt (also known as PKB or protein kinase B) and JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathways to confer cardioprotection. We hypothesized that increased cardiac PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K/Akt, is responsible for the loss of diabetic heart sensitivity to IPostC cardioprotecton. In STZ (streptozotocin)-induced Type 1 diabetic rats subjected to MI/R (30 min coronary occlusion and 120 min reperfusion), the post-ischaemic myocardial infarct size, CK-MB (creatine kinase-MB) and 15-F2t-isoprostane release, as well as cardiac PTEN expression were significantly higher than those in non-diabetic controls, concomitant with more severe cardiac dysfunction and lower cardiac Akt, STAT3 and GSK-3β (glycogen synthase kinase 3β) phosphorylation. IPostC significantly attenuated post-ischaemic infarct size, decreased PTEN expression and further increased Akt, STAT3 and GSK-3β phosphorylation in non-diabetic, but not in diabetic rats. Application of the PTEN inhibitor BpV (bisperoxovanadium) (1.0 mg/kg) restored IPostC cardioprotection in diabetic rats. HPostC (hypoxic post-conditioning) in combination with PTEN gene knockdown, but not HPostC alone, significantly reduced H/R (hypoxia/reoxygenation) injury in cardiac H9c2 cells exposed to high glucose as was evident from reduced apoptotic cell death and JC-1 monomer in cells, accompanied by increased phosphorylation of Akt, STAT3 and GSK-3β. PTEN inhibition/gene knockdown mediated restoration of IPostC/HPostC cardioprotection was completely reversed by the PI3K inhibitor wortmannin, and partially reversed by the JAK2 inhibitor AG490. Increased cardiac PTEN, by impairing PI3K/Akt and JAK2/STAT3 pathways, is a major mechanism that rendered diabetic hearts not responsive to post-conditioning cardioprotection.
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http://dx.doi.org/10.1042/CS20150496DOI Listing
March 2016

Remifentanil Preconditioning Reduces Postischemic Myocardial Infarction and Improves Left Ventricular Performance via Activation of the Janus Activated Kinase-2/Signal Transducers and Activators of Transcription-3 Signal Pathway and Subsequent Inhibition of Glycogen Synthase Kinase-3β in Rats.

Crit Care Med 2016 Mar;44(3):e131-45

1Department of Anesthesiology, the University of Hong Kong, Hong Kong SAR, China.2Department of Anesthesiology and Critical Care, the Second Affiliated Hospital of Soochow University, Suzhou, China.3Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.4State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.

Objectives: Remifentanil preconditioning attenuates myocardial ischemia reperfusion injury, but the underlying mechanism is incompletely understood. The Janus activated kinase-2 (JAK2)/signal transducers and activators of transcription-3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are critical in both ischemic and pharmacologic preconditioning cardioprotection, which involve the inactivation of glycogen synthase kinase-3β. We hypothesized that remifentanil preconditioning confers cardioprotection via the JAK2/STAT3 and/or PI3K/Akt activation-mediated glycogen synthase kinase-3β inhibition.

Design: Pharmacologic intervention.

Setting: Research laboratory.

Subjects: Male Sprague-Dawley rats.

Interventions: In vivo and in vitro treatments.

Measurements And Main Results: Male Sprague-Dawley rats (n = 6 per group) were sham operated or subjected to myocardial ischemia reperfusion injury. The JAK2 inhibitor AG490 (3 mg/kg), the PI3K inhibitor wortmannin (15 μg/kg), or the glycogen synthase kinase-3β inhibitor SB216763 (600 μg/kg) were given before inducing in vivo myocardial ischemia reperfusion injury achieved by occluding coronary artery for 30 minutes followed by 120 minutes of reperfusion in the absence or presence of remifentanil preconditioning (6 μg/kg/min). Also, isolated rat hearts were Langendorff perfused and subjected to 30 minutes of global ischemia and 120 minutes of reperfusion without or with remifentanil preconditioning (100 ng/mL) in the presence or absence of AG490 and/or SB216763. Isolated rat cardiomyocytes and H9C2 cells were subjected to hypoxia/reoxygenation alone or in combination with AG490 (100 μM), wortmannin (100 nM), or SB216763 (3 μM) without or with remifentanil preconditioning (2.5 μM). Remifentanil preconditioning reduced postischemic myocardial infarction and hemodynamic dysfunction induced by myocardial ischemia reperfusion injury concomitant with increased phosphorylation of STAT3 at tyr-705 (p-STAT3) and glycogen synthase kinase-3β but not Akt. AG490 but not wortmannin cancelled remifentanil preconditioning cardioprotection, and SB216763 restored it despite the presence of AG490. In Langendorff-perfused hearts, AG490-mediated cancellation of remifentanil preconditioning cardioprotection in attenuating postischemic myocardial infarction and creatinine kinase-MB release was reverted by concomitant administration of SB216763. Remifentanil preconditioning also attenuated posthypoxic cardiomyocyte injury and increased p-STAT3 and glycogen synthase kinase-3β in isolated primary cardiomyocytes and H9C2 cells. STAT3 gene knockdown with specific synthetic RNA cancelled remifentanil preconditioning cardioprotection, whereas glycogen synthase kinase-3β gene knockdown, which per se did not affect STAT3 under hypoxia/reoxygenation condition, preserved remifentanil preconditioning cardioprotection regardless of STAT3 abrogation.

Conclusions: Remifentanil preconditioning confers cardioprotection primarily via activation of JAK2/STAT3 signaling that can function independent of PI3K/Akt activation. Glycogen synthase kinase-3β is a critical downstream effector of remifentanil preconditioning cardioprotection.
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http://dx.doi.org/10.1097/CCM.0000000000001350DOI Listing
March 2016