Publications by authors named "Zhongqiu Lu"

78 Publications

Prediction of prokaryotic transposases from protein features with machine learning approaches.

Microb Genom 2021 Jul;7(7)

Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China.

Identification of prokaryotic transposases (Tnps) not only gives insight into the spread of antibiotic resistance and virulence but the process of DNA movement. This study aimed to develop a classifier for predicting Tnps in bacteria and archaea using machine learning (ML) approaches. We extracted a total of 2751 protein features from the training dataset including 14852 Tnps and 14852 controls, and selected 75 features as predictive signatures using the combined mutual information and least absolute shrinkage and selection operator algorithms. By aggregating these signatures, an ensemble classifier that integrated a collection of individual ML-based classifiers, was developed to identify Tnps. Further validation revealed that this classifier achieved good performance with an average AUC of 0.955, and met or exceeded other common methods. Based on this ensemble classifier, a stand-alone command-line tool designated TnpDiscovery was established to maximize the convenience for bioinformaticians and experimental researchers toward Tnp prediction. This study demonstrates the effectiveness of ML approaches in identifying Tnps, facilitating the discovery of novel Tnps in the future.
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http://dx.doi.org/10.1099/mgen.0.000611DOI Listing
July 2021

Depressive State in the Emergency Department During COVID-19: A National Cross-Sectional Survey in China.

Front Psychiatry 2021 14;12:566990. Epub 2021 Jun 14.

Department of Emergency Medicine, The First Affiliate Hospital of Xinjiang Medical University, Wulumuqi, China.

Chinese emergency department (ED) staff encountered significant mental stress while fighting the coronavirus disease 2019 (COVID-19) pandemic. We sought to investigate the prevalence and associated factors for depressive symptoms among ED staff (including physicians, nurses, allied health, and auxiliary ED staff). A cross-sectional national survey of ED staff who were on duty and participated in combating the COVID-19 pandemic was conducted March 1-15, 2020. A total of 6,588 emergency medical personnel from 1,060 hospitals responded to this survey. A majority of respondents scored above 10 points on the PHQ-9 standardized test, which is associated with depressive symptoms. Those aged 31-45, those working in the COVID-19 isolation unit, and those with relatives ≤ 16 or ≥70 years old at home all had statistically significant associations with scoring >10 points. Depressive symptoms among Chinese emergency medical staff were likely quite common during the response to the COVID-19 pandemic and reinforce the importance of targeted ED staff support during future outbreaks.
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http://dx.doi.org/10.3389/fpsyt.2021.566990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236535PMC
June 2021

Emodin alleviates LPS-induced myocardial injury through inhibition of NLRP3 inflammasome activation.

Phytother Res 2021 Jun 16. Epub 2021 Jun 16.

Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.

Myocardial injury and cardiovascular dysfunction are serious consequences of sepsis and contribute to high mortality. Currently, the pathogenesis of myocardial injury in sepsis is still unclear, and therapeutic approaches are limited. In this study, we investigated the protective effect of emodin on septic myocardial injury and the underlying mechanism. Lipopolysaccharide (LPS)-induced C57BL/6 mice and cardiomyocytes were used as models of sepsis in vivo and in vitro, respectively. The results showed that emodin alleviated cardiac dysfunction, myocardial injury and improved survival rate in LPS-induced septic mice. Emodin attenuated the levels of inflammatory cytokines and cardiac inflammation induced by LPS. Emodin reduced NOD-like receptor protein 3 (NLRP3) and Gasdermin D (GSDMD) expression in the heart tissue of LPS-induced septic mice. In vitro, emodin alleviated LPS-induced cell injury and inflammation in cardiomyocytes by inhibiting NLRP3 inflammasome activation. In addition, an NLRP3 inhibitor was used to further confirm the function of the NLRP3 inflammasome in LPS-induced myocardial injury. Taken together, our findings suggest that emodin improves LPS-induced myocardial injury and cardiac dysfunction by alleviating the inflammatory response and cardiomyocyte pyroptosis by inhibiting NLRP3 inflammasome activation, which provides a feasible strategy for preventing and treating myocardial injury in sepsis.
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http://dx.doi.org/10.1002/ptr.7191DOI Listing
June 2021

Family Resilience, Parenting Styles and Psychosocial Adjustment of Children With Chronic Illness: A Cross-Sectional Study.

Front Psychiatry 2021 12;12:646421. Epub 2021 May 12.

School of Nursing, Wenzhou Medical University, Wenzhou, China.

To evaluate the level of parent-reported family resilience, parenting styles and psychosocial adjustment of children with chronic illness and to identify the relationships between family resilience, parenting styles and psychosocial adjustment in families with children with chronic illness. A cross-sectional study was conducted between June 2019 and August 2019. A total of 236 parents of children with chronic illness and 98 parents with healthy children were recruited from general hospitals by convenience sampling. A parent completed the Chinese Family Resilience Assessment Scale, the Parenting Rearing Patterns Questionnaire and the Strengths and Difficulties Questionnaire. Family resilience, parenting styles, and psychosocial adjustment of children with chronic illness were compared with those of healthy children. Structural Equation Modeling (SEM) was performed to explore the mediation effect of parenting styles between family resilience and psychosocial adjustment among children with chronic illness. Parents of children with chronic illness reported lower level of family resilience and authoritative parenting, but more peer relationship problems compared to parents of healthy children. SEM showed that authoritative parenting fully mediated the relationship between family resilience and psychosocial adjustment of children with chronic illness. Childhood chronic illness reduces family resilience, authoritative parenting and children's psychosocial adjustment, but authoritative parenting mediated these effects, so authoritative parenting may be important for family resilience in families of children with chronic illness. Pediatric clinicians and nurses should provide family-centered interventions, as well as parenting training, to improve children's psychosocial outcomes.
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http://dx.doi.org/10.3389/fpsyt.2021.646421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149598PMC
May 2021

Thyroid hormone levels as a predictor marker predict the prognosis of patients with sepsis.

Am J Emerg Med 2021 Jul 12;45:42-47. Epub 2021 Feb 12.

Department of Emergency, the First Affiliated Hospital of WenZhou Medical University, Wenzhou 325000, China. Electronic address:

Background: Sepsis is a systemic inflammatory response syndrome with high mortality. There is an upward trend in sepsis prevalence and mortality worldwide. Early and accurate prediction of outcome in sepsis is important. There remains a great need to improve a reliable prognostic model for sepsis patients with widely available variables. The aim of this study was to explore the correlation between serum thyroid hormone levels and prognosis in sepsis patients.

Methods: Septic patients were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Factors that were found to contribute to the outcome in the uni-variate analysis at P value <0.1 were included in the multivariate. Multivariate analysis was performed by binary logistic regression analysis, which allows adjust for confounding factors. We combined an assessment of thyroid hormone and some variables together, which improve the accurate prediction of outcome. The accuracy of the test was assessed measuring the area under the ROC curve (AUROC).

Results: A total of 929 eligible septic patients were included in the data analysis. Seventy hundred and three patients had a good functional outcome, whereas 226 patients had a bad functional outcome. Thyroxin (T) level was significantly decreased in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome (P < 0.01). Binary logistic regression analyses revealed that lower thyroxin concentrations on admission were associated with a risk for poor outcomes (OR 0.556, 95% CI 0.41-0.75; P < 0.01). In addition, in ROC curve analysis, the combined model AUROC was 0.82 for ICU survival, which was significantly higher than the AUROCs of original fT (0.65 and 0.65), T (0.71 and 0.71) and SAPSII (0.70 and 0.72) (all P < 0.05).

Conclusions: Low serum thyroxin levels can be a predictive marker of short-term outcome after sepsis. A combined model (fT, T and SAPSII score) can add significant additional predictive information to the clinical score of the SAPSII.
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http://dx.doi.org/10.1016/j.ajem.2021.02.014DOI Listing
July 2021

Puerarin suppresses inflammation and ECM degradation through Nrf2/HO-1 axis in chondrocytes and alleviates pain symptom in osteoarthritic mice.

Food Funct 2021 Mar;12(5):2075-2089

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China. and Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, Zhejiang Province, China and The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China and Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, Zhejiang Province, China.

Osteoarthritis (OA) is the most common degenerative joint disorder with no effective drugs. Puerarin is a dietary supplement that has wide-ranging pharmacological effects. This study aimed to investigate the effects of Puerarin on OA. The effects of Puerarin on apoptosis, extracellular matrix (ECM) metabolism, and inflammation-related factors were assessed; also, the nuclear factor-κB (NF-κB) signaling pathway and Nrf2/HO-1 (nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1) axis were evaluated to elucidate the working mechanism of Puerarin. Mice were fed with Puerarin to evaluate the therapeutic effect of Puerarin on Osteoarthritis in vivo. The results showed that Puerarin suppressed inflammatory mediators and apoptosis induced by IL-1β treatment in chondrocytes, it may also suppress ECM degradation in IL-1β treated chondrocytes. The mechanism study revealed that Nrf2/HO-1 pathway is involved in Puerarin induced inhibition of NF-κB signaling pathway. Finally, in vivo study demonstrated that Puerarin could postpone the progression of OA in mice and relieve the symptoms of pain. In conclusion, Puerarin may potentially alleviate OA progression, and the mechanism may relate to the Nrf2/HO-1 pathway regulation.
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http://dx.doi.org/10.1039/d0fo03076gDOI Listing
March 2021

Symptom clusters of early-stage poststroke depression: A mixed-methods study.

Nurs Open 2021 Jan 20. Epub 2021 Jan 20.

School of Nursing, Wenzhou Medical University, Wenzhou, China.

Aim: To identify the symptom clusters of early-stage poststroke depression (PSD) and provide an in-depth understanding of the symptoms.

Design: A mixed-methods study with a convenient sampling method was used.

Methods: A cross-sectional questionnaire survey in 231 stroke patients and semi-structured interviews in 14 stroke patients were conducted in the neurological department of a comprehensive hospital in Southeast China. Data from the questionnaire survey were analysed through descriptive and exploratory factor analyses; data from the semi-structured interview were transcribed verbatim and analysed through inductive content analysis. This study adheres to the GRAMMS checklist.

Results: Exploratory factor analysis revealed six symptom clusters of early-stage PSD that accounted for an ideal variance in PSD: nervous, wakefulness, emotional, dull, guilt and low mood. Further, inductive content analysis revealed five themes that were like the above symptom clusters, except for the dull symptom cluster.
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http://dx.doi.org/10.1002/nop2.772DOI Listing
January 2021

MCTR3 reduces LPS-induced acute lung injury in mice via the ALX/PINK1 signaling pathway.

Int Immunopharmacol 2021 Jan 29;90:107142. Epub 2020 Nov 29.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Acute lung injury (ALI), a common respiratory distress syndrome in the intensive care unit (ICU), is mainly caused by severe infection and shock. Epithelial and capillary endothelial cell injury, interstitial edema and inflammatory cell infiltration are the main pathological changes observed in ALI animal models. Maresin conjugates in tissue regeneration (MCTR) are a new family of anti-inflammatory proteins. MCTR3 is a key enhancer of the host response, that promotes tissue regeneration and reduces infection; however, its role and mechanism in ALI are still unclear. The purpose of our research was to assess the protective effects of MCTR3 against ALI and its underlying mechanism. The work in this study was conducted in a murine model and the pulmonary epithelial cell line MLE-12. In vivo, MCTR3 (2 ng/g) was given 2 h after lipopolysaccharide (LPS) injection. We found that the treatment of mice with LPS-induced ALI with MCTR3 significantly reduced the cell number and protein levels in the bronchoalveolar lavage fluid (BALF); decreased the production of inflammatory cytokines; alleviated oxidative stress and cell apoptosis, consequently decreased lung injury; and restored pulmonary function. These protective effects of MCTR3 were dependent on down-regulation of the PTEN-induced putative kinase 1 (PINK1) pathway. Additionally, in MLE-12 cells stimulated with LPS, MCTR3 inhibited cell death, inflammatory cytokine levels and oxidative stress via the ALX/PINK1 signaling pathway. Thus, we conclude that MCTR3 protected against LPS-induced ALI partly through inactivation of the ALX/PINK1 mediated mitophagy pathway.
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http://dx.doi.org/10.1016/j.intimp.2020.107142DOI Listing
January 2021

Diastasis recti abdominis in adult women based on abdominal computed tomography imaging: Prevalence, risk factors and its impact on life.

J Clin Nurs 2021 Feb 14;30(3-4):518-527. Epub 2020 Dec 14.

School of Nursing, Wenzhou Medical University, Wenzhou, China.

Aims And Objectives: This study aimed to obtain the incidence of diastasis recti abdominis (DRA) and analyse possible risk factors in adult females. Moreover, the relationships between DRA and lower back pain, pelvic floor function and quality of life were also analysed.

Background: Diastasis recti abdominis is a separation of the abdominal muscles at the linea alba. Currently, studies on the prevalence rates, risk factors and consequences of DRA are varied. In particular, reports on DRA among adult women are lacking.

Design: A one-sample questionnaire study design is used following the STROBE checklist.

Methods: The inter-rectus distance was measured by computed tomography in 644 women. Custom questionnaires, the Oswestry Disability Index, The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were used to investigate personal information, the subjects' back pain, pelvic floor function and quality of life, respectively.

Results: The incidence of DRA was 28.4%. Age, the number of pregnancies, BMI and diabetes were influencing factors for DRA. After age stratification, pregnancy and diabetes were found to be risk factors for DRA in young women, and obesity and diabetes were risk factors for DRA in older women. This study showed that the association between DRA and low back pain was highly significant.

Conclusions: Diastasis recti abdominis is common in adult women. Avoiding multiple pregnancies, preventing diabetes and controlling weight may prevent DRA, which may be beneficial for decreasing low back pain in women.

Relevance To Clinical Practice: The findings have important implications for the health of adult women which can provide the basis for appropriate nursing implementation for DRA patients. The application of specific prevention and intervention measures for the risk factors may reduce the severity of low back pain.
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http://dx.doi.org/10.1111/jocn.15568DOI Listing
February 2021

Diagnostic potential of a gradient boosting-based model for detecting pediatric sepsis.

Genomics 2021 Jan 21;113(1 Pt 2):874-883. Epub 2020 Oct 21.

Institute of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address:

Pediatric sepsis is a major cause of mortality of children worldwide. However, there is still a lack of easy-to-use predictive tools that can accurately diagnose sepsis in children. This study aimed to develop an optimal gene model for the diagnosis of pediatric sepsis using statistics and machine learning approaches. Combining gene expression profiles from a training cohort of 364 pediatric samples with a Least Absolute Shrinkage and Selection Operator analysis produced eighteen genes as diagnostic markers. With the implementation of a Gradient Boosting algorithm, a model designated PEDSEPS-GBM, that aggregated these markers was developed with optimal performance for the diagnosis of pediatric samples in the validation and two independent cohorts. Moreover, a web calculator with a user-friendly interface was established for PEDSEPS-GBM. This study presents a diagnostic model that holds great potential for the detection of pediatric sepsis, and demonstrates the biologic and clinical relevance of this model.
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http://dx.doi.org/10.1016/j.ygeno.2020.10.018DOI Listing
January 2021

Plasma ZO-1 proteins predict the severity and outcome of sepsis: A prospective observational study.

Clin Chim Acta 2020 Nov 8;510:691-696. Epub 2020 Sep 8.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China. Electronic address:

Background: We determined whether plasma concentrations of ZO-1 proteins may be used a predictor of sepsis severity and 30-day mortality.

Methods: A total of 143 patients with sepsis and 30 healthy controls were enrolled. Plasma ZO-1 proteins concentrations were measured. Various methods, including area under the curves (AUCs), Kaplan-Meier curve, Cox regression, net reclassification improvement (NRI) and integrated discrimination improvement (IDI), were carried out to determine the value of ZO-1 in predicting 30-day mortality.

Results: Plasma ZO-1 concentrations in patients with sepsis and septic shock were significantly higher than those in healthy controls and were associated with the number of organ failures. ZO-1 concentrations also correlated with APACHE II or SOFA score and predicted 30-day mortality in sepsis patients with an AUC of 0.754. Multivariable regression analyses showed that a ZO-1 concentration ≥2.60 ng/ml remained a significant predictor of 30-day mortality in sepsis patients. Kaplan-Meier survival plots showed that patients with ZO-1 concentrations <2.60 ng/ml had a clear survival benefit. Adding ZO-1 to the SOFA score significantly improved its prognostic accuracy.

Conclusion: Plasma ZO-1 proteins appear to be a valuable prognostic biomarker for the severity of sepsis and a predictor of 30-day mortality for patients with sepsis.
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http://dx.doi.org/10.1016/j.cca.2020.09.003DOI Listing
November 2020

A Smartphone App (mDASHNa-CC) to Support Healthy Diet and Hypertension Control for Chinese Canadian Seniors: Protocol for Design, Usability and Feasibility Testing.

JMIR Res Protoc 2020 Apr 2;9(4):e15545. Epub 2020 Apr 2.

School of Nursing, Wenzhou Medical University, Wenzhou, China.

Background: This proposed study aims to translate the Dietary Approach to Stop Hypertension with Sodium (Na) Reduction for Chinese Canadians (DASHNa-CC), a classroom-based, antihypertensive, dietary educational intervention, to an innovative smartphone app (mDASHNa-CC). This study will enable Chinese Canadian seniors to access antihypertensive dietary interventions anytime, regardless of where they are. It is hypothesized that senior Chinese Canadians will be satisfied with their experiences using the mDASHNa-CC app and that the use of this app could lead to a decrease in their blood pressure and improvement in their health-related quality of life.

Objective: The goal of this study is to design and test the usability and feasibility of a smartphone-based dietary educational app to support a healthy diet and hypertension control for Chinese Canadian seniors.

Methods: A mixed-method two-phase design will be used. The study will be conducted in a Chinese immigrant community in Toronto, Ontario, Canada. Chinese Canadian seniors, who are at least 65 years old, self-identified as Chinese, living in Canada, and with elevated blood pressure, will be recruited. In Phase I, we will design and test the usability of the app using a user-centered approach. In Phase II, we will test the feasibility of the app, including implementation (primary outcomes of accrual and attrition rates, technical issues, acceptability of the app, and adherence to the intervention) and preliminary effectiveness (secondary outcomes of systolic and diastolic blood pressure, weight, waist circumference, health-related quality of life, and health service utilization), using a pilot, two-group, randomized controlled trial with a sample size of 60 participants in a Chinese Canadian community.

Results: The study is supported by the Startup Research Grant from Nipissing University, Canada. The research ethics application is under review by a university research ethics review board.

Conclusions: The study results will make several contributions to the existing literature, including illustrating the rigorous design and testing of smartphone app technology for hypertension self-management in the community, exploring an approach to incorporating traditional medicine into chronic illness management in minority communities and promoting equal access to current technology among minority immigrant senior groups.

Trial Registration: Clinicaltrials.gov NCT03988894; https://clinicaltrials.gov/ct2/show/NCT03988894.

International Registered Report Identifier (irrid): PRR1-10.2196/15545.
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http://dx.doi.org/10.2196/15545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316441PMC
April 2020

Prognostic Potential of Alternative Splicing Markers in Endometrial Cancer.

Mol Ther Nucleic Acids 2019 Dec 2;18:1039-1048. Epub 2019 Nov 2.

Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address:

Alternative splicing (AS), an important post-transcriptional regulatory mechanism that regulates the translation of mRNA isoforms and generates protein diversity, has been widely demonstrated to be associated with oncogenic processes. In this study, we systematically analyzed genome-wide AS patterns to explore the prognostic implications of AS in endometrial cancer (EC). A total of 2,324 AS events were identified as being associated with the overall survival of EC patients, and eleven of these events were further selected using a random forest algorithm. With the implementation of a generalized, boosted regression model, a prognostic AS model that aggregated these eleven markers was ultimately established with high performance for risk stratification in EC patients. Functional analysis of these eleven AS markers revealed various potential signaling pathways implicated in the progression of EC. Splicing network analysis demonstrated the notable correlation between the expression of splicing factors and AS markers in EC and further determined eight candidate splicing factors that could be therapeutic targets for EC. Taken together, the results of this study present the utility of AS profiling in identifying biomarkers for the prognosis of EC and provide comprehensive insight into the molecular mechanisms involved in EC processes.
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http://dx.doi.org/10.1016/j.omtn.2019.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889075PMC
December 2019

Gas6 attenuates lipopolysaccharide‑induced TNF‑α expression and apoptosis in H9C2 cells through NF‑κB and MAPK inhibition via the Axl/PI3K/Akt pathway.

Int J Mol Med 2019 Sep 12;44(3):982-994. Epub 2019 Jul 12.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Therapeutic agents used to treat sepsis‑induced cardiac dysfunction are designed to suppress tumor necrosis factor (TNF)‑α release and inhibit cell apoptosis. Exogenous administration of growth arrest‑specific 6 (Gas6) exerts several biological and pharmacological effects; however, the role of Gas6 in sepsis‑induced myocardial dysfunction remains unclear. In this study, H9C2 cardiomyocytes were stimulated with LPS (10 µg/ml) to mimic septic cardiac dysfunction and Gas6 (100 ng/ml) was applied exogenously. Subsequently, mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB activation, TNF‑α expression, and apoptosis in the presence or absence of TP‑0903 (15 nM) and Wortmannin (3 nM) were evaluated. The morphological alterations of H9C2 cells were visualized by phase‑contrast microscopy. Cell viability was determined using the Cell Counting kit 8 assay and lactate dehydrogenase release, and TNF‑α release was analyzed by ELISA analysis. Cell apoptosis was analyzed by flow cytometry and TUNEL assay. Nuclear morphological alterations were detected by Hoechst staining and caspase‑3 activity was measured using biochemical methods. The expression levels of Bax and Bcl‑2, and the phosphorylation and expression levels of Axl, Akt, IκB‑α, p65, c‑Jun N‑terminal protein kinase (JNK), extracellular signal‑regulated kinase (ERK) and p38 were determined by western blotting. Furthermore, immunofluorescence analysis was performed to visualize translocation of NF‑κB p65. The results demonstrated that Gas6 suppressed TNF‑α release and inhibited cell apoptosis, and attenuated nuclear factor (NF)‑κB and mitogen‑activated protein kinase (MAPK) activation via the Axl/PI3K/Akt pathway. Furthermore, the cardioprotective properties of Gas6 on the suppression of LPS‑induced TNF‑α release and apoptosis were abolished by treatment with TP‑0903 (an Axl inhibitor) and Wortmannin (a PI3K inhibitor). Pretreatment with TP‑0903 and Wortmannin abrogated the effects of Gas6 on phosphorylated‑IκB‑α, IκB‑α, NF‑κB, ERK1/2, JNK and p38 MAPK. These findings suggested that activation of Axl/PI3K/Akt signaling by Gas6 may inhibit LPS‑induced TNF‑α expression and apoptosis, as well as MAPK and NF‑κB activation.
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http://dx.doi.org/10.3892/ijmm.2019.4275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657963PMC
September 2019

Gas6 Attenuates Sepsis-Induced Tight Junction Injury and Vascular Endothelial Hyperpermeability the Axl/NF-κB Signaling Pathway.

Front Pharmacol 2019 13;10:662. Epub 2019 Jun 13.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Vascular endothelial functional dysregulation and barrier disruption are involved the initiation and development of sepsis. Growth arrest-specific protein 6 (Gas6), one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), is confirmed to have beneficial functions in hemostasis, inflammation, and cancer growth. Here, we demonstrated the protective effects of Gas6 on multi-organ dysfunction syndrome (MODS) in sepsis and the underlying mechanisms. We investigated Gas6-ameliorated MODS by inhibiting vascular endothelial hyperpermeability in a mouse model of sepsis. Additionally, , under lipopolysaccharide (LPS) stimulation in vascular endothelial cells, Gas6 attenuated vascular endothelial hyperpermeability by reinforcing the tight junction proteins occludin, zonula occludens-1 (ZO-1), and claudin5. Furthermore, Gas6 substantially suppressed NF-κB p65 activation. In addition, blocking the Gas6 receptor, Axl, partially reduced the protective effect of Gas6 on the vascular endothelial barrier and diminished the inhibitive effect of Gas6 on NF-κB p65 activation. Taken together, this study suggests that Gas6 has a protective effect on MODS in sepsis by inhibiting the vascular endothelial hyperpermeability and alteration of tight junction and that the Axl/NF-κB signaling pathway underlies these effects.
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http://dx.doi.org/10.3389/fphar.2019.00662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585310PMC
June 2019

Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis.

Free Radic Biol Med 2018 08 24;123:125-137. Epub 2018 May 24.

Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada N6A 4G5; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada N6A 4G5; Department of Medicine, Western University, London, Ontario, Canada N6A 4G5; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. Electronic address:

Aims: Sepsis-caused multiple organ failure remains the major cause of morbidity and mortality in intensive care units. Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD), which is important in regulating oxidative stress. This study investigated whether administration of NR prevented oxidative stress and organ injury in sepsis.

Methods: Mouse sepsis models were induced by injection of lipopolysaccharides (LPS) or feces-injection-in-peritoneum. NR was given before sepsis onset. Cultured macrophages and endothelial cells were incubated with various agents.

Results: Administration of NR elevated the NAD levels, and elicited a reduction of oxidative stress, inflammation and caspase-3 activity in lung and heart tissues, which correlated with attenuation of pulmonary microvascular permeability and myocardial dysfunction, leading to less mortality in sepsis models. These protective effects of NR were associated with decreased levels of plasma high mobility group box-1 (HMGB1) in septic mice. Consistently, pre-treatment of macrophages with NR increased NAD content and reduced HMGB1 release upon LPS stimulation. NR also prevented reactive oxygen species (ROS) production and apoptosis in endothelial cells induced by a conditioned-medium collected from LPS-treated macrophages. Furthermore, inhibition of SIRT1 by EX527 offset the negative effects of NR on HMGB1 release in macrophages, and ROS and apoptosis in endothelial cells.

Conclusions: Administration of NR prevents lung and heart injury, and improves the survival in sepsis, likely by inhibiting HMGB1 release and oxidative stress via the NAD/SIRT1 signaling. Given NR has been used as a health supplement, it may be a useful agent to prevent organ injury in sepsis.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236680PMC
August 2018

Curcumin attenuates sepsis-induced acute organ dysfunction by preventing inflammation and enhancing the suppressive function of Tregs.

Int Immunopharmacol 2018 Aug 17;61:1-7. Epub 2018 May 17.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Wenzhou Key Laboratory of Emergency, Critical care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; College of Nursing, Wenzhou Medical University, Wenzhou 325000, China. Electronic address:

Sepsis is characterized by the extensive release of cytokines and other mediators. It results in a dysregulated immune response and can lead to organ damage and death. Curcumin has anti-inflammatory properties and immunoregulation functions in various disorders such as sepsis, cancer, rheumatoid arthritis, cardiovascular diseases, lung fibrosis, gallstone formation, and diabetes. This paper investigates the effects of curcumin on immune status and inflammatory response in mice subjected to cecal ligation and puncture (CLP). Inflammatory tissue injury was evaluated by histological observation. Magnetic microbeads were used to isolate splenic CD4CD25regulatory T cells (Tregs), and phenotypes were then analyzed by flow cytometry. The levels of Foxp3 were detected by Western blot and real-time PCR and cytokine levels were determined by enzyme-linked immunosorbent assay. We found that the administration of curcumin significantly alleviated inflammatory injury of the lung and kidney in septic mice. The suppressive function of Treg cells was enhanced and the plasma levels of IL-10 increased after treatment with curcumin. Furthermore, the secretion of plasma TNF-α and IL-6 was notably inhibited in septic mice treated with curcumin and administration with curcumin could improve survival after CLP. These data suggest that curcumin could be used as a potential therapeutic agent for sepsis.
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http://dx.doi.org/10.1016/j.intimp.2018.04.041DOI Listing
August 2018

Diagnostic value of complete blood count in paraquat and organophosphorus poisoning patients.

Toxicol Ind Health 2018 Jul 18;34(7):439-447. Epub 2018 Apr 18.

1 Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Complete blood count (CBC) is one of the most extensively used tests in clinical practice. In order to determine the diagnostic value of the CBC in paraquat (PQ) and organophosphorus (OPPs) poisoning, the CBC indices of PQ- and OPPs-poisoned patients were investigated in this study. A total of 96 PQ poisoning patients, 90 OPPs poisoning patients, and 188 healthy subjects were included in this study. The PQ- and OPPs-poisoned patients were divided into different groups according to their clinical symptoms. All CBC indices were analyzed by Fisher discriminant, partial least-squares discriminant analysis (PLS-DA), variance analysis, and receiver operating characteristic (ROC). The discriminant results showed that 87.7% of original grouped cases correctly classified between PQ-poisoned patients, OPPs-poisoned patients, and healthy subjects. The PLS-DA results showed that the important variable order was different in PQ- and OPPs-poisoned patients. Both white blood cell (WBC) and neutrophil (NE) counts were the most important indexes in PQ- and OPPs-poisoned patients. In OPPs poisoning patients, WBC and NE showed statistical differences between the severe poisoning group and the moderate poisoning group. Their areas under the ROC curve (AUC) were 0.673 (WBC) and 0.669 (NE), which were higher than cholinesterase (CHE; AUC 0.326). In conclusion, the CBC indices had a diagnostic value in PQ and OPPs poisoning; WBC and NE were the first responses and had clinical significance in PQ and OPPs poisoning; moreover, they are better than CHE in diagnosing OPPs poisoning.
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http://dx.doi.org/10.1177/0748233718770896DOI Listing
July 2018

Klotho ameliorates sepsis-induced acute kidney injury but is irrelevant to autophagy.

Onco Targets Ther 2018 19;11:867-881. Epub 2018 Feb 19.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: The role of Klotho (KL) in sepsis-induced acute kidney injury (AKI) and the potential relationship between KL and autophagy in septic AKI were investigated.

Materials And Methods: A murine model of sepsis-induced AKI was established by cecal ligation and puncture (CLP). Mice undergoing CLP and immortalized proximal tubular epithelial human HK-2 cells that were exposed to lipopolysaccharide (LPS) were treated with recombinant KL, autophagy stimulator rapamycin (Rap), and autophagy suppressor 3-methyladenine (3-MA).

Results: Autophagy activation and KL reduction reached maximum levels in mice 24 hours after CLP. Recombinant KL and/or Rap significantly attenuated CLP-induced renal dysfunction (<0.05) and partially restored endogenous renal KL expression (<0.05). Recombinant KL had no impact on CLP-induced autophagy and apoptosis, whereas Rap significantly stimulated autophagy and reduced apoptosis in mice. 3-MA significantly exacerbated renal dysfunction, increased apoptosis, and inhibited autophagy in mice with CLP-induced AKI (all <0.05). In LPS-treated HK-2 cells, Rap significantly enhanced autophagy and reduced apoptosis (all <0.05), whereas recombinant KL had no impact, and 3-MA inhibited autophagy and significantly increased apoptosis (<0.05).

Conclusion: Recombinant KL alleviates renal dysfunction and restores renal KL expression in mice with sepsis-induced AKI, but the underlying mechanism may not be related to autophagy induction.
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http://dx.doi.org/10.2147/OTT.S156891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823070PMC
February 2018

NACHT, LRR and PYD domains-containing protein 3 inflammasome is activated and inhibited by berberine via toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB pathway, in phorbol 12-myristate 13-acetate-induced macrophages.

Mol Med Rep 2018 Feb 29;17(2):2673-2680. Epub 2017 Nov 29.

Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The present study investigated the expression of NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages, and aimed to identify the effects of berberine on the inflammasome. Human monocytic THP-1 cells were pretreated with berberine for 1 h and then induced with PMA for 48 h. Total RNA and protein were collected for reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Supernatants were collected to determine IL-1β levels by using ELISA. The present study demonstrated that NLRP3 inflammasome and IL-1β were activated in PMA-induced macrophages in a time-dependent manner, whereas berberine significantly inhibited their expression in a dose-dependent manner in PMA-induced macrophages. Furthermore, berberine also suppressed the toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (Myd88)/nuclear factor (NF)-κB signaling pathway which was activated during the conversion of THP-1 cells to macrophages by PMA. In conclusion, berberine reduced NLRP3 inflammasone expression by suppressing the activation of the TLR4/Myd88/NF-κB signaling pathway in PMA-induced macrophages. This inhibitory effect may imply an important role of berberine on chronic inflammation and atherogenic progression in coronary artery disease.
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http://dx.doi.org/10.3892/mmr.2017.8189DOI Listing
February 2018

Early Metabolome Profiling and Prognostic Value in Paraquat-Poisoned Patients: Based on Ultraperformance Liquid Chromatography Coupled To Quadrupole Time-of-Flight Mass Spectrometry.

Chem Res Toxicol 2017 12 13;30(12):2151-2158. Epub 2017 Nov 13.

Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou 325000, China.

Paraquat (PQ) has caused countless deaths throughout the world. There remains no effective treatment for PQ poisoning. Here we study the blood metabolome of PQ-poisoned patients using ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). Patients were divided into groups according to blood PQ concentration. Healthy subjects served as controls. Metabolic features were statistically analyzed using multivariate pattern-recognition techniques to identify the most important metabolites. Selected metabolites were further compared with a series of clinical indexes to assess the prognostic value. PQ-poisoned patients showed substantial differences compared with healthy subjects. Based on variable of importance in the project (VIP) values and statistical analysis, 17 metabolites were selected and identified. These metabolites well-classified low PQ-poisoned patients, high PQ-poisoned patients, and healthy subjects, which was better than that of a complete blood count (CBC). Among the 17 metabolites, 20:3/18:1-PC (PC), LPA (0:0/16:0) (LPA), 19-oxo-deoxycorticosterone (19-oxo-DOC), and eicosapentaenoic acid (EPA) had prognostic value. In particular, EPA was the most sensitive one. Besides, the levels of EPA was correlated with LPA and 19-oxo-DOC. If EPA was excessively consumed, then prognosis was poor. In conclusion, the serum metabolome is substantially perturbed by PQ poisoning. EPA is the most important biomarker in early PQ poisoning.
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http://dx.doi.org/10.1021/acs.chemrestox.7b00240DOI Listing
December 2017

A new machine-learning method to prognosticate paraquat poisoned patients by combining coagulation, liver, and kidney indices.

PLoS One 2017 19;12(10):e0186427. Epub 2017 Oct 19.

Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

The prognosis of paraquat (PQ) poisoning is highly correlated to plasma PQ concentration, which has been identified as the most important index in PQ poisoning. This study investigated the predictive value of coagulation, liver, and kidney indices in prognosticating PQ-poisoning patients, when aligned with plasma PQ concentrations. Coagulation, liver, and kidney indices were first analyzed by variance analysis, receiver operating characteristic curves, and Fisher discriminant analysis. Then, a new, intelligent, machine learning-based system was established to effectively provide prognostic analysis of PQ-poisoning patients based on a combination of the aforementioned indices. In the proposed system, an enhanced extreme learning machine wrapped with a grey wolf-optimization strategy was developed to predict the risk status from a pool of 103 patients (56 males and 47 females); of these, 52 subjects were deceased and 51 alive. The proposed method was rigorously evaluated against this real-life dataset, in terms of accuracy, Matthews correlation coefficients, sensitivity, and specificity. Additionally, the feature selection was investigated to identify correlating factors for risk status. The results demonstrated that there were significant differences in the coagulation, liver, and kidney indices between deceased and surviving subjects (p<0.05). Aspartate aminotransferase, prothrombin time, prothrombin activity, total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase, urea nitrogen, and creatinine were the most highly correlated indices in PQ poisoning and showed statistical significance (p<0.05) in predicting PQ-poisoning prognoses. According to the feature selection, the most important correlated indices were found to be associated with aspartate aminotransferase, the aspartate aminotransferase to alanine ratio, creatinine, prothrombin time, and prothrombin activity. The method proposed here showed excellent results that were better than that produced based on blood-PQ concentration alone. These promising results indicated that the combination of these indices can provide a new avenue for prognosticating the outcome of PQ poisoning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648192PMC
November 2017

Comparison of prognostic, clinical, and renal histopathological characteristics of overlapping idiopathic membranous nephropathy and IgA nephropathy versus idiopathic membranous nephropathy.

Sci Rep 2017 09 13;7(1):11468. Epub 2017 Sep 13.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.

Overlapping idiopathic membranous nephropathy (IMN) and immunoglobulin A nephropathy (IgAN) is rare. This study aims to investigate the unique prognostic, clinical, and renal histopathological characteristics of IMN+IgAN. This retrospective observational study included 73 consecutive cases of IMN+IgAN and 425 cases of IMN treated between September 2006 and November 2015. Prognostic and baseline clinical and histopathological data were compared between the two patient groups. Poor prognostic events included a permanent 50% reduction in eGFR, end-stage renal disease, and all-cause mortality. Renal histopathology demonstrated that the patients with IMN+IgAN presented with significantly increased mesangial cell proliferation and matrix expansion, increased inflammatory cell infiltration, and higher proportions of arteriole hyalinosis and lesions than the patients with IMN (all P < 0.05). Kaplan-Meier analysis showed that the patients with IMN+IgAN had significantly higher cumulative incidence rates of partial or complete remission (PR or CR, P = 0.0085). Multivariate Cox model analysis revealed that old age at biopsy and high baseline serum creatinine and uric acid levels were significantly associated with poor prognosis (all P < 0.05), and increased IgA expression correlated significantly with PR or CR (P < 0.05). The present study found that overlapping IMN and IgAN presents with unique renal histopathology and appears not to cause a poorer prognosis than IMN.
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http://dx.doi.org/10.1038/s41598-017-11838-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597578PMC
September 2017

Crosstalk between Mitochondrial Fission and Oxidative Stress in Paraquat-Induced Apoptosis in Mouse Alveolar Type II Cells.

Int J Biol Sci 2017 7;13(7):888-900. Epub 2017 Jul 7.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.

Paraquat (PQ), as a highly effective and nonselective herbicide, induces cell apoptosis through generation of superoxide anions which forms reactive oxygen species (ROS). Mitochondria, as regulators for cellular redox signaling, have been proved to play an important role in PQ-induced cell apoptosis. This study aimed to evaluate whether and how mitochondrial fission interacts with oxidative stress in PQ-induced apoptosis in mouse alveolar type II (AT-II) cells. Firstly, we demonstrated that PQ promoted apoptosis and release of cytochrome-c (Cyt-c). Furthermore, we showed that PQ broke down mitochondrial network, enhanced the expression of fission-related proteins, increased Drp1 mitochondrial translocation while decreased the expression of fusion-related proteins in AT-II cells. Besides, inhibiting mitochondrial fission using mdivi-1, a selective inhibitor of Drp1, markedly attenuated PQ-induced apoptosis, release of Cyt-c and the generation of ROS. These results indicate that mitochondrial fission involves in PQ-induced apoptosis. Further study demonstrated that antioxidant ascorbic acid inhibited Drp1 mitochondrial translocation, mitochondrial fission and attenuated PQ-induced apoptosis. Overall, our findings suggest that mitochondrial fission interplays with ROS in PQ-induced apoptosis in mouse AT-II cells and mitochondrial fission could serve as a potential therapeutic target in PQ poisoning.
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http://dx.doi.org/10.7150/ijbs.18468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555106PMC
May 2018

Effects of hemoperfusion and continuous renal replacement therapy on patient survival following paraquat poisoning.

PLoS One 2017 13;12(7):e0181207. Epub 2017 Jul 13.

Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Mortality in patients with paraquat (PQ) poisoning is related to plasma PQ levels. Concentrations lower than 5,000 ng/mL are considered critical but curable. This study assessed the effects of hemoperfusion (HP) and continuous renal replacement therapy (CRRT) on the survival of PQ-poisoned patients with plasma PQ levels below 5,000ng/mL. We analyzed the records of 164 patients with PQ poisoning who were treated at the First Affiliated Hospital of Wenzhou Medical University in China between January 2011 and May 2015. We divided these patients into six sub-groups based on baseline plasma PQ levels and treatment, compared their clinical characteristics, and analyzed their survival rates. Patient sub-groups did not differ in terms of age, sex, time between poisoning and hospital admission, or time to first gavage. Biochemical indicators improved over time in all sub-groups following treatment, and the combined HP and CRRT treatment yielded better results than HP or CRRT alone. Fatality rates in the three treatment sub-groups did not differ among patients with baseline plasma PQ levels of 50-1,000 ng/mL, but in patients with 1,000-5,000 ng/mL levels, the mortality rate was 59.2% (HP treatment group), 48% (CRRT treatment group), and 37.9% (combined treatment group). Mortality rates were higher 10-30 days after hospitalization than in the first 10 days after admission. In the early stages of PQ poisoning, CRRT is effective in reducing patient fatality rates, particularly when combined with HP. Our data could be useful in increasing survival in acute PQ poisoning patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181207PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509301PMC
September 2017

A multifactor model for predicting mortality in critically ill patients: A multicenter prospective cohort study.

J Crit Care 2017 12 16;42:18-24. Epub 2017 Jun 16.

Department of Anesthesiology and Intensive Care Unit, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China. Electronic address:

Purpose: The objective of this study was to develop a model using a combination of routine clinical variables to predict mortality in critically ill patients.

Methods: A cohort of 500 patients recruited from eight university hospital intensive care units (ICUs) was used to develop a model via logistic regression analyses. Discrimination and calibration analyses were performed to assess the model.

Results: The model included the lactate level (odds ratio [OR]=1.11, 95% confidence interval [CI] 1.01 to 1.22, P=0.029), neutrophil-to-lymphocyte ratio (OR=1.03, 95% CI 1.01 to 1.04, P=0.002), acute physiology score (OR=1.11, 95% CI 1.06 to 1.15, P<0.001), Charlson comorbidity index (OR=1.36, 95% CI 1.15 to 1.60, P<0.001) and surgery type (OR: selective=Ref, no surgery=8.04, 95% CI 3.74 to 17.30, P<0.001, emergency=3.66, 95% CI 1.60 to 8.36, P=0.002). The model showed good discrimination (area under receiver operating characteristic curve: 0.84, 95% CI: 0.80 to 0.87) and calibration (Hosmer-Lemeshow test P=0.137) for predicting in-hospital mortality.

Conclusion: The developed multifactor model can be used to effectively predict mortality in critically ill patients at ICU admission.
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http://dx.doi.org/10.1016/j.jcrc.2017.06.015DOI Listing
December 2017

Pharmacist-driven antimicrobial stewardship in intensive care units in East China: A multicenter prospective cohort study.

Am J Infect Control 2017 Sep 5;45(9):983-989. Epub 2017 Jun 5.

Department of Anesthesiology and Intensive Care Unit, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address:

Background: Antimicrobial stewardship programs, particularly pharmacist-driven programs, help reduce the unnecessary use of antimicrobial agents. The objective of this study was to assess the influence of pharmacist-driven antimicrobial stewardship on antimicrobial use, multidrug resistance, and patient outcomes in adult intensive care units in China.

Method: We conducted a multicenter prospective cohort study with a sample of 577 patients. A total of 353 patients were included under a pharmacist-driven antimicrobial stewardship program, whereas the remaining 224 patients served as controls. The primary outcome was all-cause hospital mortality.

Results: The pharmacist-driven antimicrobial stewardship program had a lower hospital mortality rate compared with the nonpharmacist program (19.3% vs 29.0%; P = .007). Furthermore, logistic regression analysis indicated that the pharmacist-driven program independently predicted hospital mortality (odds ratio, 0.57; 95% confidence interval, 0.36-0.91; P = .017) after adjustment. Meanwhile, this strategy had a lower rate of multidrug resistance (23.8% vs 31.7%; P = .037). Moreover, the strategy optimized antimicrobial use, such as having a shorter duration of empirical antimicrobial therapy (2.7 days; interquartile range [IQR], 1.7-4.6 vs 3.0; IQR, 1.9-6.2; P = .002) and accumulated duration of antimicrobial treatment (4.0; IQR, 2.0-7.0 vs 5.0; IQR, 3.0-9.5; P = .030).

Conclusions: Pharmacist-driven antimicrobial stewardship in an intensive care unit decreased patient mortality and the emergence of multidrug resistance, and optimized antimicrobial agent use.
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http://dx.doi.org/10.1016/j.ajic.2017.02.021DOI Listing
September 2017

Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.

Biochem Pharmacol 2017 Mar 30;128:12-25. Epub 2016 Dec 30.

Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China. Electronic address:

AML1-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AML1-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration- and time-dependent manner in leukemic cell lines and primary AML blasts with t(8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AML1-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AML1-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein.
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http://dx.doi.org/10.1016/j.bcp.2016.12.022DOI Listing
March 2017

Identification of a Novel lincRNA-p21-miR-181b-PTEN Signaling Cascade in Liver Fibrosis.

Mediators Inflamm 2016 16;2016:9856538. Epub 2016 Aug 16.

Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Previously, we found that long intergenic noncoding RNA-p21 (lincRNA-p21) inhibits hepatic stellate cell (HSC) activation and liver fibrosis via p21. However, the underlying mechanism of the antifibrotic role of lincRNA-p21 in liver fibrosis remains largely unknown. Here, we found that lincRNA-p21 expression was significantly downregulated during liver fibrosis. In LX-2 cells, the reduction of lincRNA-p21 induced by TGF-β1 was in a dose- and time-dependent manner. lincRNA-p21 expression was reduced in liver tissues from patients with liver cirrhosis when compared with that of healthy controls. Notably, lincRNA-p21 overexpression contributed to the suppression of HSC activation. lincRNA-p21 suppressed HSC proliferation and induced a significant reduction in α-SMA and type I collagen. All these effects induced by lincRNA-p21 were blocked down by the loss of PTEN, suggesting that lincRNA-p21 suppressed HSC activation via PTEN. Further study demonstrated that microRNA-181b (miR-181b) was involved in the effects of lincRNA-p21 on HSC activation. The effects of lincRNA-p21 on PTEN expression and HSC activation were inhibited by miR-181b mimics. We demonstrated that lincRNA-p21 enhanced PTEN expression by competitively binding miR-181b. In conclusion, our results disclose a novel lincRNA-p21-miR-181b-PTEN signaling cascade in liver fibrosis and suggest lincRNA-p21 as a promising molecular target for antifibrosis therapy.
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http://dx.doi.org/10.1155/2016/9856538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004029PMC
May 2017

An Effective Machine Learning Approach for Prognosis of Paraquat Poisoning Patients Using Blood Routine Indexes.

Basic Clin Pharmacol Toxicol 2017 Jan 29;120(1):86-96. Epub 2016 Aug 29.

Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

The early identification of toxic paraquat (PQ) poisoning in patients is critical to ensure timely and accurate prognosis. Although plasma PQ concentration has been reported as a clinical indicator of PQ poisoning, it is not commonly applied in practice due to the inconvenient necessary instruments and operation. In this study, we explored the use of blood routine indexes to identify the degree of PQ toxicity and/or diagnose PQ poisoning in patients via machine learning approach. Specifically, we developed a method based on support vector machine combined with the feature selection technique to accurately predict PQ poisoning risk status, then tested the method on 79 (42 male and 37 female; 41 living and 38 deceased) patients. The detection method was rigorously evaluated against a real-world data set to determine its accuracy, sensitivity and specificity. Feature selection was also applied to identify the factors correlated with risk status, and the results showed that there are significant differences in blood routine indexes between dead and living PQ-poisoned individuals (p-value < 0.01). Feature selection also showed that the most important correlated indexes are white blood cell and neutrophils. In conclusion, the toxicity or prognosis of PQ poisoning can be preliminarily ascertained by blood routine testing without PQ concentration data, representing an additional tool and innovative approach to assess the prognosis of PQ poisoning.
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http://dx.doi.org/10.1111/bcpt.12638DOI Listing
January 2017
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