Publications by authors named "Guangliang Hong"

42 Publications

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

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

The Neuroprotective Effect of Short Chain Fatty Acids Against Sepsis-Associated Encephalopathy in Mice.

Front Immunol 2021 28;12:626894. Epub 2021 Jan 28.

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

Short chain fatty acids (SCFAs) are known to be actively involved in multiple brain disorders, but their roles in sepsis-associated encephalopathy (SAE) remain unclear. Here, we investigated the neuroprotective effects of SCFAs on SAE in mice. Male C57BL/6 mice were intragastrically pretreated with SCFAs for seven successive days, and then subjected to SAE induced by cecal ligation and puncture. The behavioral impairment, neuronal degeneration, and levels of inflammatory cytokines were assessed. The expressions of tight junction (TJ) proteins, including occludin and zoula occludens-1 (ZO-1), cyclooxygenase-2 (COX-2), cluster of differentiation 11b (CD11b), and phosphorylation of JNK and NF-κB p65 in the brain, were measured by western blot and Immunofluorescence analysis. Our results showed that SCFAs significantly attenuated behavioral impairment and neuronal degeneration, and decreased the levels of IL-1β and IL-6 in the brain of SAE mice. Additionally, SCFAs upregulated the expressions of occludin and ZO-1 and downregulated the expressions of COX-2, CD11b, and phosphorylation of JNK and NF-κB p65 in the brain of SAE mice. These findings suggested that SCFAs could exert neuroprotective effects against SAE in mice.
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http://dx.doi.org/10.3389/fimmu.2021.626894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876449PMC
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

The effects of an enteral nutrition feeding protocol on critically ill patients: A prospective multi-center, before-after study.

J Crit Care 2020 04 17;56:249-256. Epub 2020 Jan 17.

Department of Emergency Medicine, Wenzhou Central Hospital, Wenzhou, China.

Purpose: The aim of this study was to explore the effects of an enteral nutrition (EN) feeding protocol in critically ill patients.

Methods: This was a prospective multi-center before-after study. We compared energy related and prognostic indicators between the control group (pre-implementation stage) and intervention group (post-implementation stage). The primary endpoint was the percentage of patients receiving EN within 7 days after ICU admission.

Results: 209 patients in the control group and 230 patients in the intervention group were enrolled. The implementation of the EN protocol increased the percentage of target energy reached from day 3 to day 7, and the difference between two groups reached statistical significance in day 6 (P = .01) and day 7 (P = .002). But it had no effects on proportion of patient receiving EN (P = .65) and start time of EN (P = .90). The protocol application might be associated with better hospital survival (89.1% vs 82.8%, P = .055) and reduce the incidence of EN related adverse (P = .004). There was no difference in ICU length of stay, duration of mechanical ventilation and ICU cost.

Conclusion: The implementation of the enteral feeding protocol is associated with improved energy intake and a decreased incidence of enteral nutrition related adverse events for critically ill patients, but it had no statistically beneficial effects on reducing the hospital mortality rate. Trial registration ClinicalTrials.gov, NCT02976155. Registered November 29, 2016- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02976155.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.018DOI Listing
April 2020

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

Type A aortic dissection in pregnant patients with fibrillin-1 gene mutations: Two case reports and a literature review.

Exp Ther Med 2018 Dec 19;16(6):4407-4414. Epub 2018 Sep 19.

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

In acute aortic dissection (AD) in pregnancy, increased cardiovascular stress due to pregnancy is an important factor leading to an emergent aortic event. It is rare but often results in a devastating event for both the pregnant patient and the foetus. Two cases of acute AD (Stanford type A) in pregnant females are presented in the present study. The patients were diagnosed via echocardiography, and the diagnosis was confirmed with computed tomography angiography prior to aortic surgery. Up to 50% of ADs in pregnancy occur in patients with fibrillin-1 (FBN1) gene mutations. The FBN1 gene was sequenced in both patients, and notable, novel pathogenic mutations of FBN1 were identified in both patients. A literature review was also performed on available diagnostic imaging and other measurements regarding AD during pregnancy. The authors suggest that the relevant content may have important clinical implications in raising disease awareness, arranging test rationally and choosing an intervention method.
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http://dx.doi.org/10.3892/etm.2018.6761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257332PMC
December 2018

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

Integrated Analyses Reveal Overexpressed Notch1 Promoting Porcine Satellite Cells' Proliferation through Regulating the Cell Cycle.

Int J Mol Sci 2018 Jan 16;19(1). Epub 2018 Jan 16.

National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China.

Notch signaling as a conserved cell fate regulator is involved in the regulation of cell quiescence, proliferation, differentiation and postnatal tissue regeneration. However, how Notch signaling regulates porcine satellite cells (PSCs) has not been elucidated. We stably transfected Notch1 intracellular domain (N1ICD) into PSCs to analyze the gene expression profile and miRNA-seq. The analysis of the gene expression profile identified 295 differentially-expressed genes (DEGs) in proliferating-N1ICD PSCs (P-N1ICD) and nine DEGs on differentiating-N1ICD PSCs (D-N1ICD), compared with that in control groups (P-Control and D-Control, respectively). Analyzing the underlying function of DEGs showed that most of the upregulated DEGs enriched in P-N1ICD PSCs are related to the cell cycle. Forty-four and 12 known differentially-expressed miRNAs (DEMs) were identified in the P-N1ICD PSCs and D-N1ICD PSCs group, respectively. Furthermore, we constructed the gene-miRNA network of the DEGs and DEMs. In P-N1ICD PSCs, miR-125a, miR-125b, miR-10a-5p, ssc-miR-214, miR-423 and miR-149 are downregulated hub miRNAs, whose corresponding hub genes are marker of proliferation Ki-67 (MKI67) and nuclear receptor binding SET domain protein 2 (WHSC1). By contrast, miR-27a, miR-146a-5p and miR-221-3p are upregulated hub miRNAs, whose hub genes are RUNX1 translocation partner 1 (RUNX1T1) and fibroblast growth factor 2 (FGF2). All the hub miRNAs and genes are associated with cell proliferation. Quantitative RT-PCR results are consistent with the gene expression profile and miRNA-seq results. The results of our study provide valuable information for understanding the molecular mechanisms underlying Notch signaling in PSCs and skeletal muscle development.
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http://dx.doi.org/10.3390/ijms19010271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796217PMC
January 2018

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

Biochem Biophys Res Commun 2018 02 24;496(2):245-252. Epub 2017 Nov 24.

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

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries.
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http://dx.doi.org/10.1016/j.bbrc.2017.11.159DOI 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

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

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

Prognosis and survival analysis of paraquat poisoned patients based on improved HPLC-UV method.

J Pharmacol Toxicol Methods 2016 Jul-Aug;80:75-81. Epub 2016 May 20.

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

Unlabelled: Paraquat (PQ) has caused deaths of numerous people around the world. In order to assess the lethal plasma concentration, the patients who acquired acute PQ intoxication were analyzed by plasma concentration monitoring. The plasma PQ concentrations were determined by high performance liquid chromatography (HPLC) which used 5-bromopyrimidine as internal standard and trichloroacetic acid-methanol (1:9) as protein precipitant. The liver, kidney and coagulation function were determined by automatic biochemical analyzer. According to plasma PQ concentration, 90 patients were divided into four groups: trace PQ group (<50ng/mL), low PQ group (<1000ng/mL), medium PQ group (1000-5000ng/mL) and high PQ group (>5000ng/mL). The clinical data from the four groups was statistically analyzed. The results showed the developed HPLC methods exhibited a high degree of accuracy and good linearity within 50-25000ng/mL (R=0.9998). The Spearman's correlation analysis showed PQ concentration had a strong relationship to total bilirubin, direct bilirubin, aspartic transaminase, urea nitrogen, prothrombin time, prothrombin activity, and international normalized ratio (P<0.01). The cured or survival PQ poisoned patients among the trace PQ group, the low PQ group, the medium PQ group, and the high PQ group were 19/19 (100%), 19/21 (90.47%), 11/25 (44.0%), and 0/25 (0%) respectively. The mean hospital days were (10.37±8.04), (18.76±12.06), (16.76±14.44), and (4.04±5.41) days respectively. The Cox regression analysis indicated that plasma PQ concentration was highly related to prognosis (P<0.05). In conclusion, no patient presenting with a PQ concentration over 5000ng/mL survived. The plasma PQ level is related to liver, kidney and coagulation function, which can be used as an important clinical index to judge the prognosis of PQ poisoned patients.

Chemical Compounds: Paraquat (PubChem CID: 15938), 5-bromopyrimidine (PubChem CID: 78344), acetonitrile (PubChem CID: 6342), sodium dihydrogen phosphate (PubChem CID: 23672064), sodium heptanesulfonate (PubChem CID: 23672332), methylprednisolone (PubChem CID: 6741), cyclophosphamide (PubChem CID: 2907).
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http://dx.doi.org/10.1016/j.vascn.2016.05.010DOI Listing
May 2017

[The protective effect of bone marrow mesenchymal stem cells carrying antioxidant gene superoxide dismutase on paraquat lung injury in mice].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2016 Jan;34(1):1-7

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

Objective: To explore the possible mechanism and protective effect of BMSCs (bone mesenchymal stem cells) carrying superoxide dismutase (SOD) gene on mice with paraquat-induced acute lung injury.

Methods: To establish the cell line of BMSCs bringing SOD gene, lentiviral vector bringing SOD gene was built and co-cultured with BMSCs. A total of 100 BALB/c mice were randomly divided into five groups, namely Control group, poisoning group (PQ group) , BMSCs therapy group (BMSC group) , BMSCs-Cherry therapy group (BMSC-Cherry group) , BMSCs-SOD therapy group (BMSC-SOD group) . PQ poisoning model was produced by stomach lavaged once with 1 ml of 25 mg/kg PQ solution, and the equal volume of normal saline (NS) was given to Control group mice instead of PQ. The corresponding BMSCs therapy cell lines were delivered to mice through the tail vein of mice 4h after PQ treatment.Five mice of each group were sacrificed 3 d, 7 d, 14 d and 21 days after corresponding BMSCs therapy cell lines administration, and lung tissues of mice were taken to make sections for histological analysis. The serum levels of glutathione (GSH) , malondialdehyde (MDA) , SOD, and the levels of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) in lung tissue were determined. The level of SOD was assayed by Westen-blot.

Results: Compared with Control group, the early (3 days) levels of SOD protein in lung tissue of PQ group obviously decreased, and the late (21 days) levels of SOD obviously increased, while in therapy groups, that was higher than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Compared with Control group, the levels of plasma GSH and SOD of PQ group and each therapy group wae significantly lower than those in Control group, while in therapy groups, those were higher than those of PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) .Compared with Control group, the level of plasma MDA, TNF-α and TGF-β in PQ group and therapy groups were significantly higher, while in therapy groups, that was lower than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Lung biopsy showed that, the degree of lung tissue damage in each therapy group obviously reduced.

Conclusion: SOD is the key factor of the removal of reactive oxygen species (ROS) in cells, that can obviously inhibit the oxidative stress damage and the apoptosis induced by PQ, thus significantly increasing alveolar epithelial cell ability to fight outside harmful environment.
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http://dx.doi.org/10.3760/cma.j.issn.1001-9391.2016.01.001DOI Listing
January 2016

Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.

Neurosci Lett 2016 Apr 5;618:159-166. Epub 2016 Mar 5.

School of Environmental Science and Public Health, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China. Electronic address:

Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS-induced mice, increased 5-HT concentration, increased BDNF expression, and up-regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments.
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http://dx.doi.org/10.1016/j.neulet.2016.03.003DOI Listing
April 2016

[Hemoperfusion alleviated paraquat-induced kidney inflammation injury of rabbit].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2015 Sep;33(9):658-62

Emergency Department of the first Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; E-mail:

Objective: To investigate the effect of hemoperfusion on paraquat-Induced kidney inflammation injury of rabbit and the mechanism of it.

Methods: 60 male rabbits were randomly divided into 4 groups, the normal control group (n=6, the rabbits were given NS by gavage) , blank control group (n=18, he rabbits were given 2 hours hemoperfusion once within 1 hour after given NS by gavage), paraquat poisoning group (n=18, the rabbits were given 50 mg/kg 20% paraquat solution by gavage) , hemoperfusion treatment group (n=18, the rabbits were given 2 hours hemoperfusion once within 1 hour after 20% paraquat solution espoused). The last 3 groups were divided into 3 observation time groups (1, 3, 7 day), contained 6 rabbits each group. On days 1, 3, 7 all groups rabbits were anesthetized and sacrificed, and their kidney tissues collected. The levels of NF-κB mRNA by RT-PCR, and the expression of NF-κB protein was measured by Western blotting,The expression levels of TNF-α, IL-6, iNOS measured by chemical colorimetric method to to observe inflammatory injury.

Results: Compared with the normal control group rabbits, there were no changes in the TNF-α, IL-6, iNOS, NF-κB mRNA and protein of blank control group (P>0.05), while the expression of TNF-α, IL-6, NF-κB mRNA and protein in the kidney tissue of PQ group and were significantly increased (P<0.05). The pathological results of kidney tissues were no abnormalities onnormal control group and blank control group.

Conclusion: HP significantly increase resistance to PQ-induced inflammation injury in the rabbit kidney and exert a protective effect on PQ-induced kidney injury.
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September 2015

[Effect of PON1 overexpression on mouse diaphragmatic muscle cells injury caused by acute dichlorvos poisoning].

Zhonghua Yi Xue Za Zhi 2015 Sep;95(36):2955-9

Wenzhou Medical University, Wenzhou 325000, China; Email:

Objective: To investigate the effect of paraoxonase1 (PON1) overexpression on mouse diaphragmatic muscle cells injury caused by acute dichlorvos poisoning.

Methods: Mouse diaphragmatic muscle cells were cultured routinely and infected with overexpression lentivirus. Cells were divided into normal control group, DDVP group, LV-GFP + DDVP group, LV-PON1 + DDVP group. Cell viability was determined by CCK-8 assay. Flow cytometry was used to detect cell apoptosis. The mRNA and protein expression of PON1 and Nrf2 in mouse diaphragmatic muscle cells was measured by RT-PCR and Western blot. Enzyme-linked immunosorbent assay was used to determine levels of acetyl cholinesterase (AchE), heme oxygenase 1 (HO-1) and quinone oxidoreductase-1 (NQO-1) in mouse diaphragmatic muscle cells. The activity of superoxide dismutase (SOD) and catalase (CAT) as well as malondialdehyde (MDA) content in cells was measured by chemical colorimetry.

Results: After induced by 0, 80, 160, 320, 640 µmol/L DDVP for 24 hours, the viability of mouse diaphragmatic muscle cells was (100 ± 3.82)%, (82.13 ± 2.60)%, (53.57 ± 5.05)%, (30.77 ± 3.30)%, (14.20 ± 2.19)% respectively, changing in a concentration-dependent manner (P < 0.05). After induced by 160 µmol/L DDVP for 0, 6, 12, 24 hours, the viability of mouse diaphragmatic muscle cells was (100.17 ± 2.74)%, (76.13 ± 6.01)%, (66.53 ± 3.55)%, (53.57 ± 5.05)%, changing in a time-dependent manner (P < 0.05). The PON1 protein level in LV-PON1 group was higher than that of blank control group (0.370 ± 0.015 vs 0.232 ± 0.004, 0.197 ± 0.015 vs 0.037 ± 0.003, P < 0.05). The cell viability of LV-PON1 group is higher than that of DDVP group at different time point after induction of DDVP (P < 0.05). After induced by DDVP for 24 hours, the cell apoptosis rate and MDA content in LV-PON1 group were lower than those of DDVP group (P < 0.05). While levels of AchE, PON1 and Nrf2 protein expression, SOD and CAT, HO-1 and NQO-1 were higher than those of DDVP group (P < 0.05).

Conclusions: The overexpression of PON1 could effectively alleviate AchE inhibition by DDVP and induce Nrf2 expression to exert antioxidant effect, thus protected the mouse diaphragmatic muscle cells.
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September 2015

[The effect of resveratrol on paraquat-induced acute lung injury in mice and its mechanism].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2016 Jan;28(1):33-7

Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China. Corresponding author: Lu Zhongqiu, Email:

Objective: To investigate the effect of resveratrol (Res) on paraquat (PQ)-induced acute lung injury (ALI) and mortality in mice and the mechanism of nuclear factor-ΚB (NF-ΚB) inflammatory pathway.

Methods: Sixty-eight healthy male ICR mice with grade SPF were enrolled, among them 20 mice were used for mortality observation (n = 10), and other 48 were used for determination of related parameters (n = 6). The mice were randomly divided into four groups: normal saline (NS) control group, Res control group, PQ group and PQ + Res group. The mice in the latter two groups were subdivided into 6, 24, 72 hours subgroups. The PQ poisoning model of mice was reproduced by one injection of 30 mg/kg PQ intraperitoneally. The mice in PQ + Res group were given 60 mg/kg Res intraperitoneally on the contralateral side after PQ injection. The mice were sacrificed at 6, 24, 72 hours after PQ poisoning, and lung tissue was harvested. The serum levels of tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-1β) were determined by enzyme linked immunosorbent assay (ELISA). The pathological changes in lung tissue were observed with electron microscopy. Apoptosis cells in the lung were identified by terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) for the estimation of apoptosis rate. The protein expression of NF-ΚB p65 was determined by Western Blot.

Results: Compared with PQ group, the death number of mice at 48, 72, 96 hours in PQ + Res group was slightly decreased (0 vs. 2, 2 vs. 5, 4 vs. 6) but without statistically significant difference (all P > 0.05). Under electron microscope, the lung injury in PQ group was severer than that in NS control group, and Res was found to be able to alleviate the lung injury. Compared with NS control group [(2.45±0.61)%], the apoptosis rate at 6 hours in PQ group was significantly increased [(8.42±1.48)%], and peaked at 72 hours [(21.23±3.47)%]. Res could decrease the apoptosis rate after PQ poisoning [6 hours: (5.56±1.31)% vs. (8.42±1.48)%, 24 hours: (11.14±2.07)% vs. (16.88±2.96)%, 72 hours: (13.28±2.32)% vs. (21.23±3.47)%, all P < 0.05]. The serum levels of TNF-α, IL-6, and IL-1β, and NF-ΚB p65 in lung tissue were all markedly increased after PQ poisoning, and they were significantly decreased after Res intervention as compared with those of PQ group [TNF-α (ng/L): 2.62±0.29 vs. 4.06±0.74 at 6 hours, 3.98±0.41 vs. 6.79±0.80 at 24 hours, 5.06±0.75 vs. 11.00±0.75 at 72 hours; IL-6 (ng/L): 14.19±1.54 vs. 16.55±1.24 at 6 hours, 13.21±1.37 vs. 19.73±0.85 at 24 hours, 13.72±0.56 vs. 22.45±0.72 at 72 hours; IL-1β (ng/L): 8.54±1.64 vs. 12.59±0.66 at 6 hours, 10.15±0.29 vs. 16.24±1.03 at 24 hours, 16.14±0.70 vs. 19.55±0.56 at 72 hours; 6-hour NF-ΚB p65: (1.34±0.07) folds vs. (1.86±0.11) folds when the expression in NS control group was represented as 1, all P < 0.05].

Conclusions: Res cannot lower the mortality in mice with PQ poisoning, but it seems to be able to attenuate PQ-induced ALI and cell apoptosis. The mechanism responsible for the latter maybe the inhibitive effect of Res on NF-ΚB p65 translocation and cytokines production.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2016.01.007DOI Listing
January 2016

Resveratrol protects mice from paraquat-induced lung injury: The important role of SIRT1 and NRF2 antioxidant pathways.

Mol Med Rep 2016 Feb 23;13(2):1833-8. Epub 2015 Dec 23.

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

Sirtuin 1 (SIRT1) acts via the deacetylation of a number of crucial transcription factors and has been implicated in various biological processes, including oxidative stress. Previous studies have indicated that nuclear factor, erythroid 2‑like 2 (NRF2) is an effective target of antioxidant therapy for paraquat (PQ) poisoning. However, the association between SIRT1 and NRF2 and their effects in PQ‑induced oxidative stress remains to be elucidated. The current study demonstrated that PQ exposure upregulated the expression of SIRT1 and NRF2 following 6‑ and 24‑h exposure in the lungs of mice. However, long‑term exposure to PQ significantly decreased the expression of SIRT1 and NRF2. Resveratrol is a SIRT1 activator, and strongly enhanced SIRT1 expression and attenuated the lung injury resulting from PQ exposure in the current study. Additionally, treatment with resveratrol upregulated the expression of NRF2 and glutathione, increased the activity of heme oxygenase‑1, superoxide dismutase and catalase, but depleted the expression of malondialdehyde. The present results demonstrated that resveratrol reduced PQ‑induced oxidative stress and lung injury, potentially through the positive feedback signaling loop between SIRT1 and NRF2.
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http://dx.doi.org/10.3892/mmr.2015.4710DOI Listing
February 2016

[The protective effect of ulinastatin on paraquat-induced injury in HK-2 cells and the underlying mechanisms].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2015 Jul;33(7):501-6

Emergency Department of the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; E-mial:

Objective: To investigate the protective effect of ulinastatin (UTI) on HK-2 cells during paraquat (PQ)-induced injury and its underlying mechanisms.

Methods: Routinely cultured HK-2 cells were divided into blank control group, PQ group, UTI+PQ group and UTI group. Cell viability was determined by CCK-8 assay. The concentration of PQ in HK-2 cells were measured by high performance liquid chromatography (HPLC). The production of total reactive oxygen species (ROS) were detected by fluorescence microscopy. The activities of superoxide dismutase activity (SOD) and the content of malondialdehyde (MDA) in HK-2 cells were observed by chemical colorimetry. The levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).

Results: PQ, even at a dose of 200 µM, could significant suppress the viability of HK-2 cells in a dose-dependent and time-dependent. UTI showed no significant inhibitory effect on the viability of HK-2 cells when given at a dose below 8 000 U/ml (P > 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased the viability of HK-2 cells in a dose-dependent of UTI (P < 0.05). Compared with the PQ group on the same hour, the UTI+PQ group showed decreased in PQ concentration in HK-2 cells (P < 0.05 for all except 6 h). Compared with the blank control group, the PQ group had significantly decreased SOD activity and significantly increased ROS level and MDA content (P < 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased SOD activity and significantly decreased ROS level and MDA content (P < 0.05). Compared with the blank control group, the PQ group had significantly increased IL-6 and TNF-α level (P < 0.05); Compared with the PQ group, the UTI+PQ group had significantly decreased IL-6 and TNF-α level (P < 0.05).

Conclusion: UTI significantly reduces the PQ-induced oxidative damage and inflammatory injury and its mechanism may be by reducing the accumulation of PQ in HK-2 cells.
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July 2015

Honokiol Inhibits Constitutive and Inducible STAT3 Signaling via PU.1-Induced SHP1 Expression in Acute Myeloid Leukemia Cells.

Tohoku J Exp Med 2015 11;237(3):163-72

Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University.

Constitutive and inducible activation of signal transducer and activator of transcription 3 (STAT3) signaling facilitates the carcinogenesis in most human cancers including acute myeloid leukemia (AML). Negative regulators, such as protein tyrosine phosphatases SHP1, inhibit the activated STAT3 signaling. In this study, we investigated the effect of honokiol (HNK), a constituent of Magnolia officinalis, on the STAT3 signaling. STAT3 signaling and SHP1 expression were measured by quantitative real-time PCR and western blotting in leukemic cell lines and primary AML blasts treated with HNK. HNK decreased the phosphorylated STAT3 but not the total STAT3 through increasing the expression of SHP1. In addition, HNK inhibited transcription activity of STAT3, reduced nuclear translocation of STAT3, and decreased the expression of STAT3 target genes. Knockdown of SHP1 by small hairpin RNA (shRNA) or treatment with vanadate, a protein tyrosine phosphatases inhibitor, abolished HNK-induced STAT3 inhibition, suggesting that SHP1 plays an important role in the inhibition of STAT3 signaling by HNK. Further, HNK increased the expression of transcript factor PU.1, which had been reported to activate the expression of SHP1 via binding SHP1 promoter region. Knockdown of PU.1 reversed HNK-induced upregulation of SHP1 and inactivation of STAT3 signaling. Finally, HNK increased the expression of PU.1 and SHP1 in hematopoietic progenitors isolated from patients with AML. In conclusion, our data have shown a regulatory mechanism underlying the inhibition of STAT3 signaling by HNK. Therefore, as a relative non-toxic compound, HNK may offer a therapeutic advantage in the clinical treatment for AML.
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http://dx.doi.org/10.1620/tjem.237.163DOI Listing
November 2015

[Rescue of 1 patient with red fennel poisoning with hemoperfusion].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015 Apr;27(4):319-20

The First Clinical College of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.

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http://dx.doi.org/10.3760/cma. j. issn.2095-4352.2015.04.023DOI Listing
April 2015

[The protective effect of regulation of paraoxonase 1 gene on liver oxidative stress injury induced by dichlorvos poisoning in mice].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015 Apr;27(4):285-90

Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China. Corresponding author: Lu Zhongqiu, Email:

Objective: To investigate the protective effect of paraoxonase 1 (PON1) gene against liver oxidative stress injury in mice due to dichlorvos poisoning.

Methods: Experiment 1: 12 male Balb/c mice were randomly divided into three groups, with 4 mice in each group: control group, green fluorescent protein lentivirus control group (Lv-GFP group), and recombinant PON1 lentivirus group (Lv-PON1 group). 2 × 10⁷ TU of Lv-GFP or Lv-PON1 was transfected via tail vein, while normal saline was given to those in control group. Blood was collected on 0, 1, 3, 5, 7, 9 days via fundus venous plexus for the assay of serum PON1 activity. PON1 mRNA and protein expression levels were respectively determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western Blot on the 3rd post-lentivirus transfection day. Experiment 2: according to the random number table method, another 96 male Balb/c mice were divided into four groups of 24 mice in each control group, dichlorvos group, Lv-GFP intervention group, and Lv-PON1 intervention group. Lv-GFP or Lv-PON1 was transfected via tail vein followed by intraperitoneal injection of dichlorvos 9 mg/kg, while those in control group were given normal saline. Six mice in each group were sacrificed respectively at 6, 12, 24, 48 hours, and liver tissue was collected. PON1 mRNA and nuclear factor E2-related factor 2 (Nrf2) mRNA expression levels were determined by RT-PCR, and PON1 protein level was determined by Western Blot. The content of malondialdehyde (MDA) and glutathione (GSH) in the liver tissue were determined by chemical colorimetry. The activity of superoxide dismutase (SOD) and catalase (CAT) were measured by double antibody sandwich enzyme linked immunosorbent assay (ELISA).

Results: Experiment 1: after Lv-PON1 was transfected to normal mice, PON1 activity in serum gradually increased and maintained a high level on 3rd day, while that of the control group and Lv-GFP group showed a normal low level. On the 3rd post-lentivirus transfection day, PON1 mRNA and PON1 protein expressions in liver were significantly higher than those of control group and Lv-GFP group. Experiment 2: compared with control group, the mice in dichlorvos group showed significant decreases in PON1 mRNA, PON1 protein, Nrf2 mRNA as well as GSH, SOD, CAT levels at 6 hours [PON1 mRNA (gray value): 0.237 ± 0.075 vs. 0.674 ± 0.011, PON1 protein (gray value): 0.602 ± 0.086 vs. 0.998 ± 0.124, Nrf2 mRNA (gray value): 0.089 ± 0.012 vs. 0.126 ± 0.010, GSH (mg/g): 3.84 ± 0.33 vs. 5.52 ± 0.40, SOD (μg/g): 0.383 ± 0.040 vs. 0.564 ± 0.052, CAT (ng/g): 7.32 ± 1.28 vs. 12.46 ± 1.54, all P < 0.05 ], and remarkable increase in MDA content (nmol/g: 7.78 ± 0.41 vs. 2.34 ± 0.25, P < 0.05). With the extension of time, PON1 mRNA, PON1 protein, Nrf2 mRNA and GSH, SOD, CAT levels gradually increased, MDA content gradually decreased, Nrf2 mRNA expression level had risen to the level of control group at 24 hours (0.133 ± 0.019 vs. 0.126 ± 0.009, P > 0.05), and it was higher than that of the control group at 48 hours ( 0.206 ± 0.028 vs. 0.124 ± 0.010, P < 0.05). Compared with that of the dichlorvos group, Lv-PON1 intervention group showed a significant increase in PON1 mRNA, PON1 protein, Nrf2 mRNA and GSH, SOD, CAT levels [PON1 mRNA (gray value): 0.726 ± 0.021 vs. 0.237 ± 0.075, PON1 protein (gray value): 0.739 ± 0.050 vs. 0.602 ± 0.086, Nrf2 mRNA (gray value): 0.158 ± 0.007 vs. 0.089 ± 0.012, GSH (mg/g): 4.30 ± 0.22 vs. 3.84 ± 0.33, SOD ( μg/g): 0.454 ± 0.062 vs. 0.383 ± 0.040, CAT (ng/g): 8.98 ± 1.02 vs. 7.32 ± 1.28, all P < 0.05 ], and a decrease in MDA content (nmol/g: 6.56 ± 0.44 vs. 7.78 ± 0.41, P < 0.05).

Conclusions: Regulation of PON1 gene can reduce MDA content, enhance SOD and CAT activities, increase GSH content, and it may also up-regulate Nrf2 mRNA expression to play a protective effect against oxidative stress of liver injury induced by dichlorvos poisoning.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2015.04.012DOI Listing
April 2015