Publications by authors named "Fengxia Ding"

20 Publications

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hucMSC Conditioned Medium Ameliorate Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Oxidative Stress and Inflammation via Nrf2/NF-B Signaling Pathway.

Anal Cell Pathol (Amst) 2021 13;2021:6653681. Epub 2021 Aug 13.

Department of Cardiothoracic Surgery; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.

Acute lung injury (ALI) is a common clinical syndrome in the cardiac intensive care unit with a high mortality rate. Inflammation and oxidative stress have been reported to play a crucial role in the development of ALI. Previous studies have shown that human umbilical cord mesenchymal stem cells (hucMSCs) have anti-inflammatory and antioxidative effects in various diseases. However, the anti-inflammatory and antioxidative effects of the hucMSC conditioned medium (CM) on LPS-induced ALI remain unclear. Therefore, in this study, we assessed whether the hucMSC conditioned medium could attenuate LPS-induced ALI and the underlying mechanisms. Mice were randomly divided into four groups: the control group, PBS group, LPS+PBS group, and LPS+CM group. The lung histopathology and bronchoalveolar lavage fluid (BALF) were analyzed after intervention. The Nrf2/NF-B signaling pathway and its downstream target genes were tested, and the cytokines and growth factors in CM were also measured. The results showed that CM significantly attenuated the histological alterations; decreased the wet/dry weight ratio; reduced the levels of MPO, MDA and ROS; increased SOD and GSH activity; and downregulated the level of proinflammatory cytokines such as IL-1, IL-6, and TNF-. Furthermore, CM promoted the expression of Nrf2 and its target genes NQ01, HO-1, and GCLC and inhibited the expression of NF-B and its target genes IL-6, IL-1, and TNF-. These effects may be closely related to the large amounts of cytokines and growth factors in the CM. In conclusion, our results demonstrated that CM could attenuate LPS-induced ALI, probably due to inhibition of inflammation and oxidative stress via the Nrf2/NF-B signaling pathway.
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http://dx.doi.org/10.1155/2021/6653681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380155PMC
August 2021

Blockade of GITRL/GITR signaling pathway attenuates house dust mite-induced allergic asthma in mice through inhibition of MAPKs and NF-κB signaling.

Mol Immunol 2021 09 20;137:238-246. Epub 2021 Jul 20.

Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, PR China; National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China. Electronic address:

GITRL/GITR signaling pathway plays an important role in allergy, inflammation, transplantation and autoimmunity. However, its role in asthma remains unclear. Thus, the present study aimed to investigate changes in this pathway and observe the therapeutic effect of its blocking on asthma. By using house dust mite-induced asthma model, changes of GITRL/GITR and its downstream molecules MAPKs (e.g., p38 MAPK, JNK and Erk) and NF-κB were observed. After that, GITRL in lung of mice was knocked down by recombinant adeno-associated virus to observe the impact on its downstream molecules and assess the therapeutic effect on asthma. These results showed that GITRL/GITR and its downstream molecules MAPKs/NF-κB were activated in asthmatic mice. This activation was suppressed after GITRL knockdown, and allergic airway inflammation and airway hyperresponsiveness were alleviated. These results demonstrate that GITRL/GITR-MAPKs/NF-κB signaling pathway participates in the pathogenesis of asthma. Blockade of GITRL/GITR signaling pathway exhibits protective effects in a mouse model of house dust mite-induced allergic asthma.
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http://dx.doi.org/10.1016/j.molimm.2021.07.005DOI Listing
September 2021

Pseudomonas aeruginosa outer membrane vesicles ameliorates lung ischemia-reperfusion injury by regulating the balance of regulatory T cells and Th17 cells through Tim-3 and TLR4/NF-κB pathway.

Inflamm Res 2021 Aug 5;70(8):891-902. Epub 2021 Jul 5.

Department of Cardiothoracic Surgery, Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong Dis, Chongqing, 400014, People's Republic of China.

Objective: Regulatory T cells (Tregs) and T helper (Th) 17 cells are two subsets of CD4 + T cells with opposite effects which play a crucial role in the pathogenesis of lung injury. In this study, we aim to investigate the protective effect of Pseudomonas aeruginosa outer membrane vesicles (OMVs) preconditioning on lung ischemia-reperfusion (I/R) injury and potential mechanisms.

Methods: Pathogen-free C57BL/6 mice were randomly divided into four groups: control, Control + OMVs, I/R and I/R + OMVs groups. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were collected and analyzed for pathophysiology and immune mechanism.

Results: OMVs not only attenuated tissue injury and respiratory physiologic function but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration. The numbers of total cells, macrophages, neutrophils, and lymphocytes were markedly decreased in the I/R mice following OMVs preconditioning. OMVs also decreased inflammatory cytokines associated with CD4 + T cells in both BALF and serum. In addition, the level of Tregs and its transcription factor forkhead box P3 (Foxp3) were significantly increased, while the level of Th17 cells and its transcription factor retinoid-related orphan receptor γ (RORγt) were significantly decreased following OMVs preconditioning. In the process of exploring the underlying protection mechanisms of OMVs, we found that OMVs preconditioning significantly reduced protein expression of Toll-like receptor 4 (TLR4), which in turn not only inactivated myeloid differentiation factor 88 (MyD88) and Phosphorylated nuclear factor kappa B (p-NF-κB), but also simultaneously increased the levels of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3).

Conclusions: These results suggest that OMVs preconditioning may ameliorate lung I/R injury by regulating the balance of Tregs and Th17 cells through Tim-3 and TLR4/NF-κB pathway.
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http://dx.doi.org/10.1007/s00011-021-01483-wDOI Listing
August 2021

GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4 T cell differentiation.

Respir Res 2021 Feb 8;22(1):46. Epub 2021 Feb 8.

Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Yuzhong District, No. 136, Zhongshan 2nd Road, Chongqing, 400014, China.

Background: Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) plays an important role in tumors, autoimmunity and inflammation. However, GITRL is not known to modulate the pathogenesis of allergic asthma. In this study, we investigated whether regulating GITRL expressed on dendritic cells (DCs) can prevent asthma and to elucidate its mechanism of action.

Methods: In vivo, the role of GITRL in modulating house dust mite (HDM)-induced asthma was assessed in adeno-associated virus (AAV)-shGITRL mice. In vitro, the role of GITRL expression by DCs was evaluated in LV-shGITRL bone marrow dendritic cells (BMDCs) under HDM stimulation. And the direct effect of GITRL was observed by stimulating splenocytes with GITRL protein. The effect of regulating GITRL on CD4 T cell differentiation was detected. Further, GITRL mRNA in the peripheral blood of asthmatic children was tested.

Results: GITRL was significantly increased in HDM-challenged mice. In GITRL knockdown mice, allergen-induced airway inflammation, serum total IgE levels and airway hyperresponsiveness (AHR) were reduced. In vitro, GITRL expression on BMDCs was increased after HDM stimulation. Further, knocking down GITRL on DCs partially restored the balance of Th1/Th2 and Th17/Treg cells. Moreover, GITRL stimulation in vitro inhibited Treg cell differentiation and promoted Th2 and Th17 cell differentiation. Similarly, GITRL mRNA expression was increased in the peripheral blood from asthmatic children.

Conclusions: This study identified a novel role for GITRL expressed by DCs as a positive regulator of CD4 T cells responses in asthma, which implicates that GITRL inhibitors may be a potential immunotherapy for asthma.
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http://dx.doi.org/10.1186/s12931-020-01583-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869253PMC
February 2021

Occult foreign body aspirations in pediatric patients: 20-years of experience.

BMC Pulm Med 2020 Dec 9;20(1):320. Epub 2020 Dec 9.

Department of Cardiothoracic Surgery; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong Dis, Chongqing, 400014, China.

Background: The purpose of our study was to assess the frequency of occult foreign body aspiration (FBA) and to evaluate the diagnostic difficulties and therapeutic methods for these patients.

Methods: Between May 2000 and May 2020, 3557 patients with the diagnosis of FBA were treated in our department. Thirty-five patients with occult FBA were included in this study. A retrospective analysis of medical records was performed.

Results: Twenty-three male patients (65.7%) and 12 female patients (34.3%) were hospitalized due to occult FBA. The average age was 3.60 years (range 9 months-12 years). Most of the patients were younger than 3 years old (n = 25, 71.4%). Coughing (n = 35, 100%) and wheezing (n = 18, 51.4%) were the main symptoms and signs. All the patients were found to have a FBA under the fiberoptic bronchoscope. The most common organic foreign bodies were peanuts (n = 10) and the most common inorganic foreign bodies were pen caps (n = 5). The extraction of foreign bodies under rigid bronchoscopy was applied successfully in 34 patients. Only one patient needed a surgical intervention.

Conclusions: Occult FBA should always be considered in the differential diagnosis of chronic or recurrent respiratory diseases that are poorly explained, even in the absence of a previous history of aspiration.
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http://dx.doi.org/10.1186/s12890-020-01356-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724703PMC
December 2020

Low-Dose LPS Induces Tolerogenic Treg Skewing in Asthma.

Front Immunol 2020 23;11:2150. Epub 2020 Sep 23.

Department of Pediatric Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.

The mechanism(s) underlying endotoxin tolerance in asthma remain elusive. As the endotoxin lipopolysaccharide (LPS) affects the expression of the regulatory T-cell (Treg)-suppressive glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) on antigen-presenting dendritic cells (DCs), we hypothesized that LPS-induced changes in DC GITRL expression may impact Treg-mediated T-helper (Th) cell suppression and the induction of endotoxin tolerance. Here, we propose a novel mechanism by which low-dose LPS inhalation in neonatal mice induces endotoxin tolerance, thereby offering protection from later asthma development. Three-day old wild-type and Toll-like receptor 4 (TLR4)-deficient neonatal mice were exposed to low-dose LPS (1 μg) intranasally for 10 consecutive days prior to ovalbumin (OVA)-induced asthma to better understand the tolerogenic mechanism(s) of low-dose LPS pre-exposure. findings were validated using co-culturing studies of primary CD11c DCs and CD4 T-cells with or without low-dose LPS pre-exposure before OVA stimulation. Low-dose LPS pre-exposure upregulated the Treg response and downregulated pathogenic Th2 and Th17 responses through promoting apoptosis of Th2 and Th17 cells. Low-dose LPS pre-exposure downregulated DC GITRL expression and T-cell GITR expression. Artificial DC GITRL expression abrogated the tolerogenic Treg-skewing effect of low-dose LPS pre-exposure. Low-dose LPS pre-exposure inhibited TRIF/IRF3/IFNβ signaling and upregulated expression of tolerogenic TRIF/IRF3/IFNβ negative regulators in a TLR4-dependent manner. This tolerogenic DC GITRL downregulation was attributable to TRIF/IRF3/IFNβ signaling inhibition. Low-dose LPS pre-exposure produces tolerogenic Treg skewing in neonatal asthmatic mice, a phenomenon attributable to TLR4-dependent TRIF/IRF3/IFNβ-mediated DC GITRL downregulation.
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http://dx.doi.org/10.3389/fimmu.2020.02150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538595PMC
May 2021

Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients.

J Am Acad Dermatol 2020 Sep 13;83(3):788-796. Epub 2019 Apr 13.

Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China.

Background: Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs).

Objective: We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents.

Methods: Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies.

Results: A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P < .001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P < .001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed.

Limitation: High heterogeneity in most studies.

Conclusion: High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.
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http://dx.doi.org/10.1016/j.jaad.2019.04.021DOI Listing
September 2020

Brg1 aggravates airway inflammation in asthma via inhibition of the PI3K/Akt/mTOR pathway.

Biochem Biophys Res Commun 2018 09 24;503(4):3212-3218. Epub 2018 Aug 24.

Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Number. 136, Zhong Shan 2nd Road, Yuzhong District, 400014, Chongqing, China. Electronic address:

The PI3K/Akt/mTOR pathway is thought to be closely associated with airway inflammation and is regulated by various upstream proteins. Brahma-related gene 1 (Brg1) plays an important role in chromatin remodeling and facilitates recruitment of essential transcription factors, leading to regulation of gene expression. Thus, the present study aimed at evaluating the anti-inflammatory role of Brg1 on house dust mite (HDM)-induced asthma through regulating the PI3K/Akt/mTOR pathway. The Brg mice were crossbred with the SFTPC-Cre mice to generate bronchial epithelial cell specific Brg1 knockout mice, and LY294002 was used to inhibit PI3K. Western blot, immunofluorescence, immunoprecipitation, and immunohistochemical staining were used to detect the expression of proteins. An increase in Brg1 and a decrease in the PI3K/Akt/mTOR pathway activity were detected in asthmatic mice, but not in control mice. When Brg1 was knocked out, the asthma severity was ameliorated and the PI3K/Akt/mTOR pathway was activated. However, this protective effect could be suppressed by LY294002. Additionally, we observed that Brg1 was co-localized and co-immunoprecipitated with PI3K, using immunofluorescence and immunoprecipitation assays. Our results suggest that Brg1 might play an essential role in maintaining airway inflammation and affect the PI3K/Akt/mTOR pathway in asthma.
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http://dx.doi.org/10.1016/j.bbrc.2018.08.127DOI Listing
September 2018

Lipopolysaccharide Exposure Alleviates Asthma in Mice by Regulating Th1/Th2 and Treg/Th17 Balance.

Med Sci Monit 2018 May 16;24:3220-3229. Epub 2018 May 16.

Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China (mainland).

BACKGROUND It is generally believed that endotoxin exposure exacerbates risk of developing asthmatic symptoms. However, recent studies have indicated that prior bacterial exposure may prevent future symptoms of asthma. Here, we evaluated the influence of pre-exposure to different concentrations of lipopolysaccharide (LPS) to subsequent ovalbumin (OVA) allergen sensitization and challenge. MATERIAL AND METHODS Four-week-old Balb/c mice were treated intranasally with varying concentrations of LPS (1 ug, 10 ug, and 100 ug) or sterile PBS for 10 days, then 2 weeks later they were exposed to OVA. Both the molecular and functional airway responses to OVA administration were assessed following prior exposure to different doses of LPS or controls. Additionally, the Th1/Th2 and Treg/Th17 balance was measured. RESULTS Airway responsiveness and immune cell recruitment in the bronchoalveolar lavage (BALF) were decreased in animals exposed to a low dose of LPS (1 ug) treatment compared with the asthma group. Moderate-dose (10 ug) and high-dose (100 ug) LPS administration showed no differences from controls. Further, low-dose LPS (1 ug) exposure was associated with increased Th1 cytokines, T-bet, Treg cytokine (IL-10, TGF-β), and Foxp3 expression, but decreased Th2 cytokines (IL-4,5,13), GATA3, Th17, and ROR-gt expression compared with the asthma group. Finally, higher numbers of CD4+CD25+Foxp3+Treg cells, and CD4+INF-γ+T cells, and lower CD4+IL-4+T cells and CD4+IL-17+T cells were observed in the low-dose LPS-treated groups compared to controls. CONCLUSIONS Our findings suggest that prior exposure to low doses of LPS may protect from OVA-induced airway hyperresponsiveness (AHR) and histopathologic changes through regulation of the Th1/Th2 and Treg/Th17 balance.
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http://dx.doi.org/10.12659/MSM.905202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985709PMC
May 2018

LPS Exposure in Early Life Protects Against Mucus Hypersecretion in Ovalbumin-Induced Asthma by Down-Regulation of the IL-13 and JAK-STAT6 Pathways.

Cell Physiol Biochem 2018 16;46(3):1263-1274. Epub 2018 Apr 16.

Department of Pediatric respiratory medicine, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Chongqing, China International Science and Technology Cooperation base of Child development and Critical Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China.

Background/aims: Previous studies have shown that lipopolysaccharide (LPS) exposure may have a protective effect on asthma by reducing airway hyper-responsiveness, airway inflammation and serum IgE levels. However, there are few studies investigating the effect of LPS on mucous secretion in asthma. In this study, we evaluate the relationship between LPS pre-treatment in infant mice and airway mucus hypersecretion in an OVA (ovalbumin)-induced asthma model, and further explore the mechanisms behind this effect.

Methods: Mice were pre-treated with LPS by intranasal instillation (i.n.) from the 3rd day of life for 10 consecutive days before the OVA-induced asthma model was established. In order to detect mucus secretion, periodic acid-Schiff (PAS) staining was carried out, and the expression of Muc5ac was detected. The IL-13 levels in Bronchoalveolar lavage fluid (BALF) and lung tissue were also detected. In vitro, the expression of Muc5ac mRNA and protein was quantified in IL-13-stimulated 16HBE cells with or without LPS pre-treatment. In addition, proteins in the JAK2/STAT6 pathway, transcription factors (forkhead box transcription factor A2 (FOXA2), activation protein-1(AP-1), NF-κB), and the levels of reactive oxygen species (ROS) were also measured in vivo and in vitro.

Results: LPS pre-treatment reduced mucus secretion, as demonstrated by decreased PAS staining and muc5ac expression. Further exploration of the underlying mechanisms of this phenomenon revealed that LPS pre-treatment decreased the production of IL-13, IL-13 induced ROS synthesis was reduced, and the JAK2/STAT6 pathway was inhibited. Decreased stat6 increased transcription factor FOXA2, and the relatively increased FOXA2 further decreased the level of Muc5ac and mucous hypersecretion in OVA-induced asthma.

Conclusions: LPS pre-treatment ameliorated mucus hypersecretion in an OVA-induced asthma model by inhibition of IL-13 production and by further inhibiting the JAK2/STAT6 pathway and ROS activity, and up-regulating expression of FOXA2.
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http://dx.doi.org/10.1159/000489109DOI Listing
July 2018

Correction to: Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro.

Stem Cell Res Ther 2018 03 22;9(1):76. Epub 2018 Mar 22.

Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

The original article [1] contains an error whereby the corresponding authorship is mistakenly designated to the author Fengxia Ding.
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http://dx.doi.org/10.1186/s13287-018-0845-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865288PMC
March 2018

[Brahma-related gene 1 promotes airway mucus hypersecretion via STAT6 in asthmatic mice].

Nan Fang Yi Ke Da Xue Xue Bao 2018 Jan;38(1):42-47

Respiratory Center, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.

Objective: To investigate the effect of Brahma-related gene 1 (Brg1) on mucus hypersecretion in the airway of asthmatic mice and explore the mechanism.

Methods: Female C57bl/6 mice aged 6-8 weeks were randomized into wild-type control group, wild-type asthma group, Brg1 group with Brg1 gene knockdown in type Ⅱ alveolar epithelial cells, and Brg1+ asthma group (=10). The mice in asthma group and Brg1+asthma group were sensitized with ovalbumin (OVA) to establish asthmatic models. PAS staining was used to determine the number of goblet cells and mucus secretion in the airway. Real-time PCR was used to detect the expression of MUC5AC mRNA in the lung tissues. The levels of mucin MUC5AC and interleukin-13 (IL-13) in the bronchoalveolar lavage fluid (BALF) were detected with ELISA and immunohistochemistry, and the expressions of STAT6 and p-STAT6 in the lung tissue were detected using Western blotting.

Results: Compared with the control mice, wild-type asthmatic mice showed obvious mucus hypersecretion and increased MUC5AC mRNA in the airway with significantly increased IL-13 and MUC5AC levels in the BALF and activation of p-STAT6 in the lung tissues ( < 0.05). In the transgenic mice with Brg1 gene knockdown, airway mucus secretion and MUC5AC mRNA expression was significantly reduced following OVA challenge compared with those in the wild-type asthmatic mice; IL-13 and MUC5AC levels in the BALF and p-STAT6 expression in the lung tissues were also significantly decreased in the transgenic mice ( < 0.05).

Conclusions: Brg1 gene knockdown in type Ⅱ alveolar epithelial cells alleviates OVA-induced airway mucus hypersecretion and reduces the expression of MUC5AC in C57bl/6 mice possibly by inhibiting STAT6 activation, suggesting the role of Brg1 in promoting asthmatic airway mucus hypersecretion.
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http://dx.doi.org/10.3969/j.issn.1673-4254.2018.01.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765620PMC
January 2018

Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro.

Stem Cell Res Ther 2018 01 12;9(1). Epub 2018 Jan 12.

Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

Background: Renal fibrosis is characterized by infiltration of interstitial inflammatory cells and release of inflammatory mediators, activation and proliferation of fibroblasts, and deposition of excessive extracellular matrix (ECM). The aim of this study was to evaluate the effect of human umbilical cord-derived mesenchymal stem cell (hucMSC) conditioned medium (CM) on renal tubulointerstitial inflammation and fibrosis.

Methods: Renal interstitial fibrosis was prepared in vivo using the unilateral ureteral obstruction (UUO). Rats were divided randomly into Sham group, Sham group with CM, UUO group, and UUO group with CM. The effect of hucMSC-CM on kidney injury induced by UUO was assessed by detecting kidney histopathology, serum creatinine (SCr), and blood urea nitrogen (BUN). The levels of TNF-α, IL-6, and IL-1β in serum and kidney tissues were detected by ELISA. The expression of proteins associated with fibrosis and renal inflammation was investigated using immunohistochemical staining and western blotting. The effects of hucMSC-CM on the TGF-β1-induced epithelial-mesenchymal transition (EMT) process and on inflammation in NRK-52E cells were investigated by immunofluorescent staining, ELISA, and western blotting.

Results: hucMSC-CM reduced extracellular matrix deposition and inflammatory cell infiltration as well as release of inflammatory factors in UUO-induced renal fibrosis. Furthermore, hucMSC-CM markedly attenuated the EMT process and proinflammatory cytokines in rats with UUO and TGF-β1-induced NRK-52E cells. hucMSC-CM also inhibited the TLR4/NF-κB signaling pathway in vivo and in vitro.

Conclusions: Our results suggest that hucMSC-CM has protective effects against UUO-induced renal fibrosis and that hucMSC-CM exhibits its anti-inflammatory effects through inhibiting TLR4/NF-κB signaling pathway activation.
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http://dx.doi.org/10.1186/s13287-017-0760-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767037PMC
January 2018

BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/β-catenin signalling.

Sci Rep 2017 08 22;7(1):9153. Epub 2017 Aug 22.

Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.

The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/β-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose-dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down-regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased β-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer.
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http://dx.doi.org/10.1038/s41598-017-09655-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567253PMC
August 2017

Brg1 inhibits E-cadherin expression in lung epithelial cells and disrupts epithelial integrity.

J Mol Med (Berl) 2017 10 11;95(10):1117-1126. Epub 2017 Aug 11.

Pediatrics Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

Brahma-related gene-1 (Brg1), a key chromatin remodeling factor, is associated with cell proliferation and migration in kidney and heart cells, but few reports have examined its role in airway epithelial cell. Airway epithelial injury, which is involved in the entire pathological process of asthma, is an important cause of recurrent asthma. Here, we studied the function of Brg1 in an ovalbumin (OVA)-induced asthma model (lung-specific conditional Brg1 (Brg1) knockdown mice) and human bronchial epithelial 16HBE cells stably expressing Brg1 shRNA. Our results showed that high expression of Brg1 was detected in asthmatic children and in mouse models. Brg1 mice showed improved airway hyperresponsiveness (AHR) and bronchial epithelial integrity, along with reduced inflammatory cell infiltration and airway mucus secretion, when challenged with OVA. Furthermore, cell proliferation, migration, and expression of E-cadherin increased in 16HBE cells in which Brg1 was silenced. We further demonstrated that Brg1 bound to and inactivated a critical region (-86/+60 bp) within the E-cadherin promoter in bronchial epithelial cells. Thus, Brg1 might act as an important regulator of airway epithelial integrity in asthma progression and might be a novel therapeutic target.

Key Messages: • Depletion of Brg1 improves the integrity of airway epithelium in asthma by regulating E-cadherin expression in lung epithelial cells. • Knockdown of Brg1 increased the cell proliferation and migration by human bronchial epithelial 16HBE cells. • Brg1 might bLLe a novel therapeutic target in asthma.
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http://dx.doi.org/10.1007/s00109-017-1576-7DOI Listing
October 2017

Risk of venous and arterial thromboembolic events associated with VEGFR-TKIs: a meta-analysis.

Cancer Chemother Pharmacol 2017 Sep 10;80(3):487-495. Epub 2017 Jul 10.

Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

The reported incidence of arterial and venous thromboembolic events varies markedly between VEGFR-TKI-related clinical trials. Here, we performed a meta-analysis to determine the incidence and the relative risk (RR) of venous thromboembolism events (VTEs) and arterial thromboembolic events (ATEs) associated with these agents. Databases (PubMed, Web of Science) were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RRs and 95% confidence intervals (CIs) using either random-effects or fixed-effects models according to the heterogeneity of the included studies. A total of 24,855 patients from 48 studies were included. The overall incidence of all-grade and high-grade VTEs associated with VEGFR-TKIs was 3.6% (95% CI 2.3-5.2%) and 1.6% (95% CI 1.0-2.4%), respectively. The use of VEGFR-TKIs did not significantly increase the risk of developing all-grade (RR 0.91; 95% CI 0.68-1.22; P = 0.558) and high-grade (RR 1.05; 95% CI 0.84-1.31; P = 0.769) VTEs. The overall incidence of all-grade and high-grade ATEs associated with VEGFR-TKIs was 2.7% (95% CI 1.7-3.6%) and 0.6% (95% CI 0.2-1.2%), respectively. The use of VEGFR-TKIs significantly increase the risk of developing all-grade (RR 3.09; 95% CI 1.41-6.76; P = 0.033) ATEs, and a tendency to increase the risk of high-grade (RR 1.49; 95% CI 0.99-2.24; P = 0.101) ATEs was also detected. Patients with cancer that receive VEGFR-TKIs are at high risk of developing ATEs. Physicians should be aware of these adverse effects and should monitor cancer patients receiving VEGFR-TKIs.
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http://dx.doi.org/10.1007/s00280-017-3386-6DOI Listing
September 2017

BHX Inhibits the Wnt Signaling Pathway by Suppressing β-catenin Transcription in the Nucleus.

Sci Rep 2016 12 2;6:38331. Epub 2016 Dec 2.

Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P. R. China.

BHX (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide), a Wnt signaling pathway inhibitor, effectively inhibits tumor cell growth, but the underlying mechanism is unclear. Thus, we aim to investigate the effects and associated mechanism of BHX action on A549 and MCF-7 cell lines. In our study, MTT(3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) and xenograft model assay indicated that cell growth was inhibited by BHX at a range of concentrations in vitro and in vivo. The expression of β-catenin and Wnt signaling pathway downstream target genes were decreased evidently under BHX treatment. Flow cytometry also revealed that BHX treatment significantly induced G1 arrest. Further analysis showed that BHX lowered the transcriptional level of β-catenin. In conclusion, BHX inhibited the nuclear synthesis of β-catenin, thereby suppressing the Wnt signaling pathway and further inhibiting tumor growth and proliferation.
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http://dx.doi.org/10.1038/srep38331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133598PMC
December 2016

Incidence and risk of hypertension associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a comprehensive network meta-analysis of 72 randomized controlled trials involving 30013 patients.

Oncotarget 2016 Oct;7(41):67661-67673

Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China.

Background: Tyrosine kinase inhibitors (TKIs) have been developed during the last decade that target the vascular endothelial growth factor receptor (VEGFR) are currently being evaluated as treatments for malignant tumors. The increased application of VEGFR-TKIs means that the probability of hypertension is a serious concern. However, the reported incidence varies markedly between clinical trials. Here, we undertook an up-to-date, comprehensive meta-analysis on clinical works to build the incidence of hypertension along with VEGFR-TKIs. The goal was to understand better of the overall venture of cancer patients' hypertension treated with these drugs.

Methods: Databases (EMBASE, PubMed, and Cochrane library) and the abstracts of the American Society of Clinical Oncology annual meeting and European Society of Medical Oncology were searched to identify related studies. 95% confidence intervals (CIs), summary incidences, and relative risk (RR) were calculated utilizing either fixed-effects models on the basis of the heterogeneity of the included studies or random-effects.

Results: Seventy-two randomized controlled trials (including 30013 patients) were involved. The total incidence of high-grade and all-grade hypertensive events along with VEGFR-TKIs was 23.0% (95% CI, 20.1-26.0%) and 4.4% (95% CI, 3.7-5.0%), respectively. The use of VEGFR-TKIs remarkably enhanced the venture of developing high-grade (RR, 4.60; 95% CI, 3.92-5.40; P < 0.001) and all-grade (RR, 3.85; 95% CI, 3.37-4.40; P < 0.001) hypertensive events. Subgroup analyses revealed that the risk of a hypertensive event varied significantly in accordance with tumor type, VEGFR-TKI, trial phase, VEGFR-TKIs-based regimen, control therapy, and chemotherapy regimen.

Conclusions: Patients with cancer that receive VEGFR-TKIs are at a remarkable venture of developing hypertension. Therefore, suitable treatment and monitoring should be introduced to avoid cardiovascular complications.
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http://dx.doi.org/10.18632/oncotarget.11813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341903PMC
October 2016

Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O(6)-methylguanine-DNA methyltransferase (MGMT) expression.

Am J Transl Res 2016 15;8(7):3299-308. Epub 2016 Jul 15.

Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China.

The DNA-alkylating agent temozolomide (TMZ) is an effective chemotherapeutic agent against malignant glioma, including glioblastoma multiforme (GBM). However, the clinical efficacy of TMZ is limited in many patients because of O(6)-methylguanine-DNA methyltransferase (MGMT)-driven resistance. Thus, new strategies to overcome TMZ resistance are urgently needed. Ursolic acid (UA) is a naturally derived pentacyclic triterpene acid that exerts broad anticancer effects, and shows capability to cross the blood-brain barrier. In this study, we evaluated the possible synergistic effect of TMZ and UA in resistant GBM cell lines. The results showed that UA prevented the proliferation of resistant GBM cells in a concentration-dependent manner. Compared with TMZ or UA treatment alone, the combination treatment of TMZ and UA synergistically enhanced cytotoxicity and senescence in TMZ-resistant GBM cells. This effect was correlated with the downregulation of MGMT. Moreover, experimental results with an in vivo mouse xenograft model showed that the combination treatment of UA and TMZ reduced tumor volumes by depleting MGMT. Therefore, UA as both a monotherapy and a resensitizer, might be a candidate agent for patients with refractory malignant gliomas.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969467PMC
August 2016

[Progress of Postoperative Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer].

Zhongguo Fei Ai Za Zhi 2015 Jun;18(6):374-80

Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

The morbidity and mortality of lung cancer rank the first place among all the malignant tumor. According to the histopathological characteristics, lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. Only 20% patients diagnosed with NSCLC have the chance for surgery while their 5-yr overall survival is about 30%-60%. The therapeutic outcome of surgery alone is not satisfying. Adjuvant chemotherapy after surgical resection in stage II-IIIa lung cancer showed efficacy in many randomized clinical trials, but its role in stage I disease remains controversial. The choice of appropriate chemotherapy candidates, the selection of chemotherapy regimens and the research progress on biomarker are mainly discussed in this review.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2015.06.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999912PMC
June 2015
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