Publications by authors named "Peng-Yuan Zheng"

57 Publications

Modulating oxidative stress counteracts specific antigen-induced regulatory T cell apoptosis in mice.

Eur J Immunol 2021 Apr 3. Epub 2021 Apr 3.

Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China.

Regulatory T cells (Treg) are known to have a central role in orchestrating immune responses, but less is known about the destiny of regulatory T cells after being activated by specific antigens (Ags). This study aimed to investigate the role of superoxide dismutase, an active molecule in the regulation of oxidative stress in the body, in the prevention of Treg apoptosis induced by specific Ags. Ag-specific Tregs were isolated from the DO11.10 mouse intestine. A food allergy mouse model was developed with ovalbumin as the specific Ag and here, we observed that exposure to specific Ag induced Treg apoptosis through converting the precursor of TGF-β to its mature form inside the Tregs. Oxidative stress was induced in Tregs upon exposure to specific Ags, in which Smad3 bound the latency-associated peptide to induce its degradation, converting the TGF-β precursor to its mature form, TGF-β. Suppressing oxidative stress in Tregs alleviated the specific Ag-induced Treg apoptosis in in vitro experiments and suppressed experimental food allergy by preventing the specific Ag-induced Treg apoptosis in the intestine. In conclusion, exposure to specific Ags induces Treg apoptosis and it can be prevented by up-regulating superoxide dismutase or suppressing reactive oxidative species in Tregs. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/eji.202049112DOI Listing
April 2021

Interaction of 22 risk SNPs with infection and risk of gastric cardia adenocarcinoma.

Future Oncol 2019 Nov 25;15(31):3579-3585. Epub 2019 Oct 25.

Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, PR China.

To determine the prevalence of infection and correlation between infection and single nucleotide polymorphism (SNPs) identified in gastric cardia adenocarcinoma (GCA) patients. A case control study was performed. 22 risks of GCA-related SNPs were identified by genotyping assay and the relationship between susceptibility loci for GCA and infection was further analyzed. infection was associated with GCA significantly (odds ratio: 1.40; 95% CI: 1.29-1.53 p < 0.01). Five GCA risk SNPs had their genotypes significantly different between positive patients and negative patients. The interaction between SNPs susceptibility loci and infection is associated with an increased risk of GCA.
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http://dx.doi.org/10.2217/fon-2019-0319DOI Listing
November 2019

Vasoactive intestinal peptide alleviates food allergy via restoring regulatory B cell functions.

Immunobiology 2019 11 23;224(6):804-810. Epub 2019 Aug 23.

Research Center of Allergy & Immunology, Shenzhen University School of Medicine. Shenzhen, China. Electronic address:

The immune regulatory cell dysfunction is associated with many immune diseases including food allergy (FA). This study aims to investigate the role of vasoactive intestinal peptide (VIP) in the maintenance of regulatory B cell (Br cell)'s immune suppressive functions by stabilizing thrombospondin (TSP1) expression. In this study, blood samples were collected from patients with food allergy (FA) and healthy control (HC) subjects. Br cells were isolated from the samples through flow cytometry cell sorting and analyzed by immunological approaches to determine the immune regulatory capacity. We found that the immune suppressive functions of Br cells were impaired in FA patients. The serum VIP levels were associated with the production of immune suppressive function-related mediators (interleukin-10, IL-10) of Br cells in FA patients. VIP counteracted IL-10 mRNA decay in Br cells by up regulating the TSP1 expression. TSP1 inhibited tristetraprolin (TTP) to prevent IL-10 mRNA decay in Br cells. Administration of VIP inhibited FA response through restoration of immune suppressive functions in Br cells. In conclusion, administration of VIP can alleviate FA response through up regulating expression of TSP1 to stabilize IL-10 expression in FA Br cells and recover the immune regulatory functions. The results have translational potential for the treatment of FA and other disorders associated with immune regulatory dysfunction of Br cells.
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http://dx.doi.org/10.1016/j.imbio.2019.08.006DOI Listing
November 2019

Regulating Bcl2L12 expression in mast cells inhibits food allergy.

Theranostics 2019 9;9(17):4982-4992. Epub 2019 Jul 9.

Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.

: Mast cells play a crucial role in allergic diseases. Yet, the regulation of mast cell bioactivities is not fully understood. This study aims to elucidate the role of B cell lymphoma 2 like protein 12 (Bcl2L12), one of the anti-apoptosis proteins, in regulating mast cell apoptosis. : A food allergy (FA) mouse model was developed to establish mast cell over population in the intestinal tissue. Either compound 48/80 (C48/80) or specific antigens were used to activate mast cells in the intestinal mucosa. : After treating with C48/80, apoptosis was induced in mast cells of the intestine of naive control mice, but not in FA mice. The expression of Fas ligand (FasL) was lower in the mast cells of FA mice. Interleukin (IL)-5 was responsible for the suppression of FasL by upregulating the expression of Bcl2L12 in mast cells. Bcl2L12 prevented c-Myc, the major transcription factor of FasL, from binding the FasL promoter to inhibit the expression of FasL in mast cells. Inhibition of Bcl2L12 restored the apoptosis machinery of mast cells in the FA mouse intestine. : The apoptosis machinery in mast cells is impaired in an allergic environment. Inhibition of Bcl2L12 restores the apoptosis machinery in mast cells in the FA mouse intestine.
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http://dx.doi.org/10.7150/thno.34001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691383PMC
August 2020

[Correlation between gut microbiota and behavior symptoms in children with autism spectrum disorder].

Zhongguo Dang Dai Er Ke Za Zhi 2019 Jul;21(7):663-669

Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Objective: To investigate the composition of gut microbiota and its correlation with the severity of behavior symptoms in children with autism spectrum disorder (ASD).

Methods: A total of 30 children with ASD were enrolled as the ASD group, and 20 healthy children matched for age and sex were enrolled as the healthy control group. Related clinical data were analyzed. The V3-V4 hypervariable regions of the bacterial 16S rRNA gene in fecal samples were sequenced. The severity of behavior symptoms in children with ASD was assessed using the autism behavior checklist. The Spearman's correlation analysis was used to investigate the correlation between gut microbiota and the severity of behavior symptoms in children with ASD.

Results: There was a significant difference in the composition of gut microbiota between the two groups. Compared with the healthy control group, the ASD group had significant reductions in Shannon index and Shannoneven index (P<0.05), as well as a significant reduction in the percentage of Firmicutes and a significant increase in the percentage of Acidobacteria in feces (P<0.05). In the ASD group, the dominant bacteria were Megamonas, Megasphaera, and Barnesiella, while in the healthy control group, the dominant bacteria were Eubacterium_rectale_group, Ezakiella, and Streptococcus. In the children with ASD, the abundance of Megamonas was positively correlated with the scores of health/physical/behavior and language communication (P<0.05).

Conclusions: The development of ASD and the severity of behavior symptoms are closely associated with the composition of gut microbiota.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389106PMC
July 2019

MicroRNA changes of bone marrow-derived mesenchymal stem cells differentiated into neuronal-like cells by Schwann cell-conditioned medium.

Neural Regen Res 2019 Aug;14(8):1462-1469

Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.

Bone marrow-derived mesenchymal stem cells differentiate into neurons under the induction of Schwann cells. However, key microRNAs and related pathways for differentiation remain unclear. This study screened and identified differentially expressed microRNAs in bone marrow-derived mesenchymal stem cells induced by Schwann cell-conditioned medium, and explored targets and related pathways involved in their differentiation into neuronal-like cells. Primary bone marrow-derived mesenchymal stem cells were isolated from femoral and tibial bones, while primary Schwann cells were isolated from bilateral saphenous nerves. Bone marrow-derived mesenchymal stem cells were cultured in unconditioned (control group) and Schwann cell-conditioned medium (bone marrow-derived mesenchymal stem cell + Schwann cell group). Neuronal differentiation of bone marrow-derived mesenchymal stem cells induced by Schwann cell-conditioned medium was observed by time-lapse imaging. Upon induction, the morphology of bone marrow-derived mesenchymal stem cells changed into a neural shape with neurites. Results of quantitative reverse transcription-polymerase chain reaction revealed that nestin mRNA expression was upregulated from 1 to 3 days and downregulated from 3 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. Compared with the control group, microtubule-associated protein 2 mRNA expression gradually increased from 1 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. After 7 days of induction, microRNA analysis identified 83 significantly differentially expressed microRNAs between the two groups. Gene Ontology analysis indicated enrichment of microRNA target genes for neuronal projection development, regulation of axonogenesis, and positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that Hippo, Wnt, transforming growth factor-beta, and Hedgehog signaling pathways were potentially associated with neural differentiation of bone marrow-derived mesenchymal stem cells. This study, which carried out successful microRNA analysis of neuronal-like cells differentiated from bone marrow-derived mesenchymal stem cells by Schwann cell induction, revealed key microRNAs and pathways involved in neural differentiation of bone marrow-derived mesenchymal stem cells. All protocols were approved by the Animal Ethics Committee of Institute of Radiation Medicine, Chinese Academy of Medical Sciences on March 12, 2017 (approval number: DWLI-20170311).
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http://dx.doi.org/10.4103/1673-5374.253532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524508PMC
August 2019

Bcl2L12 mediates effects of protease-activated receptor-2 on the pathogenesis of Th2-dominated responses of patients with ulcerative colitis.

Arch Biochem Biophys 2018 11 11;657:8-14. Epub 2018 Sep 11.

The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China. Electronic address:

The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4 T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4 cells. Activation of PAR2 increased expression of Bcl2L12 in CD4 T cells. Bcl2L12 mRNA decayed spontaneously in CD4 T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4 T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4 T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.
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http://dx.doi.org/10.1016/j.abb.2018.09.003DOI Listing
November 2018

Bcl2L12 plays a critical role in the development of intestinal allergy.

Immunol Lett 2018 11 5;203:87-94. Epub 2018 Sep 5.

Research Center of Allergy & Immunology, Shenzhen University Faculty of Medicine, Shenzhen, China. Electronic address:

The skewed T helper (Th) 2 response plays a central role in the pathogenesis of allergic diseases, while its initiating factors remain elusive. Recent studies indicate that Bcl2 like protein-12 (Bcl2L12) is associated with the Th2-biased inflammation. This study is designed to test a hypothesis that Bcl2L12 plays a critical role in the initiation of allergic response. In this study, peripheral CD4 T cells were isolated from food allergy (FA) patients and healthy subjects; A mouse FA model was developed to test the role of Bcl2L12 in induction of allergic response in the intestine. The results showed that expression of Bcl2L12 by CD4 T cells was higher in FA patients and FA mice and positively correlated with expression of Th2 cytokines. CD4 T cells from FA patients showed a Bcl2L12-dependent tendency to differentiate into Th2 cells. Bcl2L12 played a crucial role in induction of allergic response in the intestine. Physical contact between Bcl2L12 and GATA3 facilitated GATA3 to bind Il4 promoter to promote expression of IL-4. Adoptive transfer with Bcl2L12-deficient CD4 T cells to Rag2¯¯ mice did not reconstitute the efficient CD4 T cell response as the mice could not be induced FA, while Rag2¯¯ mice received WT CD4 T cell transfer were induced FA. In conclusion, Bcl2L12 plays a crucial role in the induction of Th2 polarization and allergic response in the intestine. The Bcl2L12 in CD4 T cells may be a potential target for the treatment of FA.
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http://dx.doi.org/10.1016/j.imlet.2018.09.001DOI Listing
November 2018

Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4 T Cell Activities.

J Immunol 2018 07 8;201(2):725-733. Epub 2018 Jun 8.

Research Center of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen 518055, China;

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4 T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4 T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4 T cells from UC patients. Naive CD4 T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the promoter to enhance the expression of IL-4 in CD4 T cells. CD4 T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.
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http://dx.doi.org/10.4049/jimmunol.1800139DOI Listing
July 2018

GWAS follow-up study of esophageal squamous cell carcinoma identifies potential genetic loci associated with family history of upper gastrointestinal cancer.

Sci Rep 2017 07 5;7(1):4642. Epub 2017 Jul 5.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.

Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.
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http://dx.doi.org/10.1038/s41598-017-04822-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498542PMC
July 2017

Micro RNA-19a suppresses thrombospondin-1 in CD35 B cells in the intestine of mice with food allergy.

Am J Transl Res 2016 15;8(12):5503-5511. Epub 2016 Dec 15.

The Research Center of Allergy & Immunology, Shenzhen University School of Medicine Shenzhen 518060, China.

Disruption of immune tolerance is associated in the pathogenesis of allergy. Thrombospondin-1 (TSP1) plays a role in the maintenance of immune tolerance, which is compromised in allergic disorders. Micro RNA (miR) is involved in the regulation of immune responses. This study tests a hypothesis that miR-17-92 cluster is involved in the regulation of TSP1 in the intestinal CD35 B cells. In this study, a food allergy mouse model was developed. The intestinal B cells were isolated to be analyzed for the expression of a miR-17-92 cluster and TSP1. The role of miR-19a in the suppression of TSP1 in B cells was tested in a cell culture model. We observed that the levels of TSP1 were significantly decreased; the levels of miR-19a were significantly increased in intestinal CD35 B cells of mice sensitized to ovalbumin (OVA) as compared with naïve controls. Exposure to interleukin (IL)-4 suppressed the expression of TSP1 in B cells, which was abolished by inhibition of miR-19a. miR-19a mediated the effects of IL-4 on repressing TSP1 expression in B cells. We conclude that IL-4 suppresses the expression of TSP1 in the intestinal CD35 B cells via up regulating miR-19a. The miR-19a may be a target to regulate the immune tolerant status in the body.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209501PMC
December 2016

Induction of colitis in mice with food allergen-specific immune response.

Sci Rep 2016 09 8;6:32765. Epub 2016 Sep 8.

The Center of Allergy &Immunology, Shenzhen University School of Medicine, Shenzhen, China.

The pathogenesis of intestinal chronic inflammation is unclear. Food allergy plays an important role in the induction of intestinal inflammation. This study aims to test a hypothesis that food allergy initiates colitis. In this study, BALB/c mice were sensitized to a common food allergen, ovalbumin (OVA) with cholera toxin (CT) as an adjuvant. The colon epithelial barrier function was assessed with Ussing chamber technique. Expression of T cell immunoglobulin mucin domain molecule-4 (TIM4) in dendritic cells was evaluated by flow cytometry, RT-PCR and Western blotting. The results showed that allergen-related colitis was induced in mice as shown by heavy infiltration of inflammatory cells in the colon mucosa, loss of body weight of mice, increases in myeloperoxidase, tumor necrosis factor-α, interleukin-4, OVA-specific IgE in the colon tissue. The colon epithelial barrier function was markedly compromised in colitis group mice, which was mimicked by exposure the colon mucosa to CT in Ussing chamber. High frequency of TIM4(+) dendritic cells was detected in the colon mucosa of colitis mice. Exposure of dendritic cells to CT markedly increased the expression of TIM4. We conclude that IBD-like inflammation can be induced in the mouse colon by the food allergen-related immune response.
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http://dx.doi.org/10.1038/srep32765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015191PMC
September 2016

Specific immunotherapy ameliorates ulcerative colitis.

Allergy Asthma Clin Immunol 2016 5;12:37. Epub 2016 Aug 5.

The Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.

Background: Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients.

Methods: Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules.

Results: After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC.

Conclusions: UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.
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http://dx.doi.org/10.1186/s13223-016-0142-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975874PMC
August 2016

Alternation of circadian clock modulates forkhead box protein-3 gene transcription in CD4 T cells in the intestine.

J Allergy Clin Immunol 2016 11 8;138(5):1446-1449.e10. Epub 2016 Jun 8.

Hangzhou Zheda Dixun Biological Gene Engineering Co, LTD, Hangzhou, China. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.04.035DOI Listing
November 2016

Flagellin modulates IgE expression in B cells to initiate food allergy in mice.

Am J Transl Res 2016 15;8(6):2748-57. Epub 2016 Jun 15.

The Research Center of Allergy & Immunology, Shenzhen University School of Medicine Shenzhen 518060, China.

The initiation mechanism of IgE expression has not been fully understood. Flagellin (FGN) is an important microbial factor in the regulation of immune responses in the intestine. This study tests a hypothesis that FGN plays a crucial role in the isotype switching of IgE in B cells and the initiation of food allergy. In this study, the expression of IgE in B cells was analyzed by real time RT-PCR, Western blotting and chromatin immunoprecipitation. A mouse model was developed to assess the role of Toll like receptor-5 in the development of IgE-mediated allergic reaction in the intestinal mucosa. The results showed that exposure to FGN suppressed the expression of Bcl6 in B cells via increasing the levels of histone deacetylase (HDAC) 7; the latter up regulated the levels of methylated H3K9 and H3K27, down regulated RNA polymerase II and STAT3 (signal transducer and activator of transcription 3) at the Bcl6 promoter locus. Exposure to FGN and IL-4 markedly increased the expression of IgE in B cells via activating p300, H3K4, Pol II and STAT6 at the IgE promoter locus. As compared with the sensitized wild mice, the sensitized TLR5-deficient mice showed no detectable OVA-specific IgE in the serum; mast cells in the intestinal mucosa were not activated, no apparent allergic symptoms were evoked after the specific antigen challenge. In conclusion, FGN facilitates the initiation of food allergy in mice by triggering IgE transcription in B cells in a Th2 polarization environment via activating HDAC7 and suppressing Bcl6 expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931168PMC
July 2016

CD4+ T cell responses in Balb/c mice with food allergy induced by trinitrobenzene sulfonic acid and ovalbumin.

Mol Med Rep 2016 Jun 21;13(6):5349-57. Epub 2016 Apr 21.

Shenzhen Key Laboratory of Ear, Nose and Throat (ENT), Department of Rhinology, Institute of ENT, Longgang ENT Hospital, Shenzhen, Guangdong 518116, P.R. China.

The rapid increase in atopic diseases is potentially linked to increased hapten exposure, however, the role of haptens in the pathogenesis of food allergy remains unknown. Further studies are required to elucidate the cluster of differentiation 4 positive (CD4+) T cell response to food allergy induced by haptens. Dendritic cells were primed by trinitrobenzene sulfonic acid (TNBS) as a hapten or ovalbumin (OVA) as a model antigen, in a cell culture model. BALB/c mice were sensitized using TNBS and/or OVA. Intestinal Th1/Th2 cell and ovalbumin specific CD4+ T cells proliferation, intestinal cytokines (interleukin‑4 and interferon‑γ) in CD4+ T cells were evaluated. TNBS increased the expression of T cell immunoglobulin and mucin domain‑4 and tumor necrosis factor ligand superfamily member 4 in dendritic cells. Skewed Th2 cell polarization, extensive expression of interleukin‑4, reduced expression of interferon‑γ and forkhead box protein P3 were elicited following concomitant exposure to TNBS and OVA, with reduced regulatory T cells in the mouse intestinal mucosa, whereas a Th1 response was detected when challenged by TNBS or OVA alone. This data suggests that TNBS, as a hapten, combined with food antigens may lead to a Th2 cell response in the intestinal mucosa.
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http://dx.doi.org/10.3892/mmr.2016.5153DOI Listing
June 2016

Interleukin-13 interferes with activation-induced t-cell apoptosis by repressing p53 expression.

Cell Mol Immunol 2016 09 20;13(5):669-77. Epub 2015 Jul 20.

Shenzhen Key Laboratory of Allergy and Immunology, Shenzhen University School of Medicine and State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen, China.

The etiology and the underlying mechanism of CD4(+) T-cell polarization are unclear. This study sought to investigate the mechanism by which interleukin (IL)-13 prevents the activation-induced apoptosis of CD4(+) T cells. Here we report that CD4(+) T cells expressed IL-13 receptor α2 in the intestine of sensitized mice. IL-13 suppressed both the activation-induced apoptosis of CD4(+) T cells and the expression of p53 and FasL. Exposure to recombinant IL-13 inhibited activation-induced cell death (AICD) along with the expression of p53, caspase 3, and tumor necrosis factor-α in CD4(+) T cells. Administration of an anti-IL-13 antibody enhanced the effect of specific immunotherapy on allergic inflammation in the mouse intestine, enforced the expression of p53 in intestinal CD4(+) T cells, and enhanced the frequency of CD4(+) T-cell apoptosis upon challenge with specific antigens. In summary, blocking IL-13 enhances the therapeutic effect of antigen-specific immunotherapy by regulating apoptosis and thereby enforcing AICD in CD4(+) T cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037282PMC
http://dx.doi.org/10.1038/cmi.2015.50DOI Listing
September 2016

Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function.

Cell Mol Immunol 2016 Jan 16;13(1):110-8. Epub 2015 Feb 16.

ENT Institute, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University, Shenzhen, China.

The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 (Trek1) in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic (Clostridium butyricum) restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment.
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http://dx.doi.org/10.1038/cmi.2014.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711681PMC
January 2016

Immunosuppressive effect of compound K on islet transplantation in an STZ-induced diabetic mouse model.

Diabetes 2014 Oct 16;63(10):3458-69. Epub 2014 May 16.

Organ Transplantation Institute, Medical College, Xiamen University, Xiamen City, Fujian Province, PR China

Islet transplantation is a therapeutic option for type 1 diabetes, but its long-term success is limited by islet allograft survival. Many factors imperil islet survival, especially the adverse effects and toxicity due to clinical immunosuppressants. Compound (Cpd) K is a synthesized analog of highly unsaturated fatty acids from Isatis tinctoria L. (Cruciferae). Here we investigated the therapeutic effect of Cpd K in diabetic mice and found that it significantly prolonged islet allograft survival with minimal adverse effects after 10 days. Furthermore, it reduced the proportion of CD4(+) and CD8(+) T cells in spleen and lymph nodes, inhibited inflammatory cell infiltration in allografts, suppressed serum interleukin-2 and interferon-γ secretion, and increased transforming growth factor-β and Foxp3 mRNA expression. Surprisingly, Cpd K and rapamycin had a synergistic effect. Cpd K suppressed proliferation of naïve T cells by inducing T-cell anergy and promoting the generation of regulatory T cells. In addition, nuclear factor-κB signaling was also blocked. Taken together, these findings indicate that Cpd K may have a potential immunosuppressant effect on islet transplantation.
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http://dx.doi.org/10.2337/db14-0012DOI Listing
October 2014

Mast cell-derived serine proteinase regulates T helper 2 polarization.

Sci Rep 2014 Apr 11;4:4649. Epub 2014 Apr 11.

ENT Institute of Shenzhen University, State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.

Although mast cells play a critical role in allergic reactions, the cells are also involved in the protective immunity in the body. This study aims to investigate the role of mast cells in immune regulation during aberrant T helper (Th)2 responses. In this study, an adoptive antigen-specific Th2 response model was established with mast cell-deficient mice to test the role of mast cell in the immune regulation. Cell culture was employed to test the role of mast cells in the modulation of the expression of B cell lymphoma 6 protein (Bcl-6) in Th2 cells. The results showed that after adoptive transfer with immune cells, the mast cell-deficient mice showed stronger Th2 pattern responses in the intestine than that in the mast cell-sufficient mice. Mast cell-derived mouse mast cell protease-6 increased the expression of Bcl-6 in Th2 cells. Bcl-6 inhibited the expression of GATA-3 in Th2 cells, subsequently, forkhead box P3 was increased and the Th2 cytokines were reduced in the cells; the cells thus showed the immune regulatory properties similar to regulatory T cells. We conclude that bedsides initiating immune inflammation, mast cells also contribute to the immune regulation on Th2 polarization.
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http://dx.doi.org/10.1038/srep04649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983597PMC
April 2014

Alphavbeta6 is required in maintaining the intestinal epithelial barrier function.

Cell Biol Int 2014 Jun 21;38(6):777-81. Epub 2014 Feb 21.

Department of Gastroenterology, the Second Hospital, Zhengzhou University, Zhengzhou, China.

Epithelial barrier dysfunction is involved in a large number of diseases, but the pathogenesis is unclear. Integrin alphavbeta6 (avb6) in involved in the maintenance of the mucosal homeostasis. We have investigated the role of avb6 in maintaining the epithelial barrier function. Using T84 monolayers cultures, transepithelial electric resistance (TER) and permeability to ovalbumin (OVA) were measured as indicators of functioning. The antigenicity of OVA collected from the Transwell basal chambers was assessed using OVA-specific T cell proliferation. Knockdown of the avb6 genes increased the permeability of T84 monolayers to OVA, but did not affect TER. The deficiency of avb6-related hyperpermeability in T84 monolayers could be compensated by adding exogenous avb6 to the culture. The OVA samples collected from the basal chambers had strong antigenicity as it markedly induced the antigen specific T cell proliferation. Addition of recombinant avb6 blocked increases in permeability of T84 monolayers to OVA induced by tumor necrosis factor-α.
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http://dx.doi.org/10.1002/cbin.10258DOI Listing
June 2014

Stress-Derived Corticotropin Releasing Factor Breaches Epithelial Endotoxin Tolerance.

PLoS One 2013 19;8(6):e65760. Epub 2013 Jun 19.

Department of Gastroenterology, the Second Hospital, Zhengzhou University, Zhengzhou, China.

Background And Aims: Loss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.

Methods: Epithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.

Results: The established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.

Conclusions: Psychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686760PMC
October 2017

Overexpression of ARK5 is associated with poor prognosis in hepatocellular carcinoma.

Tumour Biol 2013 Jun 21;34(3):1913-8. Epub 2013 Mar 21.

Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, No. 2, Jingba Rd., Zhengzhou, Henan Province, 450014, China.

ARK5 overexpression has been reported in a variety of human cancers. However, the role of ARK5 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study is to analyze the ARK5 protein expression in HCC tissue samples and to assess its prognostic significance for HCC. ARK5 mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction and Western blot in 20 pairs of fresh frozen HCC tissues and corresponding non-cancerous tissues. In addition, ARK5 expression was analyzed by immunohistochemistry in 130 clinicopathologically characterized HCC cases. The correlation of ARK5 expression with patients' survival rate was assessed by Kaplan-Meier and Cox regression. Our results showed that the expression levels of ARK5 mRNA and protein in HCC tissues were both significantly higher than those in non-cancerous tissues. Our results showed that the high expression of ARK5 in HCC was related to tumor size (p=0.005), histological differentiation (p=0.047), and tumor stage (p=0.005). Kaplan-Meier survival analysis showed that a high expression level of ARK5 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that ARK5 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. In conclusion, ARK5 might play a positive role in tumor development and could serve as an independent predictor of poor prognosis for HCC.
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http://dx.doi.org/10.1007/s13277-013-0735-xDOI Listing
June 2013

Helicobacter pylori infection induced gastric cancer; advance in gastric stem cell research and the remaining challenges.

Gut Pathog 2012 Dec 8;4(1):18. Epub 2012 Dec 8.

Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, 450000, China.

Helicobacter pylori infection is the major cause of gastric cancer, which remains an important health care challenge. Recent investigation in gastric stem cell or progenitor cell biology has uncovered valuable information in understanding the gastric gland renewal and maintenance of homeostasis, they also provide clues for further defining the mechanisms by which gastric cancer may originate and progress. Lgr5, Villin-promoter, TFF2-mRNA and Mist have recently been identified as gastric stem/progenitor cell markers; their identification enriched our understanding on the gastric stem cell pathobiology during chronic inflammation and metaplasia. In addition, advance in gastric cancer stem cell markers such as CD44, CD90, CD133, Musashi-1 reveal novel information on tumor cell behavior and disease progression implicated for therapeutics. However, two critical questions remain to be of considerable challenges for future exploration; one is how H. pylori or chronic inflammation affects gastric stem cell or their progenitors, which give rise to mucus-, acid-, pepsinogen-, and hormone-secreting cell lineages. Another one is how bacterial infection or inflammation induces oncogenic transformation and propagates into tumors. Focus on the interactions of H. pylori with gastric stem/progenitor cells and their microenvironment will be instrumental to decipher the initiation and origin of gastric cancer. Future studies in these areas will be critical to uncover molecular mechanisms of chronic inflammation-mediated oncogenic transformation and provide options for cancer prevention and intervention. We review recent progress and discuss future research directions in these important research fields.
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http://dx.doi.org/10.1186/1757-4749-4-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536631PMC
December 2012

Probiotics promote endocytic allergen degradation in gut epithelial cells.

Biochem Biophys Res Commun 2012 Sep 17;426(1):135-40. Epub 2012 Aug 17.

Department of Epidemiology & Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, China.

Background And Aims: Epithelial barrier dysfunction plays a critical role in the pathogenesis of allergic diseases; the mechanism is to be further understood. The ubiquitin E3 ligase A20 (A20) plays a role in the endocytic protein degradation in the cells. This study aims to elucidate the role of A20 in the maintenance of gut epithelial barrier function.

Methods: Gut epithelial cell line, HT-29 cell, was cultured into monolayers to evaluate the barrier function in transwells. RNA interference was employed to knock down the A20 gene in HT-29 cells to test the role of A20 in the maintenance of epithelial barrier function. Probiotic derived proteins were extracted from the culture supernatants using to enhance the expression of A20 in HT-29 cells.

Results: The results showed that the knockdown of A20 compromised the epithelial barrier function in HT-29 monolayers, mainly increased the intracellular permeability. The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. Allergens collected from the transwell basal chambers of A20-deficient HT-29 monolayers still conserved functional antigenicity. Treating with probiotic derived proteins increased the expression of A20 in HT-29 cells and promote the barrier function.

Conclusion: A20 plays an important role in the maintenance of epithelial barrier function as shown by HT-29 monolayer. Probiotic derived protein increases the expression of A20 and promote the HT-29 monolayer barrier function.
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http://dx.doi.org/10.1016/j.bbrc.2012.08.051DOI Listing
September 2012

Hapten facilitates food allergen-related intestinal hypersensitivity.

Am J Med Sci 2013 May;345(5):375-9

Department of Gastroenterology, Second Hospital, Zhengzhou University, Zhengzhou, China.

Background: Haptens can bind to proteins to elicit antigenicity. Whether haptens play a role in the pathogenesis of food allergy remains to be investigated. This article aims to elucidate the role a hapten plays in food antigen-related T helper 2 (Th2) pattern inflammation in the intestine.

Methods: The effect of trinitrobenzene sulfonic acid (TNBS; as a hapten) on the properties of dendritic cells was assessed by a cell culture model. BALB/c mice were sensitized with a mixture of TNBS and ovalbumin (OVA; as a model antigen). Intestinal Th2 response, OVA-specific immunoglobulin E and histamine were analyzed with the mouse model. In addition to the infiltration of the intestinal inflammatory cells, cytokine expression profiles were determined.

Results: TNBS increased the expression of T-cell immunoglobulin and mucin domain-4 and CD80 and decreased the levels of interleukin-12 in dendritic cells. Higher serum levels of OVA-specific immunoglobulin E, histamine expression and skewed antigen-specific Th2 polarization in the intestinal tissue were detected in mice sensitized with TNBS + OVA as compared with those treated with either OVA or TNBS alone. In addition, the TNBS-OVA-treated mice also showed an increased number of inflammatory cells, high levels of interleukin-4 and a decreased expression of interferon-γ in the lamina propria mononuclear cells.

Conclusions: Hapten TNBS can facilitate the initiation of food antigen-related Th2 pattern inflammation, such as food allergy, in the intestine.
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http://dx.doi.org/10.1097/MAJ.0b013e3182571f28DOI Listing
May 2013

[Jinghuaweikang capsules combined with triple therapy in the treatment of Helicobacter pylori associated gastritis and duodenal ulcer and analysis of antibiotic resistance: a multicenter, randomized, controlled, clinical study].

Zhonghua Yi Xue Za Zhi 2012 Mar;92(10):679-84

Department of Gastroenterology, Beijing University First Hospital, Beijing 100034, China.

Objective: To explore the efficacy of Jinghuaweikang capsules plus triple therapy (LACJ) in treatment of Helicobacter pylori (H. pylori) associated gastritis or duodenal ulcer, compare it with bismuth-containing quadruple therapy (LACB) and standard triple therapy (LAC) and analyze the antibiotic sensitivity of gastric mucosal H. pylori strains from the failed patients.

Methods: A total of 565 patients with H. pylori infection were recruited from 11 hospitals from January 2010 to June 2011. There were 336 males and 229 females. They underwent gastroendoscopy examination due to upper gastrointestinal symptoms and had never received H. pylori eradication therapies. Duodenal ulcer patients were divided randomly into LACJ therapy group, LACB therapy group and LAC therapy group while gastritis patients LACJ therapy group and LACB therapy group. Group LAC received lansoprazole 30 mg + amoxicillin 1000 mg + clarithromycin 500 mg, twice a day, for 7 d (d1-7). Group LACJ: LAC therapy plus Jinghuaweikang, 3 capsules, twice a day, for 7 d (d1-7) then Jinghuaweikang, 3 capsules, twice a day, for 14 d (d8-21). Group LACB: LAC plus bismuth potassium citrate 220 mg, twice a day, for 7 d (d1-7) and then bismuth potassium citrate 220 mg, twice a day, for 14 d (d8-21). All duodenal ulcer patients received lansoprazole (30 mg, once a day) for 14 days after the first 7-day of treatment (d 8-21). At least 28 days after the end of treatment, all patients underwent (13)C urea breath test. Gastric mucosa was collected under endoscopy from the failed patients. The detection technique of gene chip was employed to detect antibiotics resistant gene from mucosa.

Results: The eradication rates of duodenal ulcer patients in groups LACJ, LACB and LAC were as follows: per-protocol (PP), 80.2% (77/96), 89.9% (89/99) and 72.2% (70/97) (P = 0.007), intention-to-treat (ITT), 78.6% (77/98), 88.1% (89/101) and 70.0% (70/100) (P = 0.007). No statistical differences existed between groups LACJ and LACB or LAC (all P > 0.05). But there were statistical differences between groups LACB and LAC (both P = 0.002). The eradication rates of PP and ITT of chronic gastritis patients in groups LACJ and LACB were as follows: 75.8% (97/128), 74.6% (97/130) vs 83.8% (109/130), 80.1% (109/136) (both P > 0.05). The symptomatic improvements of abdominal pain, burning and acid reflux of duodenal ulcer patients in group LACJ were higher than those in groups LACB and LAC. There were statistical differences between groups LACJ and LAC (all P < 0.05). The symptomatic improvements of bloating and belching for chronic gastritis patients in group LACJ were higher than those of group LACB. But no significant difference existed between two groups (all P > 0.05). Sixty samples of gastric mucosa were collected from the failed patients. The detection rates of antibiotic-resistant gene to clarithromycin and amoxicillin were 60.0% (36/36) and 18.3% (11/60) respectively.

Conclusions: The efficacy of LACJ for the treatment of H. pylori infection patients is similar to LACB and superior to LAC. And the symptomatic improvement of patients is better than the other two regimens. The main cause of treatment failure is antibiotic resistance of H. pylori strains.
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March 2012

Intestinal epithelial cell-derived integrin αβ6 plays an important role in the induction of regulatory T cells and inhibits an antigen-specific Th2 response.

J Leukoc Biol 2011 Oct 1;90(4):751-9. Epub 2011 Jul 1.

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Toleroge nic DCs and Tregs are believed to play a critical role in oral tolerance. However, the mechanisms of the generation of tolerogenic DCs and activation of Tregs in the gut remain poorly understood. This study aims to dissect the molecular mechanisms by which IECs and protein antigen induce functional tolerogenic DCs and Tregs. Expression of αvβ6 by gut epithelial cell-derived exosomes, its coupling with food antigen, and their relationship with the development of functional tolerogenic DCs and Tregs were examined by using in vitro and in vivo approaches. The results show that IECs up-regulated the integrin αvβ6 upon uptake of antigens. The epithelial cell-derived exosomes entrapped and transported αvβ6 and antigens to the extracellular environment. The uptake of antigens alone induced DCs to produce LTGFβ, whereas exosomes carrying αvβ6/antigen resulted in the production of abundant, active TGF-β in DCs that conferred to DCs the tolerogenic properties. Furthermore, αvβ6/OVA-carrying, exosome-primed DCs were found to promote the production of active TGF-β in Tregs. Thus, in vivo administration of αvβ6/OVA-laden exosomes induced the generation of Tregs and suppressed skewed Th2 responses toward food antigen in the intestine. Our study provides important molecular insights into the molecular mechanisms of Treg development by demonstrating an important role of IEC-derived exosomes carrying αvβ6 and food antigen in the induction of tolerogenic DCs and antigen-specific Tregs.
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http://dx.doi.org/10.1189/jlb.1210696DOI Listing
October 2011