Publications by authors named "Ailin Tao"

42 Publications

Anti-DLL4 ameliorates toluene diisocyanate-induced experimental asthma by inhibiting Th17 response.

Int Immunopharmacol 2021 May 9;94:107444. Epub 2021 Feb 9.

The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 510260, China. Electronic address:

Toluene diisocyanate (TDI) exhibits an ability to induce steroid insensitive asthma with the involvement of Th17 cells. And emerging evidence has indicated that DLL4 signaling promotes Th17 differentiation through directly upregulating Rorc and IL-17 transcription. Thus, we sought to evaluate the effects of DLL4 blocking antibody on TDI-induced asthma model. Female BALB/c mice were sensitized and challenged with TDI to generate an asthma model. TDI-exposed mice were intraperitoneally injected with anti-DLL4 antibody and then analyzed for various parameters of the airway inflammatory responses. Increased expression of DLL4 in spleen and lung was detected in TDI-exposed mice. Furthermore, anti-DLL4 treatment alleviated TDI-induced airway hyperreactivity (AHR), airway inflammation, airway epithelial injury and airway smooth muscle (ASM) thickening. In the meantime, neutralizing DLL4 also blunted Th17 response via downregulation of ROR-γt expression, while had no effect on Th2 cells and regulatory T (Treg) cells. Overall, anti-DLL4 ameliorated TDI-induced experimental asthma by inhibiting Th17 response, implying the feasibility of targeting DLL4 for therapy of Th17-predominant severe asthma.
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http://dx.doi.org/10.1016/j.intimp.2021.107444DOI Listing
May 2021

China Consensus Document on Allergy Diagnostics.

Allergy Asthma Immunol Res 2021 Mar;13(2):177-205

Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

The prevalence of allergic diseases has increased dramatically in recent years in China, affecting the quality of life in 40% of the population. The identification of allergens is the key to the diagnosis of allergic diseases. Presently, several methods of allergy diagnostics are available in China, but they have not been standardized. Additionally, cross-sensitization and co-sensitization make allergy diagnostics even more complicated. Based on 4 aspects of allergic disease (mechanism, diagnosis procedures, allergen detection and as well as the distribution map of the most important airborne allergens in China) and by referring to the consensus of the European Society of Allergy and Clinical Immunology, the World Allergy Organization, and the important literature on allergy diagnostics in China in recent years, we drafted this consensus of allergy diagnostics with Chinese characteristics. It aims to standardize the diagnostic methods of allergens and provides a reference for health care givers. The current document was prepared by a panel of experts from the main stream of professional allergy associations in China.
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http://dx.doi.org/10.4168/aair.2021.13.2.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840865PMC
March 2021

Altered regulation of LncRNA analysis of human alcoholic hepatitis with Mallory-Denk Bodies (MDBs) is revealed by RNA sequencing.

Exp Mol Pathol 2020 12 27;117:104559. Epub 2020 Oct 27.

The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 510182, China; The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Electronic address:

Mallory-Denk Bodies (MDBs) are prevalent in a variety of liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Long noncoding RNAs (lncRNAs) are considered as emerging new gene regulators, which participates in many functional activities through diverse mechanisms. We previously reported the mechanisms involved in the formation of liver MDBs in mouse model and in AH livers where MDBs had formed. To investigate the regulation of mRNAs expression and the probable role of lncRNAs in AH livers with MDBs, RNA-Seq analyses was further conducted to determine the mRNA and lncRNA expression profiles of the AH livers compared with the normal livers. It showed that different lncRNAs have different information contribution degrees by principal component analysis, and the integrated analysis of lncRNA-mRNA co-expression networks were linked to endocytosis, cell cycle, p53 signaling pathways in the human. Based on the co-expression networks, we identify 36 mRNAs that could be as potential biomarkers of alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). To our knowledge, this is the first report on the regulatory network of lncRNAs associated with liver MDB formation in human, and these results might offer new insights into the molecular mechanisms of liver MDB formation and the progression of AH to HCC.
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http://dx.doi.org/10.1016/j.yexmp.2020.104559DOI Listing
December 2020

Fibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability.

Cell Mol Gastroenterol Hepatol 2021 17;11(3):683-696. Epub 2020 Oct 17.

State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address:

Background & Aims: Increased vascular permeability (VP) has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). However, the pathological causes of increased intestinal VP in IBD remain largely unknown.

Method: Fibrinogen level was measured in dextran sulphate sodium (DSS)-induced colitis and patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, was used to detect the effect of Fg inhibition on the pathogenesis of DSS-induced colitis, as indicated by tissue damage, cytokine release and inflammatory cell infiltration. Miles assay was used to detect vascular permeability.

Results: Through tandem mass tag-based quantitative proteomics, fibrinogen (Fg) was found to be upregulated in the colon of DSS-treated mice, which was consistent with increased Fg level in colon sample of patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, significantly alleviated DSS-induced colitis as indicated by improvement of body weight loss and mortality. GPRP decreased colonic inflammation and VP in DSS-treated mice. In vivo, Fg enhanced VP as indicated by Miles assay, which was significantly inhibited by GRPR, AKT (serine/threonine kinase 1) inhibitors and low doses of Jasplakinolide which induced actin polymerization, while was dramatically enhanced by Cytochalasin D (an actin polymerization inhibitor). Moreover, activation of AKT was found in vessels of DSS-treated mice. In vitro, Fg induced activation of AKT and depolymerization of microfilament and promoted cell-to-cell disaggregation. Furthermore, inhibition of AKT decreased Fg-induced microfilament depolymerization.

Conclusions: Our findings highlight the importance of Fg in regulating colitis by modulation of VP via activating AKT and subsequent depolymerization of microfilament and suggest Fg as an attractive target for anti-colitis treatment.
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http://dx.doi.org/10.1016/j.jcmgh.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843406PMC
October 2020

GRPR/Extracellular Signal-Regulated Kinase and NPRA/Extracellular Signal-Regulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch.

J Invest Dermatol 2021 Apr 9;141(4):863-873. Epub 2020 Oct 9.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Center for Immunology, Inflammation, & Immune-Mediated Disease, Guangzhou Medical University, Guangzhou, China. Electronic address:

Intractable or recurrent chronic itch greatly reduces the patients' QOL and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal-regulated kinase (ERK) 1/2 cascade is the most significantly upregulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MAPK/ERK kinase inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK was observed in the interneurons expressing the receptors of different neuropeptides for itch, including gastrin-releasing peptide receptor, natriuretic peptide receptor A, neuromedin B receptor, and sst2A. Blocking gastrin-releasing peptide receptor and natriuretic peptide receptor A by genetic approaches or toxins in mice significantly attenuated or ablated spinal phosphorylated ERK. When human embryonic kidney 293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that phosphorylated ERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.
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http://dx.doi.org/10.1016/j.jid.2020.09.008DOI Listing
April 2021

Pyridoxine induces monocyte-macrophages death as specific treatment of acute myeloid leukemia.

Cancer Lett 2020 11 26;492:96-105. Epub 2020 Aug 26.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, 510260, PR China. Electronic address:

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that gradually develops resistance to current chemotherapy treatments. The available chemotherapy drugs show serious non-specific cytotoxicity to healthy normal cells, resulting in relapse and low survival rates. Natural small molecules with less toxicity and high selectivity for AML are urgently needed. In this study, we confirmed that pyridoxine (vitamin B6) selectively induces monocyte macrophages to undergo programmed cell death in two different modes: caspase-3-dependent apoptosis in U937 cells or GSDME-mediated pyroptosis in THP-1 cells. Further molecular analysis indicated that blocking the caspase pathway could switch the death to MLKL-dependent necroptosis and subsequent extensive inflammatory response. Pyridoxine also delayed the disease progression in a THP-1 leukemia mouse model. In addition, it induced the death of primary AML cells from AML patients by activating caspase-8/3. Overall, our results identify pyridoxine, a low-toxicity natural small molecule, as a potential therapeutic drug for AML treatment.
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http://dx.doi.org/10.1016/j.canlet.2020.08.018DOI Listing
November 2020

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model.

Allergy Asthma Immunol Res 2020 Jul;12(4):608-625

The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.

Purpose: Accumulating evidence has suggested that toll-like receptor 4 (TLR4) is critically involved in the pathogenesis of asthma. The aim of this study was to investigate the role of TLR4 in toluene diisocyanate (TDI)-induced allergic airway inflammation.

Methods: TLR4 and wild-type (WT) C57BL/10J mice were sensitized and challenged with TDI to generate a TDI-induced asthma model. B-cell lymphoma 2 (Bcl-2) inhibitors, ABT-199 (4 mg/kg) and ABT-737 (4 mg/kg), were intranasally given to TDI-exposed TLR4 mice after each challenge.

Results: TDI exposure led to increased airway hyperresponsiveness (AHR), granulocyte flux, bronchial epithelial shedding and extensive submucosal collagen deposition, which were unexpectedly aggravated by TLR4 deficiency. Following TDI challenge, TLR4 mice exhibited down-regulated interleukin-17A and increased colony-stimulating factor 3 in bronchoalveolar lavage fluid (BALF), while WT mice did not. In addition, TLR4 deficiency robustly suppressed the expression of NOD-like receptor family pyrin domain containing 3 and NLR family CARD domain containing 4, decreased caspase-1 activity in TDI-exposed mice, but had no effect on the level of high mobility group box 1 in BALF. Flow cytometry revealed that TDI hampered both neutrophil and eosinophil apoptosis, of which neutrophil apoptosis was further inhibited in TDI-exposed TLR4 mice, with marked up-regulation of Bcl-2. Moreover, inhibition of Bcl-2 with either ABT-199 or ABT-737 significantly alleviated neutrophil recruitment by promoting apoptosis.

Conclusions: These data indicated that TLR4 deficiency promoted neutrophil infiltration by impairing its apoptosis via up-regulation of Bcl-2, thereby resulting in deteriorated AHR and airway inflammation, which suggests that TLR4 could be a negative regulator of TDI-induced neutrophilic inflammation.
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http://dx.doi.org/10.4168/aair.2020.12.4.608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225000PMC
July 2020

Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors.

Nat Commun 2020 03 13;11(1):1397. Epub 2020 Mar 13.

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.
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http://dx.doi.org/10.1038/s41467-020-15230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070094PMC
March 2020

Key genes and co-expression modules involved in asthma pathogenesis.

PeerJ 2020 3;8:e8456. Epub 2020 Feb 3.

The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Machine learning and weighted gene co-expression network analysis (WGCNA) have been widely used due to its well-known accuracy in the biological field. However, due to the nature of a gene's multiple functions, it is challenging to locate the exact genes involved in complex diseases such as asthma. In this study, we combined machine learning and WGCNA in order to analyze the gene expression data of asthma for better understanding of associated pathogenesis. Specifically, the role of machine learning is assigned to screen out the key genes in the asthma development, while the role of WGCNA is to set up gene co-expression network. Our results indicated that hormone secretion regulation, airway remodeling, and negative immune regulation, were all regulated by critical gene modules associated with pathogenesis of asthma progression. Overall, the method employed in this study helped identify key genes in asthma and their roles in the asthma pathogenesis.
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http://dx.doi.org/10.7717/peerj.8456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003696PMC
February 2020

Spinal GRPR and NPRA Contribute to Chronic Itch in a Murine Model of Allergic Contact Dermatitis.

J Invest Dermatol 2020 09 5;140(9):1856-1866.e7. Epub 2020 Feb 5.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Center for Immunology, Inflammation, and Immune-mediated disease, Guangzhou Medical University, Guangzhou, China. Electronic address:

Recurrent and intractable chronic itch is a worldwide problem, but mechanisms, especially the neural mechanisms, underlying chronic itch still remain unclear. In this study, we investigated the peripheral and spinal mechanisms responsible for prolonged itch in a mouse model of allergic contact dermatitis induced by squaric acid dibutylester. We found that repeated exposure of mice to squaric acid dibutylester evoked persistent spontaneous scratching and significantly aberrant cutaneous and systemic immune responses lasting for weeks. Squaric acid dibutylester-induced itch requires both nonhistaminergic and histaminergic pathways, which are likely relayed by GRPR and NPRA in the spinal cord, respectively. Employing genetic, pharmacologic, RNAscope assay, and cell-specific ablation methods, we dissected a neural circuit for prolonged itch formed as Grpr neurons act downstream of Npr1 neurons in the spinal cord. Taken together, our data suggested that targeting GRPR and NPRA may provide effective treatments for allergic contact dermatitis-associated chronic pruritus.
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http://dx.doi.org/10.1016/j.jid.2020.01.016DOI Listing
September 2020

Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses.

Elife 2020 02 4;9. Epub 2020 Feb 4.

Department of Medicine, University of California San Diego, San Diego, United States.

Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.
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http://dx.doi.org/10.7554/eLife.49416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000221PMC
February 2020

Changes of CD103-expressing pulmonary CD4 and CD8 T cells in S. japonicum infected C57BL/6 mice.

BMC Infect Dis 2019 Nov 27;19(1):999. Epub 2019 Nov 27.

Sino-French Hoffmann Institute, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.

Background: Recent studies have shown that CD103 is an important marker for tissue-resident memory T cells (TRM) which plays an important role in anti-infection. However, the role of CD103 TRM was not elucidated in the progress of S. japonicum infection induced disease.

Methods: 6-8 weeks old C57BL/6 mice were infected by S. japonicum. Mice were sacrificed and the lungs were removed 5-6 weeks after infection. Immunofluorescent staining and Q-PCR were performed to identify the expression of CD103 molecule. Single cellular populations were made, percentages of CD103 on both CD4 and CD8 T lymphocytes were dynamical observed by flow cytometry (FCM). Moreover, the expression of memory T cells related molecules CD69 and CD62L, T cell function associated molecules CD107a, IFN-γ, IL-4, IL-9, and IL-10 were compared between CD103 CD4 and CD8 T cells by FCM.

Results: CD103 cells were emerged in the lung of both naive and S. japonicum infected mice. Both the percentage and the absolute numbers of pulmonary CD4 and CD8 cells were increased after S. japonicum infection (P < 0.05). The percentage of CD103 cells in CD8 T cells decreased significantly at the early stage of S. japonicum infection (P < 0.05). Increased CD69, decreased CD62L and CD107a expressions were detected on both CD4 and CD8 CD103 T cells in the lungs of infected mice (P < 0.05). Compared to CD8 CD103 T cells, CD4 CD103 T cells from infected mice expressed higher level of CD69 and lower level CD62L molecules (P < 0.05). Moreover, higher percentage of IL-4, IL-9 and IL-10 cells on CD4 CD103 pulmonary T cells was found in infected mice (P < 0.05). Significantly increased IL-4 and IL-9, and decreased IFN-γ expressing cells were detected in CD8CD103 cells of infected mice (P < 0.05).

Conclusions: CD103-expressing pulmonary CD4 and CD8 T cells play important roles in mediating S. japonicum infection induced granulomatous inflammation in the lung.
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http://dx.doi.org/10.1186/s12879-019-4633-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880605PMC
November 2019

Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model.

Int Immunopharmacol 2019 Sep 11;74:105646. Epub 2019 Jun 11.

Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address:

Background: Maintaining an airway clear of bacteria, foreign particles and apoptotic cells by alveolar macrophages is very essential for lung homeostasis. In asthma, the phagocytic capacity of alveolar macrophages is significantly reduced, which is thought to be associated with increased oxidative stress. Hydrogen (H) has been shown to exert potent antioxidant and anti-inflammatory effects, yet its effects on phagocytosis of alveolar macrophages are unknown. This study is aimed to evaluate the beneficial effects of hydrogen gas inhalation on alveolar macrophage phagocytosis in an ovalbumin (OVA)-induced murine asthma model.

Methods: Female C57BL/6 mice were intraperitoneally sensitized with OVA before they were subject to airway challenge with aerosolized OVA. Hydrogen gas was delivered to the mice through inhalation twice a day (2 h once) for 7 consecutive days. Phagocytic function of alveolar macrophages isolated from bronchoalveolar lavage fluid was assessed by fluorescence-labeled Escherichia coli as well as flow cytometry.

Results: Alveolar macrophages isolated from OVA-induced asthmatic mice showed decreased phagocytic capacity to Escherichia coli when compared with those of control mice. Defective phagocytosis in asthmatic mice was reversed by hydrogen gas inhalation. Hydrogen gas inhalation significantly alleviated OVA-induced airway hyperresponsiveness, inflammation and goblet cell hyperplasia, diminished T2 response and decreased IL-4 as well as IgE levels, reduced malondialdehyde (MDA) production and increased superoxide dismutase (SOD) activity. Concomitantly, hydrogen gas inhalation inhibited NF-κB activation and markedly activated Nrf2 pathway in OVA-induced asthmatic mice.

Conclusions: Our findings demonstrated that hydrogen gas inhalation enhanced alveolar macrophage phagocytosis in OVA-induced asthmatic mice, which may be associated with the antioxidant effects of hydrogen gas and the activation of the Nrf2 pathway.
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http://dx.doi.org/10.1016/j.intimp.2019.05.031DOI Listing
September 2019

Heterotypic cell-in-cell structures in colon cancer can be regulated by IL-6 and lead to tumor immune escape.

Exp Cell Res 2019 09 28;382(1):111447. Epub 2019 May 28.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Center for Inflammation, Immunology, & Immune-mediated disease, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address:

Heterotypic CICs (cell-in-cell structures) have been found between tumor cells and various immune cells in a variety of cancer tissues. The frequency of CICs has been found to correlate with tumor malignancy in some studies but not in others. Herein, we examined in depth the CICs observed in colon cancer to determine their potential significance in disease progression. Heterotypic CICs were observed by histochemistry between epithelial cells and lymphocytes in an expanded spectrum of colon tissue from colitis to cancer and in vitro studies were performed using the colonic tumor cell line HCT8 and human peripheral blood lymphocytes. Our data revealed that the CICs formed by colonic epithelial cells and infiltrated lymphocytes not only positively correlated with tumor malignancy but also were upregulated by the inflammatory cytokine IL-6. In addition, we observed that colon cancer cells could initiate autophagy for survival after cytotoxic lymphocyte internalization and that IL-6 could also be involved in this process to promote the death of lymphocytes in CIC structures. Furthermore, certain changes were observed in tumor cells after experiencing CICs. Our findings suggest that CICs formed by colon cancer cells and lymphocytes contribute to tumor escape from immune surveillance, which could be facilitated by IL-6, and might represent a previously undescribed pathway for tumor cells to adapt and evade host immune defense.
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http://dx.doi.org/10.1016/j.yexcr.2019.05.028DOI Listing
September 2019

CXCL13/CXCR5 signaling contributes to diabetes-induced tactile allodynia via activating pERK, pSTAT3, pAKT pathways and pro-inflammatory cytokines production in the spinal cord of male mice.

Brain Behav Immun 2019 08 14;80:711-724. Epub 2019 May 14.

School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China. Electronic address:

Painful diabetic neuropathy (PDN) is a severely debilitating chronic pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of chronic pain induced by peripheral tissue inflammation or nerve injury. In this study we investigated whether CXCL13/CXCR5 mediates PDN and the underlying spinal mechanisms. We used the db/db type 2 diabetes mice, which showed obvious hyperglycemia and obese, long-term mechanical allodynia, and increased expression of CXCL13, CXCR5 as well as pro-inflammatory cytokines TNF-α and IL-6 in the spinal cord. Furthermore, in the spinal cord of db/db mice there is significantly increased gliosis and upregulated phosphorylation of cell signaling kinases, including pERK, pAKT and pSTAT3. Mechanical allodynia and upregulated pERK, pAKT and pSTAT3 as well as production of TNF-α and IL-6 were all attenuated by the noncompetitive NMDA receptor antagonist MK-801. If spinal giving U0126 (a selective MEK inhibitor) or AG490 (a Janus kinase (JAK)-STAT inhibitor) to db/db mice, both of them can decrease the mechanical allodynia, but only inhibit pERK (by U0126) or pSTAT3 (by AG490) respectively. Acute administration of CXCL13 in C57BL/6J mice resulted in exacerbated thermal hyperalgesia and mechanical allodynia, activation of the pERK, pAKT and pSTAT3 pathways and increased production of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), which were all attenuated by knocking out of Cxcr5. In all, our work showed that chemokine CXCL13 and its receptor CXCR5 in spinal cord contribute to the pathogenesis of PDN and may help develop potential novel therapeutic approaches for patients afflicted with PDN.
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http://dx.doi.org/10.1016/j.bbi.2019.05.020DOI Listing
August 2019

Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model.

Toxicol Sci 2019 08;170(2):462-475

The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou 510260, China.

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1β signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1β. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1β, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.
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http://dx.doi.org/10.1093/toxsci/kfz099DOI Listing
August 2019

Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells.

Cell Death Dis 2019 04 24;10(5):344. Epub 2019 Apr 24.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, 510260, Guangzhou, China.

Necroptosis of intestinal epithelial cells has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). The identification of dysregulated proteins that can regulate necroptosis in dextran sulfate sodium (DSS)-induced colitis is the key to the rational design of therapeutic strategies for colitis. Through tandem mass tag (TMT)-based quantitative proteomics, HtrA2 was found to be downregulated in the colon of DSS-treated mice. UCF-101, a specific serine protease inhibitor of HtrA2, significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss and decreased mortality. UCF-101 decreased DSS-induced colonic inflammation, prevented intestinal barrier function loss and inhibited necroptosis of intestinal epithelial cells. In vitro, UCF-101 or silencing of HtrA2 decreased necroptosis of HT-29 and L929 cells. UCF-101 decreased phosphorylation of RIPK1 and subsequent phosphorylation of RIPK3 and MLKL during necroptosis. Upon necroptotic stimulation, HtrA2 translocated from mitochondria to cytosol. HtrA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of necroptosis. Our findings highlight the importance of HtrA2 in regulating colitis by modulation of necroptosis and suggest HtrA2 as an attractive target for anti-colitis treatment.
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http://dx.doi.org/10.1038/s41419-019-1580-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482197PMC
April 2019

Curcumin-Silk Fibroin Nanoparticles for Enhanced Anti- Activity and .

J Biomed Nanotechnol 2019 Apr;15(4):769-778

Curcumin (CM) has multiple pharmacological activities including anti-fungal activity, but its clinical application is limited due to low solubility in aqueous media, poor bioavailability and extensive first pass metabolism. We aimed to resolve the limitation and enhance antifungal activity of CM using nanotechnology. Using silk fibroin (SF) as a carrier, we fabricated curcumin-silk fibroin nanoparticles (CM-SF NPs) by solution enhanced dispersion of supercritical CO₂ (SEDS) technique. The characterization of CM-SF NPs was analyzed using scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC) and thermo gravimetric apparatus (TGA). Following characterization of the NPs, we evaluated the antifungal activity of CM-SF NPs against Candida albicans and . A SF-based drug delivery system (CM-SF NPs, 85 ± 15 nm) was established by SEDS. Compared to original CM, water solubility of CM-SF NPs was improved, and its antifungal activity was enhanced. The natural compound-loaded SF nanoparticles may be a promising therapeutic candidate for fungal infection.
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http://dx.doi.org/10.1166/jbn.2019.2722DOI Listing
April 2019

Dust mite-derived Der f 3 activates a pro-inflammatory program in airway epithelial cells via PAR-1 and PAR-2.

Mol Immunol 2019 05 2;109:1-11. Epub 2019 Mar 2.

State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, China; Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, China. Electronic address:

Protease activity of allergens has been suggested to be involved in the pathogenesis of allergic diseases. The major allergen Der f 3 from Dermatophagoides farinae harbors serine protease activity, but its immunopathogenesis remains unclear. This study aims to explore the effect of Der f 3 on the airway epithelial barrier and on the molecular pathways by which Der f 3 induces inflammation. RNA-seq was performed to identify differentially expressed genes in bronchial airway epithelial cells (AEC) between native Der f 3 and heat-inactivated (H) Der f 3, coupled with real-time PCR (RT-PCR) and ELISA for validation. Unlike other protease allergens such as that induce Th2-promoting alarmins (IL-25, IL-33, TSLP) in AECs, Der f 3 induced pro-inflammatory cytokines and chemokines including IL-6, IL-8 and GM-CSF, which are known to promote Th17 response. These pro-inflammatory mediators were induced by Der f 3 via the MAPK and NF-κB pathways as well as the store-operated calcium signaling. Gene silencing with small interfering RNA in A549 and BEAS-2B cells indicated that activation of AECs by Der f 3 was mainly dependent on protease-activated receptor 2 (PAR-2), while PAR-1 was also required for the full activation of AECs. Double knock-down of PAR-1 and PAR-2 largely impaired Der f 3-inducecd IL-8 production and subsequent signaling pathways. Our data suggest that Der f 3 induces pro-inflammatory mediators in human epithelial cell lines via the PARs-MAPK-NF-κB axis. Our results provide a molecular mechanism by which Der f 3 may trigger the Th17-skewed allergic response toward house dust mites.
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http://dx.doi.org/10.1016/j.molimm.2019.02.018DOI Listing
May 2019

GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.

Gastroenterology 2019 06 2;156(8):2297-2312. Epub 2019 Mar 2.

Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.

Background & Aims: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans.

Methods: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses.

Results: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4 DCs and MDSCs; and decreased numbers of CD8 DCs. IL6 was mainly produced by CD4/CD11b, but not CD8, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival.

Conclusions: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c cells and IL6 in CD4/CD11b DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.
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http://dx.doi.org/10.1053/j.gastro.2019.02.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628260PMC
June 2019

Synergistic activation of Src, ERK and STAT pathways in PBMCs for Staphylococcal enterotoxin A induced production of cytokines and chemokines.

Asian Pac J Allergy Immunol 2020 Mar;38(1):52-63

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Sino-French Hoffmann Institute, Center for Immunology, Inflammation, & Immune-mediated disease, Guangzhou Medical University, Guangzhou 510260, China.

Background: Staphylococcal enterotoxin A (SEA) is a well-known superantigen and stimulates human peripheral blood mononuclear cells (PBMCs) involving in the pathogenesis of inflammatory disorders and cancer.

Objective: To better understand the biological activities of SEA and the possible intracellular mechanisms by which SEA plays its roles in conditions like staphylococcal inflammatory and/or autoimmune disorders and immunotherapy.

Methods: Recombinant SEA (rSEA) was expressed in a prokaryotic expression system and its effects on the cytokine and chemokine production was examined by Enzyme-linked Immunospot (ELISpot) Assay and ELISA analysis.

Results: In vitro experiments showed rSEA could significantly enhance secretion of a broad spectrum of cytokines and chemokines from PBMCs dose-dependently. Increased secretion of cytokines and chemokines from rSEA stimulated PBMCs was barely affected by C-C motif chemokine receptor 2 (CCR2) antagonist INCB3344. However, Src, ERK and STAT pathway inhibitors were able to successfully block the enhanced secretion of most of cytokines and chemokines produced by rSEA stimulated PBMCs.

Conclusions: Our work suggested that rSEA serves as a potent stimulant of PBMCs, and induces the release of cytokines and chemokines through Src, ERK and STAT pathways upon a relatively independent network. Our work also strongly supported that Src, ERK and STAT signaling inhibitors could be effective therapeutic agents against diseases like toxic shock syndrome or infection by microbes resistant to antibiotics.
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http://dx.doi.org/10.12932/AP-220818-0396DOI Listing
March 2020

IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model.

Eur Respir J 2019 04 4;53(4). Epub 2019 Apr 4.

State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic.We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F.Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies.IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.
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http://dx.doi.org/10.1183/13993003.01510-2018DOI Listing
April 2019

Transient Receptor Potential Ion Channels Mediate Adherens Junctions Dysfunction in a Toluene Diisocyanate-Induced Murine Asthma Model.

Toxicol Sci 2019 03;168(1):160-170

State Key Laboratory of Respiratory Diseases, Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510180, China.

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.
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http://dx.doi.org/10.1093/toxsci/kfy285DOI Listing
March 2019

Activation profile of THP-1 derived dendritic cells stimulated by allergen Mal f 1 beyond its IgE-binding ability.

Int Immunopharmacol 2018 Sep 10;62:139-146. Epub 2018 Jul 10.

Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China. Electronic address:

Background: Mal f 1, the first allergen cloned from Malassezia furfur, has positive IgE reactivity in sera from atopic dermatitis (AD) patients. The mechanism by which Mal f 1 induces the maturation of human dendritic cells (DCs) and maintains the symptoms of AD is not well understood.

Objective: The present study aims to explore the activation profile of THP-1 derived dendritic cells (TDDCs) stimulated by recombinant Mal f 1, as well as to explore the IgE-binding ability of rMal f 1 and its correlation with IgE-binding activity of complete allergens of M. furfur.

Methods: rMal f 1 was produced by expression in E. coli and purification with affinity chromatography. The ability of rMal f 1 and ImmunoCAP complete allergens of M. furfur to bind to serum specific IgE was assayed in parallel by ELISA and immunoblotting. Immature TDDCs were stimulated with rMal f 1 or an enzyme-digested product of rMal f 1. The expression levels of markers, CD83, CD80, CD86, and HLA-DR, were investigated by flow cytometry. The levels of interleukin (IL)-6, IL-10, IL-12p70 and tumor necrosis factor (TNF)-α in culture supernatants were determined by ELISA.

Results: Eighteen patient sera were identified that reacted positively to the complete allergens of M. furfur as determined by ImmunoCAP and also showed positive responses to rMal f 1. Five patient sera were identified that had no reaction to ImmunoCAP complete allergens of M. furfur and also exhibited negative response to rMal f 1. All sera, except for one, had no reaction to the unrelated allergen Bet v 1. rMal f 1 upregulated the maturation surface marker CD83 on TDDCs. In addition, rMal f 1 also induced high levels of CD80 and CD86. Increased expression of HLA-DR, a first signal for T cell activation, was observed. Secretion of IL-6, TNF-α and IL-10 by TDDCs increased significantly (P < 0.0001 for IL-6, P < 0.01 for TNF-α and P < 0.05 for IL-10) after stimulation by rMal f 1, while the IL-12p70 level was unaltered.

Conclusion: We have shown that rMal f 1 has ideal IgE binding ability and good correlation with binding activity to M. furfur. Moreover, we have revealed a hitherto unknown DC activation profile after rMal f 1 stimulation whereby TNF-α, IL-6, and IL-10 were significantly increased and IL-12 was unaltered, suggesting that rMal f 1 can predispose a DC bias toward the T22/T17 pathway beyond the routine IgE-dependent T2 pathway, thus providing intriguing clues for clinical treatment involving both pathways.
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http://dx.doi.org/10.1016/j.intimp.2018.05.013DOI Listing
September 2018

The Pharmacogenomics of Asthma Beyond its Endotypes.

Curr Drug Metab 2018 ;19(14):1206-1212

The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510260, China.

Background: While endotype-driven therapeutic strategies are increasingly successful for asthma, the issues of dissociated effect and drug efficacy at the target sites remain unresolved. This review is to provide a comprehensive overview of the pharmacogenomics of asthma along with its endotype subsets.

Methods: We undertook a search in NCBI All Databases by key words "pharmacogenomics AND allergen", "pharmacogenomics AND asthma AND rhinitis", etc. The remaining papers were reviewed without bias after the exclusion of redundant papers and non-English papers (except for Chinese papers). Papers regarding similar issues or items were then pooled together to support the corresponding viewpoints and subtitles, conclusions were thus drawn.

Result: Eighty of the retrieved 139 papers were included in the review. Immunopathogenesis of asthma found that the induction of asthma involves genetic variation, TLR gene-activated immune responses, cell-mediated inflammation, and other immunological changes. Human lung mast cell has a crucial effect on the symptoms of asthma. JAK-3 mediates cytokine signaling, while DNA methylation in the ADRB2 gene decreases asthma symptom severity. Pharmacotherapeutics of asthma has focused on fewer candidate genes, relating to glucocorticoid, leukotriene, and β2-adrenergic receptor pathways, and other pathways involving IgE, IL-5, IL-4, IL-13 and IL-17.

Conclusion: The genetic profiles of gene variants can predict individual disease susceptibility and risk for disease progression. Fewer genes, relating to glucocorticoid, leukotriene, histamine, and β2-adrenergic receptor pathways, have been concentrated. A personalized, tailored approach is necessary for health care delivery according to the individual variability in genes, environment and lifestyle of each individual.
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http://dx.doi.org/10.2174/1389200219666180628170113DOI Listing
April 2019

A Quantitative Method for Detecting Ara h 2 by Generation and Utilization of Monoclonal Antibodies.

J Immunol Res 2018 6;2018:4894705. Epub 2018 May 6.

The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China.

Peanut () is one of the most common food allergens that can induce fatal anaphylaxis, and Ara h 2 is one of the major allergen components involved in peanut allergy. The aim of this study was to develop a quantitative method for detecting peanut allergen using monoclonal antibodies against Ara h 2. The splenocytes of immunized mice were fused with myeloma cells (SP2/0), and stable mAb-producing clones were obtained by limiting dilution. mAbs against Ara h 2 were isolated from mouse ascites, and specificity was confirmed by immunoblotting. Five mAbs with high purity and specific reactivity were obtained, which were referred to as 1-2E10, 2-1D5, 3-1C5, 4-1C2, and 5-1G4, respectively. After screening different mAb combinations for development of a sandwich ELISA, we selected 5-1G4 as the capture antibody and 1-2E10 as the detection antibody for the measurement of Ara h 2 from which an optimal correlation between the Ara h 2 concentration and the OD value was obtained. This sandwich ELISA could specifically detect Ara h 2 in peanut extract at concentrations as low as 5 ng/mL and up to 10 g/mL. These mAbs can, therefore, serve as quantitative diagnostic reagents for peanut and peanut product risk assessment.
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http://dx.doi.org/10.1155/2018/4894705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960532PMC
October 2018

Construction, Expression, and Characterization of rSEA-EGF and In Vitro Evaluation of its Antitumor Activity Against Nasopharyngeal Cancer.

Technol Cancer Res Treat 2018 01;17:1533033818762910

1 The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University.

Staphylococcal enterotoxin A is well known as a superantigen and able to be used for cancer immunotherapy. In this study, recombinant Staphylococcal enterotoxin A was genetically conjugated to epidermal growth factor to produce a chimeric protein recombinant Staphylococcal enterotoxin A-epidermal growth factor expressed in Escherichia coli. The recombinant Staphylococcal enterotoxin A-epidermal growth factor protein was purified using Strep-Tactin affinity chromatography and Endotoxin Removal Resin and identified by sodium dodecyl sulfate-polyacrylamide gel electropheresis and liquid chromatography-tandem mass spectrometry analysis. Furthermore, in vitro experiments showed purified recombinant Staphylococcal enterotoxin A-epidermal growth factor could successfully bind to the human nasopharyngeal carcinoma cell line CNE2, significantly promote the proliferation of human peripheral blood mononuclear cells, and enhance the secretion of several cytokines that have broad antitumor activities, such as interferon-γ, tumor necrosis factor-α, and interleukin-2 . Importantly, recombinant Staphylococcal enterotoxin A-epidermal growth factor significantly inhibited proliferation of CNE2 cells and promoted apoptosis in CNE2 cells when cocultured with peripheral blood mononuclear cells. Finally, both the binding of recombinant Staphylococcal enterotoxin A-epidermal growth factor and the toxicity of recombinant Staphylococcal enterotoxin A-epidermal growth factor-activated peripheral blood mononuclear cells were demonstrated as specific and only effective on high epidermal growth factor receptor-expressing cell lines. In all, our work suggests that recombinant Staphylococcal enterotoxin A-epidermal growth factor serves as a promising novel immunotherapeutic agent. More in vivo and in vitro studies are needed to verify its antitumor potency, as well as investigate the underlying mechanisms in cancer immunotherapy.
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http://dx.doi.org/10.1177/1533033818762910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862366PMC
January 2018

Distinct roles of NMB and GRP in itch transmission.

Sci Rep 2017 11 13;7(1):15466. Epub 2017 Nov 13.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA.

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.
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http://dx.doi.org/10.1038/s41598-017-15756-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684337PMC
November 2017

PBMC activation via the ERK and STAT signaling pathways enhances the anti-tumor activity of Staphylococcal enterotoxin A.

Mol Cell Biochem 2017 Oct 3;434(1-2):75-87. Epub 2017 May 3.

The Second Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou, 510260, People's Republic of China.

Staphylococcal enterotoxin A (SEA) is well known as a superantigen and is highly potent in activating T lymphocytes. And it has been used clinically as an immunomodifier in the treatment of a number of tumors for years. However, the mechanism of its action remains largely unclear. In this study, SEA was found to significantly inhibit the proliferation and induce the death of human lung carcinoma A549 cells when co-cultured with human peripheral blood mononuclear cells (PBMCs). SEA could also induce the proliferation of human PBMCs and stimulate human PBMCs to release a wide range of cytokines that have broad anti-tumor activities such as IFN-γ, TNF-α, IL-2. Furthermore, SEA was found in PBMCs to induce a rapid and long-lasting phosphorylation of extracellular signal-regulated kinases (ERKs) which was significantly inhibited by MEK/ERK pathway inhibitors U0126 and PD0325901, and a late onset of phosphorylation of signal transducers and activators of transcription (STATs) which was significantly inhibited by a pan-JAK inhibitor Pyridone 6 (P6). Unexpectedly constitutive ERK or STATs phosphorylation was also significantly inhibited by P6 or U0126 in a dose-dependent manner, respectively. Summing up, our data reveal SEA may function as a novel protein drug used for cancer immunotherapy via inducing activation of PBMCs, immune cell crosstalk-dependent activation of ERK and STATs, and production of tumor-suppressive cytokines.
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http://dx.doi.org/10.1007/s11010-017-3038-5DOI Listing
October 2017