TET2 Regulates 5-Hydroxymethylcytosine Signature and CD4+ T-Cell Balance in Allergic Rhinitis

Tan Lu,Fu Lisheng,Zheng Li,Fan Wenjun,Tan Hanyu,Tao Zezhang,Xu Yu 대한천식알레르기학회 2022 Allergy, Asthma & Immunology Research Vol.14 No.2

Purpose: Previous studies have shown the role of ten-eleven translocation 2 (TET2) in CD4+ T cells. However, its function in CD4+ T cells under allergic inflammation is unclear. We aimed to investigate the epigenomic distribution of DNA 5-hydroxymethylcytosine (5hmC) and the role of TET2 in CD4+ T cells of allergic rhinitis (AR). Methods: The hMeDIP-seq was performed to identify sequences with 5hmC deposition in CD4+ T cells of AR patients. Tet2-deficient or wild type mice were stimulated with ovalbumin (OVA) to develop an AR mouse model. The histopathology in nasal mucosae, Th1/Th2/Treg/Th17 cell percentage, concentrations of Th-related cytokines, expression of Tet and differential hydroxymethylated genes (DhMG), and the global deposition of 5hmC in sorted CD4+ T cells were detected. Results: Epigenome-wide 5hmC landscape and DhMG in the CD4+ T cells of AR patients were identified. Tet2 depletion did not led to spontaneous inflammation. However, under the stimulation of allergen, OVA, loss of Tet2 resulted in the exacerbation of allergic inflammation, which was characterized by severer allergic symptoms, more inflammatory cells infiltrating the nasal lamina propria, sharper imbalances between Th1/Th2 and Treg/Th17 cells, and excessive secretion of OVA-specific IgE and Th2-related cytokines. Moreover, altered mRNA production of several DhMG and sharp decrease in 5hmC deposition were also observed in Tet2-deficient OVA-exposed mice. Conclusions: TET2 may regulate DNA 5hmC, DhMG expressions, and CD4+ T cell balance in AR.

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Tan, Li,Wang, Jun,Tanizaki, Junko,Huang, Zhifeng,Aref, Amir R.,Rusan, Maria,Zhu, Su-Jie,Zhang, Yiyun,Ercan, Dalia,Liao, Rachel G.,Capelletti, Marzia,Zhou, Wenjun,Hur, Wooyoung,Kim, NamDoo,Sim, Taebo,G National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.45

<P><B>Significance</B></P><P>Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for the treatment of various cancers. All currently approved kinase inhibitors eventually are rendered useless by the emergence of drug-resistant tumors. We used structure-based drug design to develop the first, to our knowledge, selective, next-generation covalent FGFR inhibitors that can overcome the most common form of kinase inhibitor resistance, the mutation of the so-called “gatekeeper” residue located in the ATP-binding pocket. We also describe a novel kinase inhibitor design strategy that uses a single electrophile to target covalently cysteines that are located in different positions within the ATP-binding pocket. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance.</P><P>The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.</P>

Dietary Tea Catechin Inclusion Changes Plasma Biochemical Parameters, Hormone Concentrations and Glutathione Redox Status in Goats

Zhong, Rongzhen,Xiao, Wenjun,Ren, Guopu,Zhou, Daowei,Tan, Chuanyan,Tan, Zhiliang,Han, Xuefeng,Tang, Shaoxun,Zhou, Chuanshe,Wang, Min Asian Australasian Association of Animal Productio 2011 Animal Bioscience Vol.24 No.12

The beneficial effects of tea catechins (TCs) are related not only to their antioxidant potential but also to the improvement of animal meat quality. In this study, we assessed the effects of dietary TC supplementation on plasma biochemical parameters, hormone responses, and glutathione redox status in goats. Forty Liuyang goats were randomly divided into four equal groups (10 animals/group) that were assigned to four experimental diets with TC supplementation at 4 levels (0, 2,000, 3,000 or 4,000 mg TC/kg DM feed). After a 60-day feeding trial, all goats were slaughtered and sampled. Dietary TC treatment had no significant effect on blood biochemical parameters, however, low-density lipoprotein cholesterol (p<0.001), triglyceride (p<0.01), plasma urea nitrogen (p<0.01), and glucose (p<0.001) decreased and total protein (p<0.01) and albumin (p<0.05) increased with the feeding time extension, and day 20 was the turning point for most of changes. Interactions were found in glutathione (p<0.001) and the ratio of reduced and oxidized glutathione (p<0.05) in whole blood between treatment and feeding time. Oxidized glutathione in blood was reduced (p<0.05) by 2,000 mg TC/kg feed supplementation, and a similar result was observed in longissimus dorsi muscle. Though plasma glutathione peroxidase (p<0.01) and glutathione reductase (p<0.05) activities were affected by treatment and feeding time interactions, and glutathione S-transferases activity increased with feeding day extension, no changed values appeared in longissimus dorsi muscle. In conclusion, dietary TC supplementation affected the concentrations of some blood metabolites and accelerated GSH depletion in the blood of goats. In terms of less high-density lipoprotein cholesterol, the highest insulin and IGF-I concentrations, the highest ratio of reduced and oxidized glutathione in plasma, the dosage of 2,000 mg TC/kg feed might be desirable for growing goats to prevent glutathione depletion and keep normal physiological metabolism.

The Mixed Kernel Function SVM-based Point Cloud Classification

Chao Chen,Xiaomin Li,Abdelkader Nasreddine Belkacem,Zhifeng Qiao,Enzeng Dong,Wenjun Tan,Duk Shin 한국정밀공학회 2019 International Journal of Precision Engineering and Vol.20 No.5

Measurement and detection of ground information by airborne Lidar are one of the hot topics in the field of intelligent sensing in recent years. This study proposes a new point cloud classification algorithm of Mixed Kernel Function SVM to distinguish different types of ground objects. Firstly, the combined features including the coordinate values, the RGB value, normalized elevation, standard deviation of elevation, and elevation difference of point cloud data were extracted. A mixed kernel function of Gauss and Polynomial was designed. Then, one-versus-rest SVM multiple classifiers was constructed. Finally, the feature of 3D point cloud data was employed to train the SVM classifiers. The overall classification accuracies of test data were 97.69% and 99.13% for two data sets, I and II respectively. In addition, the experimental results have showed that the performance of the proposed method with mixed kernel function SVM was better than standard SVM method with Gaussian kernel function and polynomial kernel function only, which demonstrates the effectiveness of the proposed method.