26 results on '"Enyu Rao"'
Search Results
2. Supplementary Figures 1 - 7, Tables 1 - 3 from Fatty Acid-Binding Protein E-FABP Restricts Tumor Growth by Promoting IFN-β Responses in Tumor-Associated Macrophages
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Bing Li, Margot P. Cleary, Edward Sauter, Shujun Liu, Kevin A.T. Silverstein, Ying Zhang, Qiang Li, Fei Yan, Enyu Rao, Yanwen Sun, and Yuwen Zhang
- Abstract
PDF file - 1745K, Supplementary Figure 1. The development of tumors in WT and E-FABP-/- mice. Supplementary Figure 2. Phenotype analysis of tumor-bearing WT and E-FABP-/- mice. Supplementary Figure 3. Dynamic changes of E-FABP-expressing TAMs in the tumor stroma. Supplementary Figure 4. Analysis of GM-BMMs from WT and E-FABP-/- mice. Supplementary Figure 5. Analysis of FABP expression and LD inhibition in GM-BMMs. Supplementary Figure 6. IFNγ production in tumor infiltrated cells and NK depletion in mice. Supplementary Figure 7. E-FABP expression in breast cancer patients. Supplementary Table 1. The selected differentially expressed genes in macrophages regulated by E-FABP. Supplementary Table 2. E-FABP expression in normal breast tissues and breast cancer tissues. Supplementary Table 3. E-FABP expression in normal breast stroma and invasive breast cancer stroma.
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- 2023
3. Recombinant Human Adenovirus-p53 Therapy for the Treatment of Cervical Cancer: A Meta-Analysis
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Yaru Guo, Jiuzhou Chen, Longzhen Zhang, Enyu Rao, Mingna Xu, Xiwen Zhang, Yong Xin, and Miao Fang
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Cancer Research ,medicine.medical_specialty ,Combination therapy ,cervical cancer ,medicine.medical_treatment ,Cochrane Library ,chemotherapy ,Gastroenterology ,chemoradiotherapy ,Internal medicine ,medicine ,RC254-282 ,radiotherapy ,Cervical cancer ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,recombinant human adenovirus-p53 ,Odds ratio ,medicine.disease ,Confidence interval ,meta-analysis ,Radiation therapy ,Oncology ,Meta-analysis ,Systematic Review ,business ,Chemoradiotherapy - Abstract
ObjectivesTo evaluate the clinical curative effects and toxicity of recombinant human adenovirus-p53 injection (rAd-p53) plus chemotherapy (CT), radiotherapy (RT), or concurrent chemoradiotherapy (CRT) for the treatment of cervical cancer.MethodsWe identified 14 eligible studies in the PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wangfangdate, CBM, and VIP databases from their inception to May 2021 and performed meta-analyses using RevMan version 5.3.ResultsThis analysis included 14 studies involving 737 patients. The results of the meta-analysis results showed significantly improved complete remission (odds ratio [OR] = 2.54, 95% confidence interval [CI]: 1.74–3.70, p < 0.00001), partial remission (OR = 1.56, 95% CI: 1.14–2.14, p = 0.006), and object response (OR = 4.47, 95% CI: 3.02–6.60, p < 0.00001) rates in the rAd-p53 combination therapy group compared to those in the CT/RT/CRT group. The results of subgroup analyses of CT/RT/CRT were consistent with the overall results. Regarding the incidence of adverse reactions, only the occurrence rate of fever (OR = 18.21, 95% CI: 10.54–31.47, p < 0.00001) in the rAd-p53 combination group was higher than that in the CT/RT/CRT group. No other significant differences were observed in other adverse reactions.ConclusionRAd-p53 combined with CT/RT/CRT for the treatment of cervical cancer showed significant advantages in efficacy and safety compared to those in the CT/RT/CRT group. Therefore, rAd-p53 has great potential as an effective therapy for cervical cancer.Systematic Review Registrationhttps://inplasy.com/inplasy-2021-5-0058/.
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- 2021
4. All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages
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Everett E. Vokes, Jiaai Wang, Hengjin Yang, Ralph R. Weichselbaum, Liangliang Wang, Xiaona Huang, Yang Xin Fu, Enyu Rao, Kaiting Yang, Jason Bugno, Hua Laura Liang, Xingchen Ding, Wenxin Zheng, Xinshuang Yu, and Yuzhu Hou
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Receptors, CCR2 ,Regulatory T cell ,T cell ,Immunology ,Retinoic acid ,Tretinoin ,CD8-Positive T-Lymphocytes ,Radiation Tolerance ,Article ,Interferon-gamma ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Neoplasms ,Radioresistance ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Macrophage ,Mice, Knockout ,Macrophages ,Chemoradiotherapy ,General Medicine ,Acquired immune system ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Cancer research ,CD8 ,030215 immunology - Abstract
Radiotherapy (RT) is an important anti-cancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared to ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a dramatic increase of TNF-α– and inducible nitric oxide synthase (iNOS)–producing inflammatory macrophages in local and distal non-irradiated (distal) tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell-derived IFN-γ are crucial for increasing inflammatory macrophage levels in IR and RA treated tumors. Notably, whereas CD8(+) T cells are required for the antitumor response to IR, CD4(+) T cells are required for the effectiveness of the IR and RA combination. Combination treatment with RA enhanced the abscopal response when radiation and PD-L1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR plus RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.
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- 2021
5. Induction of Inflammatory Macrophages in Solid Tumors by All-trans Retinoic Acid Augments Radiation Efficacy
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Hua Laura Liang, Enyu Rao, Yuzhu Hou, Jiaai Wang, Xiaona Huang, Xianbin Yu, Liangliang Wang, Chuan He, Everett Vokes, and Ralph Weichselbaum
- Subjects
Immunology ,Immunology and Allergy - Abstract
Radiotherapy is an important anticancer treatment modality that activates innate and adaptive immune responses. Local RT induces an influx of myeloid cells (mostly myeloid-derived suppressor cells MDSCs), which suppress T-cell function, in the tumor microenvironment (TME). Alleviating therapy-induced immunosuppression would address a significant barrier to the efficacy of current cancer immunotherapeutic approaches. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared with ionizing radiation (IR) alone or RA alone. The effects of combination treatment were accompanied by a marked increase of tumor necrosis factor–α– (TNFα) and inducible nitric oxide synthase (iNOS)–producing inflammatory macrophages in local and distal nonirradiated tumors. Inflammatory macrophages (Inf-MAC) are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell–derived interferon-γ are crucial for increasing inflammatory macrophage levels in IR- and RA-treated tumors. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR + RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR. Single cell RNAseq of immune infiltrates revealed unique transcriptional changes delineating the differentiation of Inf-Mac in the TME which may lead to potential specific therapeutic targets.
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- 2022
6. Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity
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Anne R. McCall, Xinshuang Yu, Ainhoa Arina, Lei Li, Liangliang Wang, Wenjun Wu, Steven J. Chmura, Yang Xin Fu, Yanbin Fu, Xiaona Huang, Sean P. Pitroda, Jason Bugno, Everett E. Vokes, Xuezhi Cao, Ralph R. Weichselbaum, Hua L. Liang, Jessica M. S. Jutzy, Zhida Liu, Sean Z. Luo, Yuzhu Hou, Enyu Rao, and Wenxin Zheng
- Subjects
Erythroid Precursor Cells ,business.industry ,medicine.medical_treatment ,Melanoma ,Artemin ,Nerve Tissue Proteins ,General Medicine ,Immunotherapy ,Adaptive Immunity ,Acquired immune system ,medicine.disease ,Article ,Mice ,Interferon ,Tumor progression ,Neoplasms ,Radioimmunotherapy ,Cancer research ,medicine ,Animals ,Humans ,business ,medicine.drug - Abstract
Tumor-induced CD45(−)Ter119(+)CD71(+) erythroid progenitor cells (EPCs), termed “Ter-cells,” promote tumor progression by secreting artemin, a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti-Programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter-cell abundance in mouse spleen and artemin secretion outside the irradiation field in an interferon- (IFN) and CD8(+) T cell-dependent manner. Recombinant erythropoietin (EPO) promoted resistance to radiotherapy or anti-PD-L1 therapies by restoring Ter-cell numbers and serum artemin concentration. Blockade of artemin or potential artemin signaling partners, or depletion of Ter-cells augmented the anti-tumor effects of both IR and anti-PD-L1 therapies in mice. Analysis of samples from patients who received radio-immunotherapy demonstrated that IR-mediated reduction of Ter-cells, artemin, and GFRα3, an artemin signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or “abscopal,” effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes following radiotherapy and immunotherapy.
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- 2021
7. RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth
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Joohyun Ryu, Mee-Hyun Lee, Ke Yao, Sung Young Lee, Tatyana A. Zykova, Lei Wang, Bing Li, H. S. Chen, Kangdong Liu, Zigang Dong, Wei He, Yuwen Zhang, Wei-Ya Ma, Yi Zhang, Ann M. Bode, Cong Peng, Ziming Dong, Ge Gao, and Enyu Rao
- Subjects
Male ,0301 basic medicine ,Lung Neoplasms ,chemical and pharmacologic phenomena ,Transfection ,Peripheral blood mononuclear cell ,Metastasis ,Ribosomal s6 kinase ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Serine ,medicine ,Animals ,Humans ,Interferon gamma ,Phosphorylation ,Bone Marrow Transplantation ,Gene knockdown ,Multidisciplinary ,biology ,Kinase ,Ribosomal Protein S6 Kinases ,Liver Neoplasms ,hemic and immune systems ,Biological Sciences ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Isoenzymes ,030104 developmental biology ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Immunology ,Leukocytes, Mononuclear ,Cancer research ,biology.protein ,Female ,Signal transduction ,T-Box Domain Proteins ,Whole-Body Irradiation ,Signal Transduction ,medicine.drug - Abstract
Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.
- Published
- 2017
8. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells
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Yuwen Zhang, Fei Yan, Jiuxia Pang, Bing Li, Aref Al-Kali, Enyu Rao, Dong-Er Zhang, Mark R. Litzow, Ann M. Bode, Na Shen, and Shujun Liu
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STAT3 Transcription Factor ,0301 basic medicine ,Cancer Research ,Apoptosis ,Biology ,Diet, High-Fat ,Fatty Acid-Binding Proteins ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Gene silencing ,DNA (Cytosine-5-)-Methyltransferases ,Obesity ,Interleukin 6 ,Cell Proliferation ,Regulation of gene expression ,Acute leukemia ,Interleukin-6 ,Myeloid leukemia ,Hematology ,DNA Methylation ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,DNMT1 ,biology.protein - Abstract
Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.
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- 2016
9. Epidermal FABP Prevents Chemical-Induced Skin Tumorigenesis by Regulation of TPA-Induced IFN/p53/SOX2 Pathway in Keratinocytes
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Jill Suttles, Jun Zeng, Yuwen Zhang, Enyu Rao, Margot P. Cleary, V Douglas Landers, Jiaqing Hao, Qiang Li, Bing Li, Rebecca J. Morris, Yanwen Sun, Lianliang Liu, and Anita Mandal
- Subjects
0301 basic medicine ,Keratinocytes ,Male ,Skin Neoplasms ,Carcinogenesis ,Adipose tissue ,Inflammation ,Dermatology ,12-O-Tetradecanoylphorbol-13-acetate ,medicine.disease_cause ,Fatty Acid-Binding Proteins ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,RNA, Neoplasm ,Molecular Biology ,Regulation of gene expression ,Innate immune system ,Epidermis (botany) ,integumentary system ,7,12-Dimethylbenz[a]anthracene ,SOXB1 Transcription Factors ,Cell Biology ,Interferon-beta ,Neoplasms, Experimental ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Cancer research ,Tetradecanoylphorbol Acetate ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Epidermis ,Tumor Suppressor Protein p53 - Abstract
Skin lipids (e.g., fatty acids) are essential for normal skin functions. Epidermal FABP (E-FABP) is the predominant FABP expressed in skin epidermis. However, the role of E-FABP in skin homeostasis and pathology remains largely unknown. Herein, we utilized the 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanolyphorbol-13-acetate–induced skin tumorigenesis model to assess the role of E-FABP in chemical-induced skin tumorigenesis. Compared to their wild-type littermates, mice deficient in E-FABP, but not adipose FABP, developed more skin tumors with higher incidence. 12-O-tetradecanolyphorbol-13-acetate functioning as a tumor promoter induced E-FABP expression and initiated extensive flaring inflammation in skin. Interestingly, 12-O-tetradecanolyphorbol-13-acetate -induced production of IFN-β and IFN-λ in the skin tissue was dependent on E-FABP expression. Further protein and gene expression arrays demonstrated that E-FABP was critical in enhancing IFN-induced p53 responses and in suppressing SOX2 expression in keratinocytes. Thus, E-FABP expression in skin suppresses chemical-induced skin tumorigenesis through regulation of IFN/p53/SOX2 pathway. Collectively, our data suggest an unknown function of E-FABP in prevention of skin tumor development, and offer E-FABP as a therapeutic target for improving skin innate immunity in chemical-induced skin tumor prevention.
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- 2017
10. Fatty Acid-Binding Protein E-FABP Restricts Tumor Growth by Promoting IFN-β Responses in Tumor-Associated Macrophages
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Fei Yan, Kevin A. T. Silverstein, Yuwen Zhang, Bing Li, Enyu Rao, Yanwen Sun, Shujun Liu, Margot P. Cleary, Qiang Li, Ying Zhang, and Edward R. Sauter
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Cancer Research ,Gene Expression ,Biology ,Fatty Acid-Binding Proteins ,Article ,Fatty acid-binding protein ,Mice ,Downregulation and upregulation ,Lipid droplet ,Gene expression ,Tumor Cells, Cultured ,Animals ,Humans ,Mammary tumor ,Epidermis (botany) ,Effector ,Macrophages ,Mammary Neoplasms, Experimental ,Interferon-beta ,Lipids ,Cell biology ,Killer Cells, Natural ,Mice, Inbred C57BL ,Oncology ,Experimental pathology ,Female ,lipids (amino acids, peptides, and proteins) ,Epidermis - Abstract
Fatty acid-binding proteins (FABP) are known central regulators of both metabolic and inflammatory pathways, but their role in tumor development remains largely unexplored. Here, we report that host expression of epidermal FABP (E-FABP) protects against mammary tumor growth. We find that E-FABP is highly expressed in macrophages, particularly in a specific subset, promoting their antitumor activity. In the tumor stroma, E-FABP–expressing tumor-associated macrophages (TAM) produce high levels of IFN-β through upregulation of lipid droplet formation in response to tumors. E-FABP–mediated IFN-β signaling can further enhance recruitment of tumoricidal effector cells, in particular natural killer cells, to the tumor stroma for antitumor activity. These findings identify E-FABP as a new protective factor to strengthen IFN-β responses against tumor growth. Cancer Res; 74(11); 2986–98. ©2014 AACR.
- Published
- 2014
11. Shaping Immune Responses by Dysregulated Adipokines in Obesity
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Enyu Rao, Yuwen Zhang, and Bing Li
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medicine.medical_specialty ,business.industry ,Public health ,Cancer ,Adipokine ,medicine.disease ,Bioinformatics ,Obesity ,Pathogenesis ,Immune system ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Epidemiology ,medicine ,business - Abstract
Obesity is a major epidemic worldwide. According to the Centers for Disease Control and Prevention (CDC), about 34.9% of adults and 17% of children and adolescents are obese in the United States. The increasing prevalence of obesity poses a major threat to public health. Clinical and epidemiological data have established that obesity not only links to the development of diabetes, atherosclerosis and cardiovascular diseases, but also increases the risk of many types of cancer [1]. Although tremendous effort has been taken to investigate the pathogenesis of obesity and its associated diseases, the molecular mechanisms by which obesity negatively impacts on metabolic and immunologic homeostasisand increases the morbidity and mortality of many maladies remain largely unknown.
- Published
- 2014
12. Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing Ceramide Production
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Bing Li, Jun Zeng, Edward R. Sauter, Shujun Liu, Jill Suttles, Enyu Rao, Yuwen Zhang, Jiaqing Hao, Margot P. Cleary, Yanwen Sun, and David A. Bernlohr
- Subjects
0301 basic medicine ,Programmed cell death ,Ceramide ,Immunology ,Blotting, Western ,Adipose tissue ,Inflammation ,Biology ,Ceramides ,Diet, High-Fat ,Fatty Acid-Binding Proteins ,Real-Time Polymerase Chain Reaction ,Fatty acid-binding protein ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Microscopy, Electron, Transmission ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Obesity ,Mice, Knockout ,Microscopy, Confocal ,Cell Death ,Binding protein ,Macrophages ,Fatty Acids ,Flow Cytometry ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Saturated fatty acid ,lipids (amino acids, peptides, and proteins) ,medicine.symptom - Abstract
Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms underlying the response of macrophages to elevated fatty acids (FAs) and their contribution to metabolic inflammation in obesity remain to be fully elucidated. In this article, we report a new mechanism by which dietary FAs, in particular, saturated FAs (sFAs), are able to directly trigger macrophage cell death. We demonstrated that excess sFAs, but not unsaturated FAs, induced the production of cytotoxic ceramides (Cers) in macrophage cell lines. Most importantly, expression of adipose FA binding protein (A-FABP) in macrophages facilitated metabolism of excess sFAs for Cer synthesis. Inhibition or deficiency of A-FABP in macrophage cell lines decreased sFA-induced Cer production, thereby resulting in reduced cell death. Furthermore, we validated the role of A-FABP in promoting sFA-induced macrophage cell death with primary bone marrow–derived macrophages and high-fat diet–induced obese mice. Altogether, our data reveal that excess dietary sFAs may serve as direct triggers in induction of Cer production and macrophage cell death through elevated expression of A-FABP, thus establishing A-FABP as a new molecular sensor in triggering macrophage-associated sterile inflammation in obesity.
- Published
- 2016
13. AMPK-dependent and independent effects of AICAR and compound C on T-cell responses
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Jiaqing Hao, Nejat K. Egilmez, Jill Suttles, Qiang Li, Yuwen Zhang, Bing Li, and Enyu Rao
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0301 basic medicine ,AMPK ,medicine.medical_treatment ,T-Lymphocytes ,AMP-Activated Protein Kinases ,Lymphocyte Activation ,0302 clinical medicine ,AMP-activated protein kinase ,Cells, Cultured ,Mice, Knockout ,biology ,Cell Death ,TOR Serine-Threonine Kinases ,Research Paper: Immunology ,Cell biology ,Cytokine ,medicine.anatomical_structure ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Cytokines ,Immunology and Microbiology Section ,Programmed cell death ,medicine.medical_specialty ,Genotype ,T cell ,Enzyme Activators ,03 medical and health sciences ,Enzyme activator ,Internal medicine ,medicine ,Animals ,Immunologic Factors ,Calcium Signaling ,Immune response ,Protein kinase A ,Protein Kinase Inhibitors ,Dose-Response Relationship, Drug ,business.industry ,Wild type ,Immunity ,Aminoimidazole Carboxamide ,Enzyme Activation ,030104 developmental biology ,Endocrinology ,Pyrimidines ,T cell responses ,biology.protein ,Pyrazoles ,Ribonucleosides ,business - Abstract
As a master metabolic sensor, AMP-activated protein kinase (AMPK) is involved in different fundamental cellular processes. Regulation of AMPK activity either by agonists (e.g., AICAR) or by antagonists (e.g., Compound C) has been widely employed to study the physiological functions of AMPK. However, mounting evidence indicates AMPK-independent effects for these chemicals and how they regulate immune cell functions remains largely unknown. Herein, using T cells from AMPK conditional knockout mice and their wild type littermates, we demonstrate that AICAR and Compound C can, indeed, activate or inhibit AMPK activity in T cells, respectively. Specifically, AICAR inhibits, but Compound C promotes, Ca2+-induced T cell death in an AMPK-dependent manner. In contrast, our data also demonstrate that AICAR and Compound C inhibit T cell activation and cytokine production in an AMPK-independent manner. Moreover, we find that the AMPK-independent activity of AICAR and Compound Cis mediated via the mTOR signaling pathway in activated T cells. Our results not only reveal the critical role of AMPK in regulating T cell survival and function, but also demonstrate AMPK-dependent and independent rolesof AICAR/Compound C in regulating T cell responses, thus suggesting a context-dependent effect of these "AMPK regulators".
- Published
- 2016
14. miR-17-92 plays an oncogenic role and conveys chemo-resistance to cisplatin in human prostate cancer cells
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Yong Zhao, Jun Zhou, Feng Guo, Peng Zhou, Min Jiang, Enyu Rao, and Liang Ma
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0301 basic medicine ,Male ,Cancer Research ,MAP Kinase Signaling System ,Biology ,medicine.disease_cause ,Bioinformatics ,03 medical and health sciences ,Prostate cancer ,DU145 ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Oncogene ,Akt/PKB signaling pathway ,Integrin beta1 ,Cancer ,Prostatic Neoplasms ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,RNA, Long Noncoding ,Cisplatin ,Carcinogenesis - Abstract
The mir-17-92 cluster consists of six mature miRNAs and is implicated in diverse human cancers by targeting mRNAs involved in distinct pathways that either promote or inhibit carcinogenesis. However, the molecular mechanism underlying the mir-17-92 cluster-mediated pro-tumorigenic or anti-tumorigenic effects has not been clearly elucidated in prostate cancer. In the present study, the role of the mir-17-92 cluster in diverse aspects of prostate cancer cells has been thoroughly investigated. Forced introduction of the mir-17-92 cluster into the androgen-independent DU145 prostate cancer cells evidently promoted cell growth due to disruption of the balance between cellular proliferation and apoptosis. Overexpression of the mir-17-92 cluster significantly improved the migration and invasion of the DU145 cells, attributed to the induction of integrin β-1. Notably, the mir-17-92 cluster conveyed chemo-resistance to cisplatin. We demonstrated that the mir-17-92 cluster suppressed the expression of inhibitor of the AKT signaling pathway and activated the AKT pathway subsequently, which played a central role in regulating cellular proliferation, apoptosis and chemo-resistance. Continuously activated ERK1/2 signaling also contributed importantly to these processes. The present study provides key evidence for crucial oncogenic role of the miR-17-92 cluster in prostate cancer cells. Further investigations are warranted to determine whether miR-17-92 cluster can be targeted for future treatment of human prostate cancer.
- Published
- 2016
15. Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy
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Hua Liang, Meng Xu, Xinshuang Yu, Yuan Zhang, Ralph R. Weichselbaum, Wenxin Zheng, Liufu Deng, Yang Xin Fu, Helena J. Mauceri, Xiaona Huang, Yuzhu Hou, Ainhoa Arina, and Enyu Rao
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Transcription Factor RelA ,Melanoma, Experimental ,Tumor initiation ,Biology ,Radiation Tolerance ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immunity ,Radiation, Ionizing ,Radioresistance ,medicine ,Animals ,Humans ,Immunology and Allergy ,Melanoma ,Immunity, Cellular ,Radiotherapy ,NF-kappa B ,Membrane Proteins ,NF-κB ,DNA ,Dendritic Cells ,Neoplasms, Experimental ,Xenograft Model Antitumor Assays ,Radiation therapy ,Disease Models, Animal ,Sting ,030104 developmental biology ,Infectious Diseases ,chemistry ,Receptors, Pattern Recognition ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Signal Transduction - Abstract
The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-κB pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-κB pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-κB pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.
- Published
- 2018
16. Abstract 2127: RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth
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Bing Li, Kangdong Liu, Cong Peng, Wei-Ya Ma, H. S. Chen, Zigang Dong, Enyu Rao, Yuwen Zhang, Mee-Hyun Lee, Joohyun Ryu, Tatyana A. Zykova, Ke Yao, and Ann M. Bode
- Subjects
Cancer Research ,Oncology ,Colorectal cancer ,business.industry ,Cancer research ,medicine ,Phosphorylation ,medicine.disease ,business ,Metastasis - Abstract
Metastasis is the major cause of death for patients with solid malignancies. Approximately 80 and 20% of colorectal cancer (CRC) patients develop liver metastasis and lung metastasis, respectively. We found that at different stages of colon cancer, the patients' interferon (IFN) γ secretion from peripheral blood mononuclear cells (PBMCs), was decreased compared with healthy people. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their role in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice, revealed that the level of IFNγ was significantly lower in RSK2 KO mice as compared to WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, a colon cancer liver metastasis experiment was conducted. We found that metastasis was significantly increased in RSK2 KO mice, compared to WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knocking down RSK2 expression or over-expressing T-bet S498A/S502A mutants reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, a constitutively active mutant T-bet (S498E/S502E) was over-expressed in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for inhibiting colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling. Citation Format: Ke Yao, Cong Peng, Yuwen Zhang, Tatyana A. Zykova, Mee-Hyun Lee, Hanyong Chen, Joohyun Ryu, Enyu Rao, Wei-Ya Ma, kangdong liu, Ann M. Bode, Bing Li, zigang dong. RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2127.
- Published
- 2018
17. Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis
- Author
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Enyu Rao, Bing Li, Yuwen Zhang, Young In Chi, Jill Suttles, Puja Singh, and Yan Li
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Encephalomyelitis ,Immunology ,Central nervous system ,Drug Evaluation, Preclinical ,T lymphocytes ,chemical and pharmacologic phenomena ,Biology ,Fatty Acid-Binding Proteins ,Fatty acid-binding protein ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Fatty acid binding protein ,Molecular Targeted Therapy ,Antigen present cells ,030304 developmental biology ,Autoimmune disease ,0303 health sciences ,EAE ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Cell Differentiation ,Dendritic Cells ,medicine.disease ,Neoplasm Proteins ,3. Good health ,Mice, Inbred C57BL ,Molecular Docking Simulation ,medicine.anatomical_structure ,Cytokines ,030217 neurology & neurosurgery ,Research Article - Abstract
Background Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP), widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE). Methods In the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE. Results We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] bound to the lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) while increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in mouse models. Conclusions Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.
- Published
- 2015
18. Epidermal Fatty Acid binding protein promotes skin inflammation induced by high-fat diet
- Author
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Bing Li, Rebecca J. Morris, Michael E. Grossmann, Margot P. Cleary, Enyu Rao, Yanwen Sun, Yuwen Zhang, and Qiang Li
- Subjects
Male ,medicine.medical_specialty ,T-Lymphocytes ,Immunology ,CD11c ,Inflammation ,Biology ,Diet, High-Fat ,Fatty Acid-Binding Proteins ,Skin Diseases ,Epidermal Fatty Acid-Binding Protein ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Lipid droplet ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,integumentary system ,Effector ,High fat diet ,Immunohistochemistry ,3. Good health ,Neoplasm Proteins ,Mice, Inbred C57BL ,Infectious Diseases ,Endocrinology ,030220 oncology & carcinogenesis ,Cytokines ,lipids (amino acids, peptides, and proteins) ,medicine.symptom - Abstract
SummaryDefining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c+ macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1β and IL-18 signaling, which further promoted the cytokines IFN-γ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency of E-FABP in obese mice decreased recruitment of CD11c+ macrophages in skin tissues, reduced production of IL-1β and IL-18, and consequently dampened activation of effector T cells. Furthermore, E-FABP-deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation.
- Published
- 2014
19. Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-induced Cell Death through Ceramide Production in Macrophages
- Author
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Yuwen Zhang, Enyu Rao, Jun Zeng, Jiaqing Hao, Yanwen Sun, Edward Sauter, Margot Cleary, and Bing Li
- Subjects
Immunology ,Immunology and Allergy - Abstract
Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms of how macrophages respond to elevated fatty acids (FAs) and contribute to sterile inflammation in obesity remain to be fully elucidated. Here, we report a new mechanism by which dietary FAs, in particular saturated FAs, were able to directly trigger macrophage cell death. We demonstrated that excess saturated FAs, but not unsaturated FAs, induced the production of cytotoxic ceramides in macrophages. Most importantly, expression of adipose fatty acid binding protein (A-FABP) in macrophages facilitated metabolism of excess saturated FAs for ceramide synthesis. Inhibition or deficiency of A-FABP in macrophages decreased saturated FA-induced ceramide production, thereby resulting in reduced cell death. Furthermore, A-FABP-deficient obese mice exhibited increased percentage of CD36+ macrophages in peripheral as compared to WT control mice. Altogether, our data suggest that excess saturated FAs in diets serve as new triggers in inducing ceramide production and macrophage cell death through elevated expression of A-FABP, thus contributing to sterile inflammation in obesity.
- Published
- 2016
20. AMPK-dependent and independent effects of AICAR and Compound C on T-cell responses
- Author
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Enyu Rao, Yuwen Zhang, Qiang Li, Jiaqing Hao, Nejat Egilmez, and Bing Li
- Subjects
Immunology ,Immunology and Allergy - Abstract
As a master metabolic sensor, AMP-activated protein kinase (AMPK) is involved in different fundamental cellular processes. Regulation of AMPK activity either by agonists (e.g., AICAR) or by antagonists (e.g., Compound C) has been widely employed to study the physiological functions of AMPK. However, mounting evidence indicates AMPK-independent effects for these chemicals. Herein, using T cells from AMPK conditional knockout mice and their wild type littermates, we demonstrate that AICAR and Compound C can, indeed, activate or inhibit AMPK activity in T cells, respectively. Specifically, AICAR inhibits, but Compound C promotes, Ca2+-induced T cell death in an AMPK-dependent manner. In contrast, our data also demonstrate that AICAR and Compound C inhibit T cell activation and cytokine production in an AMPK-independent manner. Moreover, we find that the AMPK-independent activity of AICAR and Compound C is mediated via the mTOR signaling pathway in activated T cells. Our results not only reveal the critical role of AMPK in regulating T cell survival and function, but also demonstrate AMPK-dependent and independent roles of AICAR/Compound C in regulating T cell responses, thus suggesting a context-dependent effect of these “AMPK regulators”.
- Published
- 2016
21. The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation
- Author
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W. C. Chan, Georg Lenz, Enyu Rao, Javeed Iqbal, George E. Wright, Xin Huang, Ming Ji, Louis M. Staudt, Yong Zhao, Timothy W. McKeithan, Kai Fu, and Chunsun Jiang
- Subjects
Cancer Research ,Transplantation, Heterologous ,Down-Regulation ,Antineoplastic Agents ,Lymphoma, Mantle-Cell ,Mice, SCID ,Cell Line ,Mice ,Phosphatidylinositol 3-Kinases ,Downregulation and upregulation ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,microRNA ,medicine ,PTEN ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,biology ,Bcl-2-Like Protein 11 ,Gene Expression Profiling ,PTEN Phosphohydrolase ,Membrane Proteins ,Hematology ,medicine.disease ,Molecular biology ,Transplantation ,Gene expression profiling ,Enzyme Activation ,MicroRNAs ,Oncology ,Apoptosis ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Mantle cell lymphoma ,Female ,Apoptosis Regulatory Proteins ,Proto-Oncogene Proteins c-akt ,Cell Division - Abstract
The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P=0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.
- Published
- 2011
22. Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis (THER7P.947)
- Author
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Enyu Rao, Puja Singh, Yan Li, Yuwen Zhang, Young-In Chi, Jill Suttles, and Bing Li
- Subjects
Immunology ,Immunology and Allergy - Abstract
Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP) widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels their overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE). In the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE. We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] binded lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) but increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in different mouse models. Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.
- Published
- 2015
23. The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice
- Author
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Chun Zeng, Baojun Zhang, Yanyan Qu, Liang Zhao, Enyu Rao, Guangwei Liu, Yong Zhao, and Haixia Ma
- Subjects
medicine.medical_treatment ,Immunology ,Cell ,Fluorescent Antibody Technique ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Immune tolerance ,Flow cytometry ,Mice ,Immune system ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Animals ,IL-2 receptor ,Sirolimus ,Transplantation ,medicine.diagnostic_test ,Interleukin-2 Receptor alpha Subunit ,FOXP3 ,hemic and immune systems ,Forkhead Transcription Factors ,Flow Cytometry ,Molecular biology ,In vitro ,Mice, Inbred C57BL ,Immunosuppressive drug ,medicine.anatomical_structure ,Lymphocyte Culture Test, Mixed ,Immunosuppressive Agents - Abstract
CD4(+)CD25(+)Regulatory T (Treg) cells are crucial for negatively regulating immune responses. Rapamycin (rapa) is an immunosuppressive agent which is widely used for preventing acute graft rejection in patients and has been used to induce operational tolerance in mouse models. The aim of the present study was to determine the effect of rapa on CD4(+)CD25(+)Foxp3(+)Treg cells in a mouse model. After C57BL/6 mice were intraperitoneally given 1.5 mg/kg/day of rapa for 14 days, the percentages, cell numbers, phenotype and function of CD4(+)CD25(+)Treg cells were determined by flow cytometry as well as the in vitro and in vivo functional assays. The cell numbers of CD4(+) and CD4(+)CD25(+)Treg cell subsets were markedly decreased in rapa-treated mice as reported. However, rapa significantly enhanced the ratios of CD4(+)CD25(+)Treg cells or CD4(+)CD25(+)Foxp3(+)Treg cells to CD4(+)T cells in spleens and thymi of mice (P
- Published
- 2006
24. Abstract 2881: E-FABP protects host from tumor development
- Author
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Yuwen Zhang, Bing Li, and Enyu Rao
- Subjects
Cancer Research ,Host (biology) ,Wild type ,CD11c ,Cancer ,Biology ,medicine.disease ,Immune system ,Oncology ,Immunology ,Knockout mouse ,medicine ,lipids (amino acids, peptides, and proteins) ,CD8 ,Function (biology) - Abstract
Epidermal fatty acid-binding protein (E-FABP) is constitutively expressed in many immune cells, including dendritic cells, macrophages and T lymphocytes. However, the role of E-FABP in host immunity against tumor and cancer development is unknown. We hypothesize that E-FABP plays an essential role in host immune responses to ward off tumor challenges. Here we utilize a murine breast cancer model and E-FABP knockout mice to study the function of E-FABP in host immune responses to tumor challenges. It is found that implanted breast cancer cells develops much faster into tumor in E-FABP knockout mice than in wild type ones. It is also discovered that, when compared to wild type mice, F4/80+CD11c+ macrophages in tumor stroma from E-FABP knockout mice show a defective protective immune response to breast cancer cells. Moreover, tumors in E-FABP knockout mice contained much lower numbers of NK cells, CD8+ and CD4+ T cells than those in WT mice. All these results suggest E-FABP protects host from tumor development, implicating a significant role of E-FABP in host immunity against tumor formation. Citation Format: Yuwen Zhang, Enyu Rao, Bing Li. E-FABP protects host from tumor development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2881. doi:10.1158/1538-7445.AM2013-2881
- Published
- 2013
25. The Mir-17~92 Cluster Enhances Cell Growth and Resistance to Chemotherapy in Mantle Cell Lymphoma by Down-Regulating PTEN, PHLPP2 and BIM
- Author
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George E. Wright, Ming Ji, Javeed Iqbal, Timothy W. McKeithan, Kai Fu, Wing C. Chan, Chunsun Jiang, Yong Zhao, Louis M. Staudt, and Enyu Rao
- Subjects
biology ,Cell growth ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Molecular biology ,Cyclin D1 ,hemic and lymphatic diseases ,microRNA ,biology.protein ,medicine ,Cancer research ,PTEN ,Mantle cell lymphoma ,Carcinogenesis ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy and is characterized by the chromosome translocation t(11;14)(q13;q32), which results in aberrant expression of cyclin D1. The t(11;14)(q13;q32) alone is not sufficient to result in lymphoma, and additional genetic alterations are necessary. Secondary genomic alterations are frequently detected in MCL, of which chromosome 13q31–q32 gain/amplification is one of the most frequent. Amplification at chromosome 13q31–q32 targets a microRNA cluster, miR-17~92, which resides within intron 3 of c13orf25, a non-protein-coding gene at 13q31.3. The miR-17~92 cluster consists of seven miRNAs, and overexpression of the cluster accelerates the development of MYC-induced lymphoma in mice and contributes to carcinogenesis in the lung. Nevertheless, the functional role of miR-17~92 in MCL has not been investigated. Based on gene expression profiling study of 82 primary MCL biopsy specimens using whole genome Affymetrix U133 2.0 plus arrays, we found that overexpression of miR-17~92 was associated with worse overall survival in patients with MCL (p=0.021). We further demonstrated that enforced expression of miR-17~92 reduced chemotherapy-induced apoptosis in retrovirally transduced MCL cell lines. Immunoblot analysis showed that PTEN was down-modulated in MCL cells with overexpression of miR-17~92, and the level of PTEN was restored with reduction of miR-20a levels using an antisense oligonucleotide or a “sponge” plasmid with multiple tandem miR-20a binding sites. The finding was further confirmed by luciferase assays using a reporter plasmid containing the PTEN 3′UTR, and the effect was abrogated by mutating the miR-20 binding site in reporter plasmid, indicating that PTEN was downregulated through the binding of miRNA to the 3′UTR of the transcript. Furthermore, we demonstrated that overexpression of miR-17~92 in MCL cells increased the phosphorylation of AKT and its downstream targets. Interestingly, we found that the protein phosphatase PHLPP2, a negative regulator of the PI3K/Akt pathway, was also a direct target of the miR-17~92 cluster. Moreover, we found that BIM, a BH3-only proapoptotic protein, was a direct target of the miR-17~92 and down-modulation of BIM negatively impacted the intrinsic pathway of apoptosis. In summary, we demonstrated that overexpression of miR-17~92 in MCL cells downmodulates multiple proteins involved in PI3K/Akt signaling and apoptosis, and that downregulation of these targets collaboratively enhances cell growth and chemoresistance in tumor cells. As a consequence, overexpression of miR-17~92 may be associated with poorer survival in MCL patients. Our findings disclose a novel oncogenic pathway in MCL and suggest that targeting the miR-17~92 cluster may provide a novel therapeutic approach for this disease, which is incurable with current chemotherapeutic regimens.
- Published
- 2008
26. Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein
- Author
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Margot P. Cleary, Young In Chi, Bing Li, Jiaqing Hao, Yan Li, Enyu Rao, Ganqian Zhu, Yuwen Zhang, Xiuhong Zhai, Puja Singh, and Rhoderick E. Brown
- Subjects
Models, Molecular ,Inflammation ,Stimulation ,Biology ,Fatty Acid-Binding Proteins ,Fatty acid-binding protein ,Epidermal Fatty Acid-Binding Protein ,Mice ,In vivo ,Lipid droplet ,Nitriles ,tumor treatment ,medicine ,Animals ,Humans ,Oxazoles ,interferon β ,Mammary tumor ,tumor associated macrophages ,Activator (genetics) ,Macrophages ,Mammary Neoplasms, Experimental ,Interferon-beta ,E-FABP ,Macrophage Activation ,3. Good health ,Oncology ,Biochemistry ,Cancer research ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Research Paper - Abstract
Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNβ responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5-(benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.
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