36 results on '"Keman Xu"'
Search Results
2. 29 m6A-RNA Methylation (Epitranscriptomic) Regulators Are Regulated in 41 Diseases including Atherosclerosis and Tumors Potentially via ROS Regulation – 102 Transcriptomic Dataset Analyses
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Ming Liu, Keman Xu, Fatma Saaoud, Ying Shao, Ruijing Zhang, Yifan Lu, Yu Sun, Charles Drummer, Li Li, Sheng Wu, Satya P. Kunapuli, Gerard J. Criner, Jianxin Sun, Huimin Shan, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Article Subject ,Immunology ,Immunology and Allergy ,General Medicine - Abstract
We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m6A-RNA methylation (epitranscriptomic) regulators (m6A-RMRs) in 41 diseases and cancers and made significant findings: (1) a few m6A-RMRs were upregulated; and most m6A-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 m6A-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated m6A-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated m6A-RMRs; end-stage renal failure (ESRF) downregulated 85% of m6A-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated m6A-RMRs the most among viral infections; (6) proinflammatory oxPAPC modulated m6A-RMRs more than DAMP stimulation including LPS and oxLDL; (7) upregulated m6A-RMRs were more than downregulated m6A-RMRs in cancer types; five types of cancers upregulated ≥10 m6A-RMRs; (8) proinflammatory M1 macrophages upregulated seven m6A-RMRs; (9) 86% of m6A-RMRs were differentially expressed in the six clusters of CD4+Foxp3+ immunosuppressive Treg, and 8 out of 12 Treg signatures regulated m6A-RMRs; (10) immune checkpoint receptors TIM3, TIGIT, PD-L2, and CTLA4 modulated m6A-RMRs, and inhibition of CD40 upregulated m6A-RMRs; (11) cytokines and interferons modulated m6A-RMRs; (12) NF-κB and JAK/STAT pathways upregulated more than downregulated m6A-RMRs whereas TP53, PTEN, and APC did the opposite; (13) methionine-homocysteine-methyl cycle enzyme Mthfd1 downregulated more than upregulated m6A-RMRs; (14) m6A writer RBM15 and one m6A eraser FTO, H3K4 methyltransferase MLL1, and DNA methyltransferase, DNMT1, regulated m6A-RMRs; and (15) 40 out of 165 ROS regulators were modulated by m6A eraser FTO and two m6A writers METTL3 and WTAP. Our findings shed new light on the functions of upregulated m6A-RMRs in 41 diseases and cancers, nine cellular and molecular mechanisms, novel therapeutic targets for inflammatory disorders, metabolic cardiovascular diseases, autoimmune diseases, organ failures, and cancers.
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- 2022
3. Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways
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Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W. Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L. Williams, Chuanfu Li, Laisel Martinez, Roberto I. Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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General Medicine - Abstract
We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in non-liver tissues, whether TMAO promotes inflammation via trained immunity (TI) and made the following findings: Endoplasmic reticulum (ER) stress genes were co-upregulated with mitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas,;4) TMAO trans-differentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1; TMAO upregulated 3 mitochondrial genes and downregulated inflammation inhibitor DARS2, induced mitoROS; and mitoTEMPO inhibited TMAO-induced ICAM-1; and -glucan priming followed by TMAO re-stimulation upregulated TNF-α by inducing metabolic reprogramming; and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided novel insights over TMAO roles in inducing EC activation and innate immune trans-differentiation, inducing metabolic reprogramming and TI for enhanced vascular inflammation and new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammations, transplantation, aging, and cancers.
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- 2023
4. Early Hyperlipidemia Triggers Metabolomic Reprogramming with Increased Sah, Increased Acetyl-Coa-Cholesterol Synthesis, and Decreased Glycolysis
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Keman Xu, Fatma Saaoud, Ying Shao, Yifan Lu, Sheng Wu, Huaqing Zhao, Kaifu Chen, Roberto Vazquez-Padron, Xiaohua Jiang, Hong Wang, and xiao-feng Yang
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- 2023
5. Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD
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Charles I. V. Drummer, Keman Xu, Fatma Saaoud, Yifan Lu, Xiaohua Jiang, Xiaofeng Yang, Ying Shao, Diana Atar, Candice Johnson, Li Liu, Huimin Shen, Nirag Jhala, Yu Sun, and Hong Wang
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Article Subject ,Immunology ,Hyperlipidemias ,Inflammation ,Glycine N-Methyltransferase ,Diet, High-Fat ,Methylation ,digestive system ,Proinflammatory cytokine ,Mice ,Immune system ,Downregulation and upregulation ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Humans ,Immunology and Allergy ,Liver X receptor ,Mice, Knockout ,business.industry ,Caspase 1 ,Immunity ,nutritional and metabolic diseases ,Inflammasome ,Methionine Adenosyltransferase ,General Medicine ,RC581-607 ,medicine.disease ,digestive system diseases ,Transplantation ,Disease Models, Animal ,Caspases ,Cancer research ,Cytokines ,Immunologic diseases. Allergy ,Inflammation Mediators ,medicine.symptom ,business ,Research Article ,medicine.drug - Abstract
We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid β-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.
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- 2021
6. Editorial: Endothelial cells as innate immune cells
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Yifan, Lu, Yu, Sun, Keman, Xu, Ying, Shao, Fatma, Saaoud, Nathaniel W, Snyder, Ling, Yang, Jun, Yu, Sheng, Wu, Wenhui, Hu, Jianxin, Sun, Hong, Wang, and Xiaofeng, Yang
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Inflammation ,Immunology ,Humans ,Endothelial Cells ,Immunology and Allergy ,Immunity, Innate - Published
- 2022
7. Trained Immunity and Reactivity of Macrophages and Endothelial Cells
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Xiaofeng Yang, Dong Ni, Keman Xu, Fatma Saaoud, Hong Wang, Xiaohua Jiang, Yu Sun, Yifan Lu, Ying Shao, Diana Atar, and Charles Drummer
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0301 basic medicine ,Inflammation ,030204 cardiovascular system & hematology ,Infections ,Article ,Epigenesis, Genetic ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Metabolic Diseases ,Risk Factors ,Immunity ,medicine ,Animals ,Humans ,Macrophage ,Glutaminolysis ,Innate immune system ,Chemistry ,Macrophages ,Models, Immunological ,Endothelial Cells ,Immunity, Innate ,Chromatin ,Cell biology ,030104 developmental biology ,Cardiovascular Diseases ,Reperfusion Injury ,Cytokines ,medicine.symptom ,Energy Metabolism ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,Immunologic Memory ,Metabolic Networks and Pathways - Abstract
Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.
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- 2021
8. Chronic Exposure to the Combination of Cigarette Smoke and Morphine Decreases CD4+ Regulatory T Cell Numbers by Reprogramming the Treg Cell Transcriptome
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Ying Shao, William Cornwell, Keman Xu, Aaron Kirchhoff, Fatma Saasoud, Yifan Lu, Xiaohua Jiang, Gerard J. Criner, Hong Wang, Thomas J. Rogers, and Xiaofeng Yang
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Immunology ,Immunology and Allergy ,chemical and pharmacologic phenomena - Abstract
There is a high incidence of tobacco use among intravenous opioid drug users. It is well established that opioids and tobacco smoke induce a degree of immune activation, and recent work suggests that the combination of these drugs promotes further activation of the immune system. Our approach involved the treatment of wild-type mice with cigarette smoke (SM) for a period of eight weeks, and the chronic continuous administration of morphine (M) via mini-pumps for the final four weeks. In an effort to examine the responses of CD4+CD25highCD127low regulatory T (Treg) cells, the major immune suppressive cell type, to the combined chronic administration of SM and M, we determined the frequency of these cells in the spleen, lymph nodes and lungs. Flow cytometric analyses showed that SM and M individually, and the combination (SM + M) have differential effects on the numbers of Treg in the spleen, lymph node, and lung. Either SM or M alone increased Treg cell numbers in the spleen, but SM+M did not. Furthermore, SM + M decreased Treg cell numbers in the lymph node and lung. We then performed RNA-Seq on Treg cells from mice treated with SM, M, or SM + M, and we found that the S + M induced a number of significant changes in the transcriptome, that were not as apparent following treatment with either SM or M alone. This included an activation of TWEAK, PI3K/AKT and OXPHOS pathways and a shift to Th17 immunity. Our results have provided novel insights on tissue Treg cell changes, which we suggest are the result of transcriptomic reprogramming induced by SM, M, and SM + M, respectively. We believe these results may lead to the identification of novel therapeutic targets for suppressing smoke and opioid induced Treg cell impairment.
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- 2022
9. Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity
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Yifan, Lu, Yu, Sun, Keman, Xu, Fatma, Saaoud, Ying, Shao, Charles, Drummer, Sheng, Wu, Wenhui, Hu, Jun, Yu, Satya P, Kunapuli, John R, Bethea, Roberto I, Vazquez-Padron, Jianxin, Sun, Xiaohua, Jiang, Hong, Wang, and Xiaofeng, Yang
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NF-E2-Related Factor 2 ,Angiotensin II ,Caspase 1 ,Immunology ,COVID-19 ,Endothelial Cells ,Cell Differentiation ,stomatognathic system ,Cell Transdifferentiation ,Middle East Respiratory Syndrome Coronavirus ,cardiovascular system ,Cytokines ,Humans ,Immunology and Allergy ,Renal Insufficiency, Chronic ,Aorta ,Secretome - Abstract
To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel–Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang-II induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase 1 SGs play roles at early MERS-CoV infected ECs whereas caspase 4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase 1 SGs may function as drivers for trained immunity (innate immune memory); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.
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- 2022
10. Chronic Exposure to the Combination of Cigarette Smoke and Morphine Decreases CD4
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Ying, Shao, William, Cornwell, Keman, Xu, Aaron, Kirchhoff, Fatma, Saasoud, Yifan, Lu, Xiaohua, Jiang, Gerard J, Criner, Hong, Wang, Thomas J, Rogers, and Xiaofeng, Yang
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Analgesics, Opioid ,Mice ,Phosphatidylinositol 3-Kinases ,Morphine ,Animals ,Transcriptome ,T-Lymphocytes, Regulatory ,Cigarette Smoking - Abstract
There is a high incidence of tobacco use among intravenous opioid drug users. It is well established that opioids and tobacco smoke induce a degree of immune activation, and recent work suggests that the combination of these drugs promotes further activation of the immune system. Our approach involved the treatment of wild-type mice with cigarette smoke (SM) for a period of eight weeks, and the chronic continuous administration of morphine (M)
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- 2022
11. Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation
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Keman Xu, Ying Shao, Fatma Saaoud, Aria Gillespie, Charles Drummer, Lu Liu, Yifan Lu, Yu Sun, Hang Xi, Çagla Tükel, Domenico Pratico, Xuebin Qin, Jianxin Sun, Eric T. Choi, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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secretomes ,Chemistry ,aortic endothelial cell ,Cardiovascular Medicine ,Cell biology ,RNA-Seq analysis ,Transcriptome ,Endothelial stem cell ,chemistry.chemical_compound ,inflammation ,RC666-701 ,Lysophosphatidylinositol ,Diseases of the circulatory (Cardiovascular) system ,Profiling (information science) ,Cardiology and Cardiovascular Medicine ,transcriptomic analysis ,Original Research - Abstract
To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.
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- 2021
12. Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids
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Aimilia Rigakou, Eleni Melliou, Bohan Chen, Diomedes E. Logothetis, Meng Cui, Prokopios Magiatis, Keman Xu, and Panagiotis Diamantakos
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Functional assay ,Mediterranean diet ,Science ,Calcium mobilization ,Bitter taste receptor activity ,Article ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Phenols ,stomatognathic system ,Oleuropein ,Target identification ,Humans ,Iridoids ,Food science ,Olive Oil ,Natural products ,Multidisciplinary ,Small molecules ,food and beverages ,Chemical biology ,HEK293 Cells ,chemistry ,Medicine ,Bitter taste receptors ,TAS2R14 ,psychological phenomena and processes ,Olive oil - Abstract
Extra-virgin olive oil (EVOO) is a critical component of the Mediterranean diet, which has been found beneficial to human health. Bitterness is often positively associated with the presence of phenolic compounds in EVOO. There are twenty-five bitter taste receptors (TAS2Rs) in humans, each of which responds to specific bitter tastants. The identity of phenolic compounds and the bitter taste receptors they stimulate remain unknown. In this study, we isolated 12 phenolic and secoiridoid compounds from the olive fruit and the oil extracted from it, and tested their ability to stimulate bitter taste receptor activity, using a calcium mobilization functional assay. Our results showed that seven out of twelve studied compounds activated TAS2R8, and five of them activated TAS2R1, TAS2R8, and TAS2R14. The phenolic compounds oleuropein aglycon and ligstroside aglycon were the most potent bitter tastants in olive oil. TAS2R1 and TAS2R8 were the major bitter taste receptors activated most potently by these phenolic compounds. The results obtained here could be utilized to predict and control the bitterness of olive oil based on the concentration of specific bitter phenolics produced during the milling process of olives.
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- 2021
13. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms
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Fatma Saaoud, Keman Xu, Xiaohua Jiang, Ying Shao, Yu Sun, Xiaofeng Yang, Hong Wang, Huimin Shan, William Y. Yang, Ethan M. Shevach, Yifan Lu, and Charles Drummer
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CD4-Positive T-Lymphocytes ,Receptors, CCR5 ,Mice, Knockout, ApoE ,Programmed Cell Death 1 Receptor ,Cardiology ,chemical and pharmacologic phenomena ,Spleen ,Inflammation ,Biology ,T-Lymphocytes, Regulatory ,Mice ,Chemokine receptor ,TIGIT ,Cell Movement ,medicine ,Animals ,Receptors, Immunologic ,Receptor ,Aorta ,Mice, Knockout ,Interleukins ,TOR Serine-Threonine Kinases ,FOXP3 ,RNA ,Forkhead Transcription Factors ,hemic and immune systems ,Cellular immune response ,General Medicine ,Atherosclerosis ,Phenotype ,Interleukin-10 ,medicine.anatomical_structure ,Cancer research ,Cytokines ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article - Abstract
Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE–/– mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35–deficient (IL-35P35–deficient) mice on an ApoE–/– background and found Treg reduction in the spleen and aorta compared with ApoE–/– controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE–/– Tregs, and we have validated higher CCR5 expression in ApoE–/– Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE–/– have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
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- 2021
14. 29 m
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Ming, Liu, Keman, Xu, Fatma, Saaoud, Ying, Shao, Ruijing, Zhang, Yifan, Lu, Yu, Sun, Charles, Drummer, Li, Li, Sheng, Wu, Satya P, Kunapuli, Gerard J, Criner, Jianxin, Sun, Huimin, Shan, Xiaohua, Jiang, Hong, Wang, and Xiaofeng, Yang
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Inflammation ,Adenosine ,Metabolic Diseases ,Gene Expression Profiling ,Neoplasms ,Datasets as Topic ,Humans ,RNA, Messenger ,Atherosclerosis ,Reactive Oxygen Species ,Methylation ,Autoimmune Diseases ,Epigenesis, Genetic - Abstract
We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m
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- 2021
15. Reply to Comment on Shen H
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Haitao, Shen, Na, Wu, Gayani, Nanayakkara, Hangfei, Fu, Qian, Yang, William Y, Yang, Angus, Li, Yu, Sun, Charles Drummer, Iv, Candice, Johnson, Ying, Shao, Luqiao, Wang, Keman, Xu, Wenhui, Hu, Marion, Chan, Vincent, Tam, Eric T, Choi, Hong, Wang, and Xiaofeng, Yang
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T-Lymphocytes ,Cell Plasticity ,Immune Tolerance ,Signal Transduction - Abstract
No abstract present.
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- 2021
16. Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators
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Ming Liu, Na Wu, Keman Xu, Fatma Saaoud, Eleni Vasilopoulos, Ying Shao, Ruijing Zhang, Jirong Wang, Haitao Shen, William Y. Yang, Yifan Lu, Yu Sun, Charles Drummer, Lu Liu, Li Li, Wenhui Hu, Jun Yu, Domenico Praticò, Jianxin Sun, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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0301 basic medicine ,Autophagosome ,organelle crosstalk ,viral infections ,Cell ,Inflammation ,Cardiovascular Medicine ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Lysosome ,Mitophagy ,medicine ,Diseases of the circulatory (Cardiovascular) system ,IL-2 receptor ,Original Research ,Endoplasmic reticulum ,endothelial cell activation ,Cell biology ,Treg ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,RC666-701 ,030220 oncology & carcinogenesis ,cancers and tumors ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
To examine whether the expressions of 260 organelle crosstalk regulators (OCRGs) in 16 functional groups are modulated in 23 diseases and 28 tumors, we performed extensive -omics data mining analyses and made a set of significant findings: (1) the ratios of upregulated vs. downregulated OCRGs are 1:2.8 in acute inflammations, 1:1 in metabolic diseases, 1:1.2 in autoimmune diseases, and 1:3.8 in organ failures; (2) sepsis and trauma-upregulated OCRG groups such as vesicle, mitochondrial (MT) fission, and mitophagy but not others, are termed as the cell crisis-handling OCRGs. Similarly, sepsis and trauma plus organ failures upregulated seven OCRG groups including vesicle, MT fission, mitophagy, sarcoplasmic reticulum–MT, MT fusion, autophagosome–lysosome fusion, and autophagosome/endosome–lysosome fusion, classified as the cell failure-handling OCRGs; (3) suppression of autophagosome–lysosome fusion in endothelial and epithelial cells is required for viral replications, which classify this decreased group as the viral replication-suppressed OCRGs; (4) pro-atherogenic damage-associated molecular patterns (DAMPs) such as oxidized low-density lipoprotein (oxLDL), lipopolysaccharide (LPS), oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), and interferons (IFNs) totally upregulated 33 OCRGs in endothelial cells (ECs) including vesicle, MT fission, mitophagy, MT fusion, endoplasmic reticulum (ER)–MT contact, ER– plasma membrane (PM) junction, autophagosome/endosome–lysosome fusion, sarcoplasmic reticulum–MT, autophagosome–endosome/lysosome fusion, and ER–Golgi complex (GC) interaction as the 10 EC-activation/inflammation-promoting OCRG groups; (5) the expression of OCRGs is upregulated more than downregulated in regulatory T cells (Tregs) from the lymph nodes, spleen, peripheral blood, intestine, and brown adipose tissue in comparison with that of CD4+CD25− T effector controls; (6) toll-like receptors (TLRs), reactive oxygen species (ROS) regulator nuclear factor erythroid 2-related factor 2 (Nrf2), and inflammasome-activated regulator caspase-1 regulated the expressions of OCRGs in diseases, virus-infected cells, and pro-atherogenic DAMP-treated ECs; (7) OCRG expressions are significantly modulated in all the 28 cancer datasets, and the upregulated OCRGs are correlated with tumor immune infiltrates in some tumors; (8) tumor promoter factor IKK2 and tumor suppressor Tp53 significantly modulate the expressions of OCRGs. Our findings provide novel insights on the roles of upregulated OCRGs in the pathogenesis of inflammatory diseases and cancers, and novel pathways for the future therapeutic interventions for inflammations, sepsis, trauma, organ failures, autoimmune diseases, metabolic cardiovascular diseases (CVDs), and cancers.
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- 2021
17. Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways
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Dong Ni, TingTing Tang, Yifan Lu, Keman Xu, Ying Shao, Fatma Saaoud, Jason Saredy, Lu Liu, Charles Drummer, Yu Sun, Wenhui Hu, Jahaira Lopez-Pastrana, Jin J. Luo, Xiaohua Jiang, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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0301 basic medicine ,Immunology ,Caspase 1 ,chemical and pharmacologic phenomena ,Biology ,Exosomes ,Models, Biological ,T-Lymphocytes, Regulatory ,Exosome ,Gene Expression Regulation, Enzymologic ,Mice ,03 medical and health sciences ,0302 clinical medicine ,canonical secretome ,Immunity ,Neoplasms ,Animals ,Humans ,Immunology and Allergy ,Original Research ,innate immune caspase-4/11 dependent secretome ,Innate immune system ,Gene Expression Profiling ,Computational Biology ,FOXP3 ,hemic and immune systems ,RC581-607 ,Immunity, Innate ,Immune checkpoint ,Microvesicles ,immune checkpoint receptors ,Gene Expression Regulation, Neoplastic ,Transplantation ,030104 developmental biology ,Organ Specificity ,Caspases ,030220 oncology & carcinogenesis ,Cancer research ,CD4+Foxp3+ regulatory T cells (Treg) ,innate immune caspase-1 dependent secretome ,Disease Susceptibility ,Immunologic diseases. Allergy ,Reactive Oxygen Species ,Biomarkers ,Signal Transduction - Abstract
We performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.
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- 2021
18. A novel small-molecule selective activator of homomeric GIRK4 channels
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Meng Cui, Keman Xu, Kirin D. Gada, Boris Shalomov, Michelle Ban, Giasemi C. Eptaminitaki, Takeharu Kawano, Leigh D. Plant, Nathan Dascal, and Diomedes E. Logothetis
- Subjects
Models, Molecular ,Phosphatidylinositol 4,5-Diphosphate ,Indoles ,G Protein-Coupled Inwardly-Rectifying Potassium Channels ,Humans ,Cell Biology ,Molecular Biology ,Biochemistry - Abstract
G protein-sensitive inwardly rectifying potassium (GIRK) channels are important pharmaceutical targets for neuronal, cardiac, and endocrine diseases. Although a number of GIRK channel modulators have been discovered in recent years, most lack selectivity. GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers. Activators, such as ML297, ivermectin, and GAT1508, have been shown to activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. In addition, VU0529331 was discovered as the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 (or G4) homomeric channels. Here, we report the first highly selective small-molecule activator targeting GIRK4 homomeric channels, 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). We show that 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. Using molecular modeling, mutagenesis, and electrophysiology, we analyzed the binding site of 3hi2one-G4 formed by the transmembrane 1, transmembrane 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site, and show that it causes channel activation by strengthening channel-phosphatidylinositol-4,5-bisphosphate interactions. We also identify slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2, as a major determinant of isoform-specific selectivity. We propose that 3hi2one-G4 could serve as a useful pharmaceutical probe in studying GIRK4 channel function and may also be pursued in drug optimization studies to tackle GIRK4-related diseases such as primary aldosteronism and late-onset obesity.
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- 2022
19. A benzopyran with antiarrhythmic activity is an inhibitor of Kir3.1-containing potassium channels
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Haozhou Tan, Diomedes E. Logothetis, Ganesh A. Thakur, Mengmeng Chang, Said EI-Haou, Obada Abou-Assali, Leigh D. Plant, Keman Xu, Yaser Alhamshari, Meng Cui, Lucas Cantwell, Sami F. Noujaim, James T. Milnes, Meghan Masotti, and Giasemi C. Eptaminitaki
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0301 basic medicine ,Carbachol ,AF, atrial fibrillation ,Protein subunit ,homology modeling ,Action Potentials ,Pharmacology ,Biochemistry ,Kir3, G-protein-gated inwardly rectifying K+ channel subfamily 3 ,IKACh, acetylcholine-activated inwardly rectifying K+ current ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,HK, high potassium ,Atrial Fibrillation ,medicine ,Animals ,Humans ,benzopyran- (BP-) G1, (3R,4S)-7-(hydroxymethyl)-2,2,9-trimethyl-4-(2-phenylethylamino)-3,4-dihydropyrano[2,3-g]quinolin-3-ol ,Channel blocker ,Benzopyrans ,Molecular Biology ,Ion channel ,Proarrhythmia ,HBC, helix bundle crossing ,030102 biochemistry & molecular biology ,Cell Biology ,molecular docking ,medicine.disease ,MD, molecular dynamics ,Potassium channel ,molecular dynamics ,Benzopyran ,Molecular Docking Simulation ,030104 developmental biology ,TEVC, two electrode voltage-clamp ,chemistry ,Mechanism of action ,G Protein-Coupled Inwardly-Rectifying Potassium Channels ,ion channel ,inhibition mechanism ,medicine.symptom ,Anti-Arrhythmia Agents ,Ion Channel Gating ,medicine.drug ,Research Article - Abstract
Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia and is associated with increased morbidity and mortality. Currently approved AF antiarrhythmic drugs have limited efficacy and/or carry the risk of ventricular proarrhythmia. The cardiac acetylcholine activated inwardly rectifying K+ current (IKACh), composed of Kir3.1/Kir3.4 heterotetrameric and Kir3.4 homotetrameric channel subunits, is one of the best validated atrial-specific ion channels. Previous research pointed to a series of benzopyran derivatives with potential for treatment of arrhythmias, but their mechanism of action was not defined. Here, we characterize one of these compounds termed Benzopyran-G1 (BP-G1) and report that it selectively inhibits the Kir3.1 (GIRK1 or G1) subunit of the KACh channel. Homology modeling, molecular docking, and molecular dynamics simulations predicted that BP-G1 inhibits the IKACh channel by blocking the central cavity pore. We identified the unique F137 residue of Kir3.1 as the critical determinant for the IKACh-selective response to BP-G1. The compound interacts with Kir3.1 residues E141 and D173 through hydrogen bonds that proved critical for its inhibitory activity. BP-G1 effectively blocked the IKACh channel response to carbachol in an in vivo rodent model and displayed good selectivity and pharmacokinetic properties. Thus, BP-G1 is a potent and selective small-molecule inhibitor targeting Kir3.1-containing channels and is a useful tool for investigating the role of Kir3.1 heteromeric channels in vivo. The mechanism reported here could provide the molecular basis for future discovery of novel, selective IKACh channel blockers to treat atrial fibrillation with minimal side effects.
- Published
- 2021
20. A Novel Subset of CD95
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Candice, Johnson, Charles, Drummer Iv, Huimin, Shan, Ying, Shao, Yu, Sun, Yifan, Lu, Fatma, Saaoud, Keman, Xu, Gayani, Nanayakkara, Pu, Fang, Zsolt, Bagi, Xiaohua, Jiang, Eric T, Choi, Hong, Wang, and Xiaofeng, Yang
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Male ,Vasculitis ,obesity ,Mice, Knockout, ApoE ,Macrophage ,Adipose Tissue, White ,Immunology ,Aortic Diseases ,Diet, High-Fat ,miR-155 ,Mice ,metabolic ,Animals ,Humans ,fas Receptor ,Aorta ,Cells, Cultured ,Original Research ,Inflammation ,Obesity, Metabolically Benign ,CD95 (Fas) ,Macrophages ,Endothelial Cells ,Atherosclerosis ,Intercellular Adhesion Molecule-1 ,metabolic disease ,adipose tissue ,Mice, Inbred C57BL ,MicroRNAs ,Culture Media, Conditioned ,Disease Progression ,Female ,B7-2 Antigen - Abstract
Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.
- Published
- 2020
21. Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis
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Hangfei Fu, Yu Sun, Ying Shao, Jason Saredy, Ramon Cueto, Lu Liu, Charles Drummer, Candice Johnson, Keman Xu, Yifan Lu, Xinyuan Li, Shu Meng, Eric R. Xue, Judy Tan, Nirag C. Jhala, Daohai Yu, Yan Zhou, Kayla J. Bayless, Jun Yu, Thomas J. Rogers, Wenhui Hu, Nathaniel W. Snyder, Jianxin Sun, Xuebin Qin, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Male ,lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Angiogenesis ,medicine.medical_treatment ,Immunology ,Neovascularization, Physiologic ,Cell Line ,Extracellular matrix ,angiogenesis ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Ischemia ,Extracellular ,medicine ,Animals ,Humans ,Immunology and Allergy ,ischemia and hypoxia ,Original Research ,Mice, Knockout ,Tube formation ,Neovascularization, Pathologic ,Chemistry ,Interleukins ,IL-12Rβ2 ,Receptors, Interleukin-12 ,Interleukin ,endothelial cells ,Extracellular Matrix ,Hindlimb ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Cytokine ,IL-35 ,Interleukin 35 ,Reactive Oxygen Species ,lcsh:RC581-607 ,030215 immunology - Abstract
Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii) HLI-induced angiogenesis is improved in Il12rb2−/− mice, in ApoE−/−/Il12rb2−/− mice compared to WT and ApoE−/− controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase.
- Published
- 2020
22. Vascular Endothelial Cells and Innate Immunity
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Charles Drummer, Hong Wang, Candice Johnson, Ying Shao, Xiaohua Jiang, Yifan Lu, Keman Xu, Xiaofeng Yang, William Y. Yang, Jason Saredy, Fatma Saaoud, and Yu Sun
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0301 basic medicine ,Arteriosclerosis ,medicine.medical_treatment ,animal diseases ,Antigen presentation ,Receptors, Cytoplasmic and Nuclear ,chemical and pharmacologic phenomena ,030204 cardiovascular system & hematology ,Biology ,Cardiovascular System ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immune Tolerance ,Humans ,Receptor ,Inflammation ,Antigen Presentation ,Innate immune system ,Macrophages ,Endothelial Cells ,Immunosuppression ,Thrombosis ,biochemical phenomena, metabolism, and nutrition ,Immune checkpoint ,Immunity, Innate ,030104 developmental biology ,Obesity, Abdominal ,Immunology ,bacteria ,Cytokines ,Cytokine secretion ,Cardiology and Cardiovascular Medicine ,Immunologic Memory ,Signal Transduction - Abstract
In addition to the roles of endothelial cells (ECs) in physiological processes, ECs actively participate in both innate and adaptive immune responses. We previously reported that, in comparison to macrophages, a prototypic innate immune cell type, ECs have many innate immune functions that macrophages carry out, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular patterns-, and danger-associated molecular patterns-sensing, proinflammatory, immune-enhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity. In this highlight, we introduce recent advances published in both ATVB and many other journals: (1) several significant characters classify ECs as novel immune cells not only in infections and allograft transplantation but also in metabolic diseases; (2) several new receptor systems including conditional danger-associated molecular pattern receptors, nonpattern receptors, and homeostasis associated molecular patterns receptors contribute to innate immune functions of ECs; (3) immunometabolism and innate immune memory determine the innate immune functions of ECs; (4) a great induction of the immune checkpoint receptors in ECs during inflammations suggests the immune tolerogenic functions of ECs; and (5) association of immune checkpoint inhibitors with cardiovascular adverse events and cardio-oncology indicates the potential contributions of ECs as innate immune cells.
- Published
- 2020
23. End-stage renal disease is different from chronic kidney disease in upregulating ROS-modulated proinflammatory secretome in PBMCs - A novel multiple-hit model for disease progression
- Author
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Yifan Lu, Ya-Feng Li, Yu Sun, Ying Shao, Daohai Yu, Elizabeth Cutler, Ming Liu, Jason Saredy, Eric T. Choi, William Y. Yang, Charles Drummer, Rongshan Li, Fatma Saaoud, Ruijing Zhang, Li Liu, Keman Xu, Tian Yao, Hong Wang, Jirong Wang, Lihua Wang, Xiaofeng Yang, Xiaohua Jiang, Hangfei Fu, and Candice Johnson
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0301 basic medicine ,Microarray ,IGFBP7 ,PBMC secretome ,CD58 ,Clinical Biochemistry ,Inflammation ,Trained immunity ,urologic and male genital diseases ,Biochemistry ,(CKD) ,Proinflammatory cytokine ,End stage renal disease ,03 medical and health sciences ,End-stage renal disease ,0302 clinical medicine ,Downregulation and upregulation ,stomatognathic system ,Chronic kidney disease ,Medicine ,Humans ,Renal Insufficiency, Chronic ,lcsh:QH301-705.5 ,lcsh:R5-920 ,business.industry ,Organic Chemistry ,(ESRD) ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,lcsh:Biology (General) ,Immunology ,Disease Progression ,Leukocytes, Mononuclear ,Articles from the Special Issue on Redox Signalling and Cardiovascular Disease ,Edited by Christopher Kevil and Yabing Chen ,Kidney Failure, Chronic ,(ROS) ,medicine.symptom ,lcsh:Medicine (General) ,business ,Reactive oxygen species ,030217 neurology & neurosurgery ,Kidney disease - Abstract
Background The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined. Methods We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG). Results 1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1β and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-β1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent. Conclusions Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).
- Published
- 2019
24. Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors
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Bin Lai, Jiwei Wang, Alexander Fagenson, Yu Sun, Jason Saredy, Yifan Lu, Gayani Nanayakkara, William Y. Yang, Daohai Yu, Ying Shao, Charles Drummer, Candice Johnson, Fatma Saaoud, Ruijing Zhang, Qian Yang, Keman Xu, Kevin Mastascusa, Ramon Cueto, Hangfei Fu, Susu Wu, Lizhe Sun, Peiqian Zhu, Xuebin Qin, Jun Yu, Daping Fan, Ying H. Shen, Jianxin Sun, Thomas Rogers, Eric T. Choi, Hong Wang, and Xiaofeng Yang
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Immunology ,Inflammation ,Biology ,Exosome ,Proinflammatory cytokine ,trained immunity ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Neoplasms ,medicine ,Data Mining ,Humans ,Immunology and Allergy ,Macrophage ,Original Research ,Innate immune system ,Microarray analysis techniques ,Immune checkpoint ,macrophages ,immune checkpoint receptors ,030104 developmental biology ,disease-specific and shared pathways ,medicine.symptom ,lcsh:RC581-607 ,immunometabolism pathways ,Signal Transduction ,030215 immunology - Abstract
The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations.
- Published
- 2019
25. Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation
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Fatma Saaoud, Charles Drummer, Xiaohua Jiang, Eric T. Choi, Xiaofeng Yang, Keman Xu, Gayani Nanayakkara, Hong Wang, Ying Shao, Yifan Lu, Li Liu, and Yu Sun
- Subjects
MAPK/ERK pathway ,Medicine (General) ,QH301-705.5 ,Aortic endothelial cell ,Clinical Biochemistry ,Caspase 1 ,Biochemistry ,R5-920 ,Interferon ,medicine ,Humans ,Biology (General) ,Nuclear export signal ,Aorta ,Inflammation ,Activator (genetics) ,Chemistry ,Organic Chemistry ,Endothelial Cells ,Lysophosphatidylcholines ,Cell biology ,Nuclear localization ,Secretomes ,Transplantation ,Cytosol ,Caspase-1 ,Cytochrome P-450 CYP1B1 ,lipids (amino acids, peptides, and proteins) ,Reactive Oxygen Species ,Nuclear localization sequence ,Research Paper ,medicine.drug - Abstract
To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).
- Published
- 2021
26. Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells
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Tracy Gao, William Y. Yang, Xiaofeng Yang, Muriel Lavallee, Keman Xu, Hong Wang, Pu Fang, Kylie Chan, and Xinyuan Li
- Subjects
0301 basic medicine ,Pharmacology ,Mitochondrial ROS ,chemistry.chemical_classification ,Reactive oxygen species ,Cell signaling ,ATP synthase ,biology ,Physiology ,medicine.medical_treatment ,T cell ,General Medicine ,Cell biology ,Endothelial activation ,03 medical and health sciences ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,chemistry ,Physiology (medical) ,Immunology ,biology.protein ,medicine ,Pathological - Abstract
Mitochondrial reactive oxygen species (mtROS) are signaling molecules, which drive inflammatory cytokine production and T cell activation. In addition, cardiovascular diseases, cancers, and autoimmune diseases all share a common feature of increased mtROS level. Both mtROS and ATP are produced as a result of electron transport chain activity, but it remains enigmatic whether mtROS could be generated independently from ATP synthesis. A recent study shed light on this important question and found that, during endothelial cell (EC) activation, mtROS could be upregulated in a proton leak-coupled, but ATP synthesis-uncoupled manner. As a result, EC could upregulate mtROS production for physiological EC activation without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and EC death. Thus, a novel pathophysiological role of proton leak in driving mtROS production was uncovered for low grade EC activation, patrolling immunosurveillance cell trans-endothelial migration and other signaling events without compromising cellular survival. This new working model explains how mtROS could be increasingly generated independently from ATP synthesis and endothelial damage or death. Mapping the connections among mitochondrial metabolism, physiological EC activation, patrolling cell migration, and pathological inflammation is significant towards the development of novel therapies for inflammatory diseases and cancers.
- Published
- 2017
27. Co-signaling receptors regulate T-cell plasticity and immune tolerance
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Gayani Nanayakkara, Marion M. Chan, Vincent H. Tam, William Y. Yang, Keman Xu, Wenhui Hu, Xiaofeng Yang, Haitao Shen, Hong Wang, Ying Shao, Luqiao Wang, Candice Johnson, Angus Li, Hangfei Fu, Qian Yang, Na Wu, Charles Drummer, Eric T. Choi, and Yu Sun
- Subjects
0301 basic medicine ,T cell ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Priming (immunology) ,Antigen-Presenting Cells ,Gene Expression ,Inflammation ,Biology ,Lymphocyte Activation ,Article ,Immune tolerance ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Immune Tolerance ,Animals ,Humans ,CD40 Antigens ,Receptor ,CD40 ,Receptors, Chimeric Antigen ,Gene Expression Profiling ,Macrophages ,Inflammasome ,Cell Differentiation ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,B7-1 Antigen ,medicine.symptom ,CD80 ,030215 immunology ,medicine.drug ,Signal Transduction - Abstract
We took an experimental database mining analysis to determine the expression of 28 co-signaling receptors in 32 human tissues in physiological/pathological conditions. We made the following significant findings: 1) co-signaling receptors are differentially expressed in tissues; 2) heart, trachea, kidney, mammary gland and muscle express co-signaling receptors that mediate CD4(+)T cell functions such as priming, differentiation, effector, and memory; 3) urinary tumor, germ cell tumor, leukemia and chondrosarcoma express high levels of co-signaling receptors for T cell activation; 4) expression of inflammasome components are correlated with the expression of co-signaling receptors; 5) CD40, SLAM, CD80 are differentially expressed in leukocytes from patients with trauma, bacterial infections, polarized macrophages and in activated endothelial cells; 6) forward and reverse signaling of 50% co-inhibition receptors are upregulated in endothelial cells during inflammation; and 7) STAT1 deficiency in T cells upregulates MHC class II and co-stimulation receptors. Our results have provided novel insights into co-signaling receptors as physiological regulators and potentiate identification of new therapeutic targets for the treatment of sterile inflammatory disorders.
- Published
- 2018
28. Molecular Mechanism of the Potent Benzopyran-G1 Blocker of Heteromeric G-Protein Gated Potassium Channels
- Author
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Sami F. Noujaim, Keman Xu, Haozhou Tan, Diomedes E. Logothetis, Said EI-Haou, James T. Milnes, Leigh D. Plant, Obada Abou-Assali, Meghan Masotti, Giasemi C. Eptaminitaki, Meng Cui, Mengmeng Chang, Yaser Alhamshari, Lucas Cantwell, and Ganesh A. Thakur
- Subjects
chemistry.chemical_compound ,Chemistry ,G protein ,Biophysics ,Molecular mechanism ,Potassium channel ,Benzopyran - Published
- 2021
29. Reply to Comment on Shen H, et al. 'Co-signaling receptors regulate T-cell plasticity and immune tolerance'. Frontiers in Bioscience-Landmark. 2019; 24: 96–132
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Xiaofeng Yang, Haitao Shen, Charles Drummer, Yu Sun, Ying Shao, Na Wu, Wenhui Hu, Luqiao Wang, Candice Johnson, Marion M. Chan, Keman Xu, Angus Li, Hong Wang, Vincent H. Tam, Qian Yang, Hangfei Fu, William Y. Yang, Eric T. Choi, and Gayani Nanayakkara
- Subjects
T cell plasticity ,General Immunology and Microbiology ,Biology ,Receptor ,Neuroscience ,General Biochemistry, Genetics and Molecular Biology ,Immune tolerance - Published
- 2021
30. High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia
- Author
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Xiaoyan Ke, Hongmei Jing, Huaping Fu, Jing Wang, Jinlong Shi, Kai Hu, Lei Tian, Keman Xu, Ji-Jun Wang, and Lin Fu
- Subjects
Adult ,Male ,0301 basic medicine ,RUNX1 ,Adolescent ,Microarray ,Kaplan-Meier Estimate ,CN-AML ,Bioinformatics ,Disease-Free Survival ,law.invention ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Text mining ,law ,hemic and lymphatic diseases ,microRNA ,Biomarkers, Tumor ,medicine ,Humans ,prognostic biomarker ,Gene ,Aged ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,Cohort ,Cancer research ,Suppressor ,Female ,business ,Research Paper - Abstract
Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways.
- Published
- 2016
31. Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice
- Author
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Fatma Saaoud, Lu Liu, Xiaohua Jiang, Kwan N. Lau, Hong Wang, Alexander M. Fagenson, Antonio Di Carlo, Xiaofeng Yang, Yu Sun, Nirag Jhala, Keman Xu, Charles Drummer, Gayani Nanayakkara, and Sunil S. Karhadkar
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_treatment ,Caspase 1 ,lcsh:Medicine ,Caspase-11 ,caspase 11 ,Liver transplantation ,urologic and male genital diseases ,Article ,trained immunity ,03 medical and health sciences ,0302 clinical medicine ,caspase 1 ,medicine ,Immunology and Allergy ,cardiovascular diseases ,inflammasomes ,Molecular Biology ,ischemia reperfusion injury ,Liver injury ,TUNEL assay ,General Immunology and Microbiology ,urogenital system ,business.industry ,lcsh:R ,fungi ,Pyroptosis ,Inflammasome ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,Infectious Diseases ,Cancer research ,business ,Reperfusion injury ,030215 immunology ,medicine.drug - Abstract
Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.
- Published
- 2020
32. Increased Plasticity of FOXP3+ Treg under Pathological Conditions Convert Treg into Either Novel Treg or Th1‐Treg
- Author
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Gayani Nanayakkara, Wenhui Hu, Hong Wang, Eric T. Choi, Ying Shao, Keman Xu, Fan Yang, Xiaofeng Yang, and William Y. Yang
- Subjects
Immunology ,Genetics ,FOXP3 ,Biology ,Plasticity ,Molecular Biology ,Biochemistry ,Pathological ,Biotechnology - Published
- 2018
33. STAT1 (Signal Transducer and Activator of Transcription 1) Deficiency in T Cells Upregulates MHC Class II and Co‐stimulation Receptors, Suggesting that STAT1 deficiency in T Cells May Increase the Plasticity and Convert in to Atypical Antigen Presenting Cells
- Author
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Wenhui Hu, Hangfei Fu, Gayani Nanayakkara, Xiaofeng Yang, Haitao Shen, Charles Drummer, Ying Shao, Luqiao Wang, Qian Yang, Na Wu, Hong Wang, Keman Xu, William Y. Yang, and Eric T. Choi
- Subjects
MHC class II ,biology ,Chemistry ,Plasticity ,Biochemistry ,Cell biology ,Co-stimulation ,Genetics ,biology.protein ,STAT protein ,STAT1 ,Receptor ,Antigen-presenting cell ,Molecular Biology ,Biotechnology - Published
- 2018
34. Molecular predictors of post-transplant survival in acute myeloid leukemia
- Author
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Sun Wu, Li Chen, Keman Xu, Chao Wang, Jinlong Shi, Huaping Fu, Hongmian Zhao, Lin Fu, Yu Han, Yifan Pang, Zhiheng Cheng, Tong Qin, Xiaoyan Ke, Yijie Zhang, and Kailin Xu
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,lcsh:RC254-282 ,Disease-Free Survival ,Group B ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Correspondence ,medicine ,Humans ,Transplantation, Homologous ,Young adult ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Proportional hazards model ,business.industry ,Hematopoietic Stem Cell Transplantation ,Cytogenetics ,Myeloid leukemia ,Cancer ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Mutation ,Female ,business ,030215 immunology - Published
- 2017
35. MOESM1 of High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions
- Author
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Fu, Lin, Huaping Fu, Qingyun Wu, Yifan Pang, Keman Xu, Zhou, Lei, Jianlin Qiao, Xiaoyan Ke, Kailin Xu, and Jinlong Shi
- Abstract
Additional file 1. The hierarchical differentiation tree of relationship between ETS2 expression level and hematopoietic cell differentiation.
- Published
- 2017
- Full Text
- View/download PDF
36. A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia
- Author
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Lin, Fu, Shi, Jinlong, Liu, Anqi, Zhou, Lei, Jiang, Mengmeng, Huaping, Fu, Keman, Xu, Dandan, Li, Deng, Ailing, Zhang, Qingyi, Pang, Yifan, Guo, Yujie, Kai, Hu, Zhou, Jiansuo, Wang, Yapeng, Huang, Wenrong, Jing, Yu, Dou, Liping, Wang, Lili, Kailin, Xu, Xiaoyan, Ke, Nervi, Clara, Yonghui, Li, and Li, Yu
- Subjects
miR-9-1 ,t (8 ,Oncogene Proteins, Fusion ,Carcinogenesis ,21) ,Down-Regulation ,acute myeloid leukemia ,Translocation, Genetic ,Cell Line ,RUNX1 Translocation Partner 1 Protein ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Humans ,medicine (all) ,RUNX1-RUNX1T1 ,Gene Expression Regulation, Leukemic ,Cell Differentiation ,oncology ,cancer research ,U937 Cells ,DNA Methylation ,Chromatin ,Leukemia, Myeloid, Acute ,MicroRNAs ,HEK293 Cells ,Core Binding Factor Alpha 2 Subunit ,Chromosomes, Human, Pair 8 ,Transcription Factors - Abstract
MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 downregulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex. In this study, we demonstrate that miR-9-1 expression increases significantly after the treatment of RUNX1-RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1 by binding to RUNX1-binding sites in the promoter region of miR-9-1 and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR-9-1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1-RUNX1T1 are all regulated by miR-9-1, the silencing of miR-9-1 enhances the oncogenic activity of these genes. Besides, overexpression of miR-9-1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1, contributing to leukemogenesis in RUNX1-RUNX1T1 (+) AML cell lines.
- Published
- 2015
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