67 results on '"Candice Johnson"'
Search Results
2. A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity
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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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Macrophage ,CD95 (Fas) ,atherosclerosis ,metabolic disease ,obesity ,metabolic ,Immunologic diseases. Allergy ,RC581-607 - 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.
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- 2021
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3. Ultrasound May Suppress Tumor Growth, Inhibit Inflammation, and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS, Immune Checkpoints, Cytokines, and Trained Immunity/Tolerance
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Qian Yang, Ruijing Zhang, Peng Tang, Yu Sun, Candice Johnson, Jason Saredy, Susu Wu, Jiwei Wang, Yifan Lu, Fatma Saaoud, Ying Shao, Charles Drummer, Keman Xu, Daohai Yu, Rongshan Li, Shuping Ge, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Background. The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. Methods. We used microarray datasets from the NCBI GEO DataSet repository and conducted comprehensive data-mining analyses, where we examined the gene expression of 1376 innate immune regulators (innatome genes (IGs) in cells treated with LIUS. Results. We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. (2) LIUS upregulates IGs encoded for proteins localized in the cytoplasm, extracellular space, and others, but downregulates IG proteins localized in nuclear and plasma membranes, and LIUS downregulates phosphatases. (3) LIUS-modulated IGs act partially via several important pathways of reactive oxygen species (ROS), reverse signaling of immune checkpoint receptors B7-H4 and BTNL2, inflammatory cytokines, and static or oscillatory shear stress and heat generation, among which ROS is a dominant mechanism. (4) LIUS upregulates trained immunity enzymes in lymphoma cells and downregulates trained immunity enzymes and presumably establishes trained tolerance in BM cells. (5) LIUS modulates chromatin long-range interactions to differentially regulate IGs expression in cancer cells and noncancer cells. Conclusions. Our analysis suggests novel molecular mechanisms that are utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.
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- 2021
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4. Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD
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Charles I. V. Drummer, Fatma Saaoud, Yu Sun, Diana Atar, Keman Xu, Yifan Lu, Ying Shao, Candice Johnson, Lu Liu, Huimin Shen, Nirag C. Jhala, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Immunologic diseases. Allergy ,RC581-607 - 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
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5. 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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IL-35 ,angiogenesis ,ischemia and hypoxia ,endothelial cells ,IL-12Rβ2 ,Immunologic diseases. Allergy ,RC581-607 - 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.
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- 2020
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6. Approaching Inflammation Paradoxes—Proinflammatory Cytokine Blockages Induce Inflammatory Regulators
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Ming Liu, Jason Saredy, Ruijing Zhang, Ying Shao, Yu Sun, William Y. Yang, Jirong Wang, Lu Liu, Charles Drummer, Candice Johnson, Fatma Saaoud, Yifan Lu, Keman Xu, Li Li, Xin Wang, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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proinflammatory cytokine blockage ,proinflammatory cytokines ,inflammation ,innate immune regulators ,reactive oxygen species ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The mechanisms that underlie various inflammation paradoxes, metabolically healthy obesity, and increased inflammations after inflammatory cytokine blockades and deficiencies remain poorly determined. We performed an extensive –omics database mining, determined the expressions of 1367 innate immune regulators in 18 microarrays after deficiencies of 15 proinflammatory cytokines/regulators and eight microarray datasets of patients receiving Mab therapies, and made a set of significant findings: 1) proinflammatory cytokines/regulators suppress the expressions of innate immune regulators; 2) upregulations of innate immune regulators in the deficiencies of IFNγ/IFNγR1, IL-17A, STAT3 and miR155 are more than that after deficiencies of TNFα, IL-1β, IL-6, IL-18, STAT1, NF-kB, and miR221; 3) IFNγ, IFNγR and IL-17RA inhibit 10, 59 and 39 proinflammatory cytokine/regulator pathways, respectively; in contrast, TNFα, IL-6 and IL-18 each inhibits only four to five pathways; 4) The IFNγ-promoted and -suppressed innate immune regulators have four shared pathways; the IFNγR1-promoted and -suppressed innate immune regulators have 11 shared pathways; and the miR155-promoted and -suppressed innate immune regulators have 13 shared pathways, suggesting negative-feedback mechanisms in their conserved regulatory pathways for innate immune regulators; 5) Deficiencies of proinflammatory cytokine/regulator-suppressed, promoted programs share signaling pathways and increase the likelihood of developing 11 diseases including cardiovascular disease; 6) There are the shared innate immune regulators and pathways between deficiency of TNFα in mice and anti-TNF therapy in clinical patients; 7) Mechanistically, up-regulated reactive oxygen species regulators such as myeloperoxidase caused by suppression of proinflammatory cytokines/regulators can drive the upregulation of suppressed innate immune regulators. Our findings have provided novel insights on various inflammation paradoxes and proinflammatory cytokines regulation of innate immune regulators; and may re-shape new therapeutic strategies for cardiovascular disease and other inflammatory diseases.
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- 2020
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7. 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
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Ruijing Zhang, Jason Saredy, Ying Shao, Tian Yao, Lu Liu, Fatma Saaoud, William Y. Yang, Yu Sun, Candice Johnson, Charles Drummer, IV, Hangfei Fu, Yifan Lu, Keman Xu, Ming Liu, Jirong Wang, Elizabeth Cutler, Daohai Yu, Xiaohua Jiang, Yafeng Li, Rongshan Li, Lihua Wang, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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Chronic kidney disease ,(CKD) ,End-stage renal disease ,(ESRD) ,PBMC secretome ,Reactive oxygen species ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - 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).
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- 2020
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8. 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
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macrophages ,disease-specific and shared pathways ,immune checkpoint receptors ,trained immunity ,immunometabolism pathways ,Immunologic diseases. Allergy ,RC581-607 - 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.
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- 2019
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9. A comprehensive data mining study shows that most nuclear receptors act as newly proposed homeostasis-associated molecular pattern receptors
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Luqiao Wang, Gayani Nanayakkara, Qian Yang, Hongmei Tan, Charles Drummer, Yu Sun, Ying Shao, Hangfei Fu, Ramon Cueto, Huimin Shan, Teodoro Bottiglieri, Ya-feng Li, Candice Johnson, William Y. Yang, Fan Yang, Yanjie Xu, Hang Xi, Weiqing Liu, Jun Yu, Eric T. Choi, Xiaoshu Cheng, Hong Wang, and Xiaofeng Yang
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Nuclear receptors (NRs) ,Homeostasis-associated molecular pattern receptors ,Atherosclerosis ,Metabolic disease ,Cardiovascular disease ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Nuclear receptors (NRs) can regulate gene expression; therefore, they are classified as transcription factors. Despite the extensive research carried out on NRs, still several issues including (1) the expression profile of NRs in human tissues, (2) how the NR expression is modulated during atherosclerosis and metabolic diseases, and (3) the overview of the role of NRs in inflammatory conditions are not fully understood. Methods To determine whether and how the expression of NRs are regulated in physiological/pathological conditions, we took an experimental database analysis to determine expression of all 48 known NRs in 21 human and 17 murine tissues as well as in pathological conditions. Results We made the following significant findings: (1) NRs are differentially expressed in tissues, which may be under regulation by oxygen sensors, angiogenesis pathway, stem cell master regulators, inflammasomes, and tissue hypo-/hypermethylation indexes; (2) NR sequence mutations are associated with increased risks for development of cancers and metabolic, cardiovascular, and autoimmune diseases; (3) NRs have less tendency to be upregulated than downregulated in cancers, and autoimmune and metabolic diseases, which may be regulated by inflammation pathways and mitochondrial energy enzymes; and (4) the innate immune sensor inflammasome/caspase-1 pathway regulates the expression of most NRs. Conclusions Based on our findings, we propose a new paradigm that most nuclear receptors are anti-inflammatory homeostasis-associated molecular pattern receptors (HAMPRs). Our results have provided a novel insight on NRs as therapeutic targets in metabolic diseases, inflammations, and malignancies.
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- 2017
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10. Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study
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Hangfei Fu, Nish Vadalia, Eric R. Xue, Candice Johnson, Luqiao Wang, William Y. Yang, Claudette Sanchez, Jun Nelson, Qian Chen, Eric T. Choi, Jian-Xing Ma, Jun Yu, Hong Wang, and Xiaofeng Yang
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Angiogenic genes ,Tissue expression of genes ,Pathological modulation of angiogenesis ,Immune regulation of angiogenesis ,Angiogenic leukocytes ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions and how angiogenesis is regulated in various disease conditions. Methods In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro-angiogenic, anti-angiogenic, and bi-functional C/Cs. Results We made the following findings: (1) the human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; (2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; (3) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; (4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; (5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; and (6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease. Conclusions Our results demonstrate that thrombus-derived leukocytes express more endothelial cell-specific angiogenic markers to directly promote angiogenesis after myocardial infarction and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others.
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- 2017
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11. Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways
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Ya-feng Li, Gayani Nanayakkara, Yu Sun, Xinyuan Li, Luqiao Wang, Ramon Cueto, Ying Shao, Hangfei Fu, Candice Johnson, Jiali Cheng, Xiongwen Chen, Wenhui Hu, Jun Yu, Eric T. Choi, Hong Wang, and Xiao-feng Yang
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Caspase-1 ,Microarray datasets ,Meta-analysis ,Inflammation and transcriptome ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1β, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the effects exerted by caspase-1 on transcriptome are mediated only by its well-known substrates. Therefore, we hypothesized that the effects of caspase-1 on transcriptome may be partially independent from IL-1β, IL-18, and Sirt-1. Methods To determine new global and tissue-specific gene regulatory effects of caspase-1, we took novel microarray data analysis approaches including Venn analysis, cooperation analysis, and meta-analysis methods. We used these statistical methods to integrate different microarray datasets conducted on different caspase-1 knockout tissues and datasets where caspase-1 downstream targets were manipulated. Results We made the following important findings: (1) Caspase-1 exerts its regulatory effects on the majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by sirtuin-1 during organ injury and inflammation in adipose tissue but not in the liver; (3) Caspase-1 cooperates with IL-1β in regulating less than half of the genes involved in cardiovascular disease, organismal injury, and cancer in mouse liver; (4) The meta-analysis identifies 40 caspase-1 globally regulated genes across tissues, suggesting that caspase-1 globally regulates many novel pathways; and (5) The meta-analysis identified new cooperatively and non-cooperatively regulated genes in caspase-1, IL-1β, IL-18, and Sirt-1 pathways. Conclusions Our findings suggest that caspase-1 regulates many new signaling pathways potentially via its known substrates and also via transcription factors and other proteins that are yet to be identified.
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- 2017
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12. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study
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Luqiao Wang, Hangfei Fu, Gayani Nanayakkara, Yafeng Li, Ying Shao, Candice Johnson, Jiali Cheng, William Y. Yang, Fan Yang, Muriel Lavallee, Yanjie Xu, Xiaoshu Cheng, Hang Xi, Jonathan Yi, Jun Yu, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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Caspase-1 ,Trafficking ,Nuclear gene regulation ,Inflammation propagation ,Exosome ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Caspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named “inflammasomes” for proteolytic activation. However, it remains unclear whether the proteolytic activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1. Methods We conducted meticulous data analysis method s on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies. Results We made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation. Conclusions Our identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers.
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- 2016
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13. Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells – Novel qualification markers for chronic disease risk factors and conditional DAMPs
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Yifan Lu, Yu Sun, Charles Drummer, IV, Gayani K. Nanayakkara, Ying Shao, Fatma Saaoud, Candice Johnson, Ruijing Zhang, Daohai Yu, Xinyuan Li, William Y. Yang, Jun Yu, Xiaohua Jiang, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245). Keywords: Trained immunity, Human aortic endothelial cell activation, Proatherogenic lipids lysophosphatidycholine (LPC), RNA-Seq, Chromatin long range interaction
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- 2019
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14. Increasing Upstream Chromatin Long–Range Interactions May Favor Induction of Circular RNAs in LysoPC-Activated Human Aortic Endothelial Cells
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Angus Li, Yu Sun, Charles Drummer, Yifan Lu, Daohai Yu, Yan Zhou, Xinyuan Li, Simone J. Pearson, Candice Johnson, Catherine Yu, William Y. Yang, Kevin Mastascusa, Xiaohua Jiang, Jianxin Sun, Thomas Rogers, Wenhui Hu, Hong Wang, and Xiaofeng Yang
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circular RNAs ,human aortic endothelial cell activation ,proatherogenic lipid lysophosphatidylcholine ,RNA-Seq ,chromatin long–range interaction ,Physiology ,QP1-981 - Abstract
Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC-induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; (3) Upregulation of 47 circRNAs is temporally associated with mRNAs-mediated LPC-upregulated cholesterol synthesis-SREBP2 pathway and LPC-downregulated TGF-β pathway; (4) Increase in upstream chromatin long-range interaction sites to circRNA related genes is associated with preferred circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long-range interaction sites from downstream to upstream may promote induction of a list of circRNAs in lysoPC-activated HAECs; (5) Six significantly changed circRNAs may have sponge functions for miRNAs; and (6) 74% significantly changed circRNAs contain open reading frames, suggesting that putative short proteins may interfere with the protein interaction-based signaling. Our findings have demonstrated for the first time that a new set of LPC-induced circRNAs may contribute to homeostasis in LPC-induced HAEC activation. These novel insights may lead to identifications of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations, and cancers.
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- 2019
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15. Increased Expression of Resistin in MicroRNA-155-Deficient White Adipose Tissues May Be a Possible Driver of Metabolically Healthy Obesity Transition to Classical Obesity
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Candice Johnson, Charles Drummer, Anthony Virtue, Tracy Gao, Susu Wu, Miguel Hernandez, Lexy Singh, Hong Wang, and Xiao-Feng Yang
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microRNAs ,atherosclerosis ,diabetes ,fatty liver disease ,obesity ,resistin ,Physiology ,QP1-981 - Abstract
We reported that microRNA-155 (miR-155) deficiency in ApoE-/- mice yields a novel metabolically healthy obese (MHO) model, which exhibits improved atherosclerosis but results in obesity, non-alcoholic fatty liver disease (NAFLD) without insulin resistance. Using experimental data mining approaches combined with experiments, we found that, among 109 miRNAs, miR-155, and miR-221 are significantly modulated in all four hyperlipidemia-related diseases (HRDs), namely atherosclerosis, NAFLD, obesity and type II diabetes (T2DM). MiR-155 is significantly upregulated in atherosclerosis and decreased in other HRDs. MiR-221 is increased in three HRDs but reduced in obesity. These findings led to our new classification of types I and II MHOs, which are regulated by miR-221 and miR-155, respectively. Western blots showed that the proinflammatory adipokine, resistin, is significantly increased in white adipose tissues (WAT) of the MHO mice, revealing our newly proposed, miR-155-suppressed “secondary wave inflammatory state (SWIS),” characteristic of MHO transition to classical obesity (CO). Taken together, we are first to show that MHO may have heterogeneity in comorbidities, and is therefore classified into type I, and type II MHOs; and that increased expression of resistin in miR-155-/- white adipose tissues may be a driver for SWIS in MHO transition to CO. Our findings provide novel insights into the pathogenesis of MHO, MHO transition to CO, hyperlipidemic pathways related to cancer, and new therapeutic targets.
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- 2018
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16. Low-Intensity Ultrasound-Induced Anti-inflammatory Effects Are Mediated by Several New Mechanisms Including Gene Induction, Immunosuppressor Cell Promotion, and Enhancement of Exosome Biogenesis and Docking
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Qian Yang, Gayani K. Nanayakkara, Charles Drummer, Yu Sun, Candice Johnson, Ramon Cueto, Hangfei Fu, Ying Shao, Luqiao Wang, William Y. Yang, Peng Tang, Li-Wen Liu, Shuping Ge, Xiao-Dong Zhou, Mohsin Khan, Hong Wang, and Xiaofeng Yang
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ultrasound ,anti-inflammatory gene induction ,exosomes ,immunosuppressor cells ,ultrasound for cancer therapy ,Physiology ,QP1-981 - Abstract
Background: Low-intensity ultrasound (LIUS) was shown to be beneficial in mitigating inflammation and facilitating tissue repair in various pathologies. Determination of the molecular mechanisms underlying the anti-inflammatory effects of LIUS allows to optimize this technique as a therapy for the treatment of malignancies and aseptic inflammatory disorders.Methods: We conducted cutting-edge database mining approaches to determine the anti-inflammatory mechanisms exerted by LIUS.Results: Our data revealed following interesting findings: (1) LIUS anti-inflammatory effects are mediated by upregulating anti-inflammatory gene expression; (2) LIUS induces the upregulation of the markers and master regulators of immunosuppressor cells including MDSCs (myeloid-derived suppressor cells), MSCs (mesenchymal stem cells), B1-B cells and Treg (regulatory T cells); (3) LIUS not only can be used as a therapeutic approach to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, and lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4) LIUS upregulates the expression of extracellular vesicle/exosome biogenesis mediators and docking mediators; (5) Exosome-carried anti-inflammatory cytokines and anti-inflammatory microRNAs inhibit inflammation of target cells via multiple shared and specific pathways, suggesting exosome-mediated anti-inflammatory effect of LIUS feasible; and (6) LIUS-mediated physical effects on tissues may activate specific cellular sensors that activate downstream transcription factors and signaling pathways.Conclusions: Our results have provided novel insights into the mechanisms underlying anti-inflammatory effects of LIUS, and have provided guidance for the development of future novel therapeutic LIUS for cancers, inflammatory disorders, tissue regeneration and tissue repair.
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- 2017
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17. Exploring Parent and Teacher Perceptions of Parent Involvement and Socioeconomic Status in Suburban Southern Georgia Elementary Schools: A Case Study
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Broome, Candice Johnson
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The purpose of this qualitative exploratory single case study was to explore how parents and teachers perceive the influence of socioeconomic status on parental involvement in suburban southern Georgia elementary schools. Two research questions were posed to fulfill the purpose of this study: How do parents perceive the influence of socioeconomic status on parental involvement in suburban southern Georgia elementary schools? and How do teachers perceive the influence of socioeconomic status on parental involvement in suburban southern Georgia elementary schools? Epstein's Framework for Parent Involvement and Hoover-Dempsey and Sandler's Model of Parent Involvement served as the theoretical foundations. Purposive sampling was used to select 22 parent and 59 teacher participants. Data collection comprised of semi-structured interviews of parents and teachers, questionnaires, and archival review of school documents to triangulate the data. Data were analyzed using a thematic analysis approach. Thematic analysis identified five themes: Defining Parent Involvement, Perception of Socioeconomic Status, Communication Methods, Perception of Involvement, and School Environment. Findings of this study revealed that elementary parents and teachers in South Georgia have differing perceptions of the influence of socioeconomic status on parent involvement. Overall, data revealed that while parent and teacher perceptions varied, they indicated that communication and the school environment were the most pertinent factors to their involvement. The implications for this study implicate that sharing the results of this study with both parents and teachers could possibly clarify expectations of each group and open a dialogue. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]
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- 2018
18. Implementation of
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Glenn J, Myatt, Arianna, Bassan, Dave, Bower, Candice, Johnson, Scott, Miller, Manuela, Pavan, and Kevin P, Cross
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Article - Abstract
Mechanistically-driven alternative approaches to hazard assessment invariably require a battery of tests, including both in silico models and experimental data. The decision-making process, from selection of the methods to combining the information based on the weight-of-evidence, is ideally described in published guidelines or protocols. This ensures that the application of such approaches is defendable to reviewers within regulatory agencies and across the industry. Examples include the ICH M7 pharmaceutical impurities guideline and the published in silico toxicology protocols. To support an efficient, transparent, consistent and fully documented implementation of these protocols, a new and novel interactive software solution is described to perform such an integrated hazard assessment based on public and proprietary information.
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- 2023
19. Evaluating Confidence in Toxicity Assessments Based on Experimental Data and
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Candice, Johnson, Lennart T, Anger, Romualdo, Benigni, David, Bower, Frank, Bringezu, Kevin M, Crofton, Mark T D, Cronin, Kevin P, Cross, Magdalena, Dettwiler, Markus, Frericks, Fjodor, Melnikov, Scott, Miller, David W, Roberts, Diana, Suarez-Rodriguez, Alessandra, Roncaglioni, Elena, Lo Piparo, Raymond R, Tice, Craig, Zwickl, and Glenn J, Myatt
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Article - Abstract
Understanding the reliability and relevance of a toxicological assessment is important for gauging the overall confidence and communicating the degree of uncertainty related to it. The process involved in assessing reliability and relevance is well defined for experimental data. Similar criteria need to be established for in silico predictions, as they become increasingly more important to fill data gaps and need to be reasonably integrated as additional lines of evidence. Thus, in silico assessments could be communicated with greater confidence and in a more harmonized manner. The current work expands on previous definitions of reliability, relevance, and confidence and establishes a conceptional framework to apply those to in silico data. The approach is used in two case studies: 1) phthalic anhydride, where experimental data are readily available and 2) 4-hydroxy-3-propoxybenzaldehyde, a data poor case which relies predominantly on in silico methods, showing that reliability, relevance, and confidence of in silico assessments can be effectively communicated within Integrated approaches to testing and assessment (IATA).
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- 2023
20. Implementation of In Silico Toxicology Protocols in Leadscope
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Kevin, Cross, Candice, Johnson, and Glenn J, Myatt
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Databases, Factual ,Quantitative Structure-Activity Relationship ,Computer Simulation ,Toxicology ,Software - Abstract
In silico toxicology protocols help ensure the results from computational toxicology models are performed and documented in a standardized, consistent, transparent, and accepted manner. In silico toxicology protocols for skin sensitization and genetic toxicology have been previously published and have been implemented within the Leadscope software. The following chapter outlines how such protocols have been deployed in the Leadscope platform including integration with toxicology databases and a battery of computational toxicology models.
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- 2022
21. O-105 Maternal occupation as a nail technician or hairdresser during pregnancy and birth defects, National Birth Defects Prevention Study, 1997–2011
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Miriam R Siegel, Carissa M Rocheleau, Kendra Broadwater, Albeliz Santiago-Colón, Michele L Herdt, I-Chen Chen, Christina C Lawson, and Candice Johnson
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- 2021
22. In silico approaches in organ toxicity hazard assessment: Current status and future needs for predicting heart, kidney and lung toxicities
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Jean-Pierre Valentin, Daniel P. Russo, David T. Szabo, Lidiya Stavitskaya, Patricia Ruiz, Craig Zwickl, Louise Neilson, Vinicius M. Alves, Candice Johnson, Andreas Bender, Arianna Bassan, Lennart T. Anger, Reena Sandhu, David Woolley, Lisa Beilke, Manuela Pavan, Raymond Kemper, Mark T. D. Cronin, Moiz Mumtaz, Glenn J. Myatt, Alexander Amberg, Yogesh Sabnis, Jui-Hua Hsieh, Markus Schaefer, Amy Pointon, Autumn Bernal, and Julia Pletz
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RA1190 ,medicine.medical_specialty ,Lung ,Kidney Toxicity ,business.industry ,Health, Toxicology and Mutagenesis ,In silico ,Toxicology ,Article ,Computer Science Applications ,RS ,QH301 ,medicine.anatomical_structure ,RA0421 ,Toxicity ,medicine ,Intensive care medicine ,business ,Chronic toxicity ,Vital organ ,ADME - Abstract
The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on in vitro and in silico approaches. This paper reviews the current state of the art in predicting these organ toxicities. It outlines the biological basis, processes and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization as well as functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing such assessment would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. However, a number of factors impede their widespread deployment including a lack of a comprehensive mechanistic understanding, limited in vitro testing approaches and limited in vivo databases suitable for modeling, a limited understanding of how to incorporate absorption, distribution, metabolism, and excretion (ADME) considerations into the overall process, a lack of in silico models designed to predict a safe dose and an accepted framework for organizing the key characteristics of these organ toxicants.
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- 2021
23. Editorial: In silico toxicology protocols initiative
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Kevin P. Cross, Candice Johnson, and Glenn J. Myatt
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Health, Toxicology and Mutagenesis ,Toxicology ,Computer Science Applications - Published
- 2022
24. Ultrasound May Suppress Tumor Growth, Inhibit Inflammation, and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS, Immune Checkpoints, Cytokines, and Trained Immunity/Tolerance
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Xiaofeng Yang, Qian Yang, Ying Shao, Candice Johnson, Peng Tang, Fatma Saaoud, Hong Wang, Rongshan Li, Shuping Ge, Susu Wu, Daohai Yu, Charles Drummer, Keman Xu, Jiwei Wang, Xiaohua Jiang, Jason Saredy, Ruijing Zhang, Yifan Lu, and Yu Sun
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Article Subject ,Immunology ,Inflammation ,Biology ,Adaptive Immunity ,Models, Biological ,Proinflammatory cytokine ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,medicine ,Immunology and Allergy ,Humans ,Lius ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Innate immune system ,Gene Expression Profiling ,General Medicine ,Hyperthermia, Induced ,RC581-607 ,biology.organism_classification ,Acquired immune system ,Immune Checkpoint Proteins ,Immune checkpoint ,Immunity, Innate ,Cell biology ,Ultrasonic Waves ,030220 oncology & carcinogenesis ,Heat generation ,Cytokines ,Tumor Escape ,medicine.symptom ,Immunologic diseases. Allergy ,Reactive Oxygen Species ,Signal Transduction ,Research Article - Abstract
Background. The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. Methods. We used microarray datasets from the NCBI GEO DataSet repository and conducted comprehensive data-mining analyses, where we examined the gene expression of 1376 innate immune regulators (innatome genes (IGs) in cells treated with LIUS. Results. We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. (2) LIUS upregulates IGs encoded for proteins localized in the cytoplasm, extracellular space, and others, but downregulates IG proteins localized in nuclear and plasma membranes, and LIUS downregulates phosphatases. (3) LIUS-modulated IGs act partially via several important pathways of reactive oxygen species (ROS), reverse signaling of immune checkpoint receptors B7-H4 and BTNL2, inflammatory cytokines, and static or oscillatory shear stress and heat generation, among which ROS is a dominant mechanism. (4) LIUS upregulates trained immunity enzymes in lymphoma cells and downregulates trained immunity enzymes and presumably establishes trained tolerance in BM cells. (5) LIUS modulates chromatin long-range interactions to differentially regulate IGs expression in cancer cells and noncancer cells. Conclusions. Our analysis suggests novel molecular mechanisms that are utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.
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- 2021
25. Increasing the acceptance of in silico toxicology through development of protocols and position papers
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Glenn J. Myatt, Arianna Bassan, Dave Bower, Kevin M. Crofton, Kevin P. Cross, Jessica C. Graham, Catrin Hasselgren, Robert A. Jolly, Scott Miller, Manuela Pavan, Raymond R Tice, Craig Zwickl, and Candice Johnson
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Health, Toxicology and Mutagenesis ,Toxicology ,Computer Science Applications - Published
- 2022
26. 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.
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- 2020
27. Orthotics and Assistive Devices
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Michael J. Peterson, Jennifer Klein, Candice Johnson, William Nolin, Janey McGeary Farber, and Marcie Ward
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Engineering ,medicine.medical_specialty ,Physical medicine and rehabilitation ,business.industry ,medicine ,Orthotics ,business - Published
- 2020
28. 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.
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- 2020
29. 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
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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).
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- 2019
30. Uremic toxins are conditional danger- or homeostasis-associated molecular patterns
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Yu Sun, Jun Zhou, Xiaofeng Yang, Xin Wang, Eric T. Choi, Ya-Feng Li, Ying Shao, Gayani Nanayakkara, Yifan Lu, Hong Wang, William Y. Yang, Rongshan Li, Claudette Sanchez, Hangfei Fu, Luqiao Wang, and Candice Johnson
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0301 basic medicine ,medicine.medical_treatment ,Caspase 1 ,Inflammation ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Metabolome ,medicine ,Alarmins ,Homeostasis ,Humans ,Renal Insufficiency, Chronic ,Receptor ,Toxins, Biological ,Uremia ,business.industry ,Gene Expression Profiling ,Gene expression profiling ,030104 developmental biology ,Cytokine ,Cardiovascular Diseases ,Cancer research ,Cytokines ,Inflammation Mediators ,Signal transduction ,medicine.symptom ,business ,Signal Transduction - Abstract
We mined novel uremic toxin (UT) metabolomics/gene databases, and analyzed the expression changes of UT receptors and UT synthases in chronic kidney disease (CKD) and cardiovascular disease (CVD). We made the following observations: 1) UTs represent only 1/80th of human serum small-molecule metabolome; 2) Some UTs are increased in CKD and CVD; 3) UTs either induce or suppress the expression of inflammatory molecules; 4) The expression of UT genes is significantly modulated in CKD patients, and coronary artery disease (CAD) patients; 5) The expression of UT genes is upregulated by caspase-1 and TNF-alpha pathways but is inhibited in regulatory T cells. These results demonstrate that UTs are selectively increased, and serve as danger signal-associated molecular patterns (DAMPs) and homeostasis-associated molecular patterns (HAMPs) that modulate inflammation. These results also show that some UT genes are upregulated in CKD and CAD via caspase-1/inflammatory cytokine pathways, rather than by purely passive accumulation.
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- 2018
31. A comprehensive data mining study shows that most nuclear receptors act as newly proposed homeostasis-associated molecular pattern receptors
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Qian Yang, Weiqing Liu, Eric T. Choi, Jun Yu, Hongmei Tan, William Y. Yang, Teodoro Bottiglieri, Ya-Feng Li, Ying Shao, Hang Xi, Hangfei Fu, Gayani Nanayakkara, Xiaoshu Cheng, Huimin Shan, Charles Drummer, Xiaofeng Yang, Yanjie Xu, Luqiao Wang, Candice Johnson, Ramon Cueto, Fan Yang, Yu Sun, and Hong Wang
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0301 basic medicine ,Cancer Research ,Receptors, Cytoplasmic and Nuclear ,Angiogenesis Pathway ,Metabolic disease ,Biology ,lcsh:RC254-282 ,03 medical and health sciences ,Downregulation and upregulation ,Gene expression ,medicine ,Data Mining ,Homeostasis ,Humans ,Nuclear receptors (NRs) ,Receptor ,Molecular Biology ,Transcription factor ,Innate immune system ,lcsh:RC633-647.5 ,Research ,Homeostasis-associated molecular pattern receptors ,Inflammasome ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,Atherosclerosis ,Cardiovascular disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,humanities ,Cell biology ,030104 developmental biology ,Oncology ,Nuclear receptor ,Immunology ,human activities ,medicine.drug - Abstract
Background Nuclear receptors (NRs) can regulate gene expression; therefore, they are classified as transcription factors. Despite the extensive research carried out on NRs, still several issues including (1) the expression profile of NRs in human tissues, (2) how the NR expression is modulated during atherosclerosis and metabolic diseases, and (3) the overview of the role of NRs in inflammatory conditions are not fully understood. Methods To determine whether and how the expression of NRs are regulated in physiological/pathological conditions, we took an experimental database analysis to determine expression of all 48 known NRs in 21 human and 17 murine tissues as well as in pathological conditions. Results We made the following significant findings: (1) NRs are differentially expressed in tissues, which may be under regulation by oxygen sensors, angiogenesis pathway, stem cell master regulators, inflammasomes, and tissue hypo-/hypermethylation indexes; (2) NR sequence mutations are associated with increased risks for development of cancers and metabolic, cardiovascular, and autoimmune diseases; (3) NRs have less tendency to be upregulated than downregulated in cancers, and autoimmune and metabolic diseases, which may be regulated by inflammation pathways and mitochondrial energy enzymes; and (4) the innate immune sensor inflammasome/caspase-1 pathway regulates the expression of most NRs. Conclusions Based on our findings, we propose a new paradigm that most nuclear receptors are anti-inflammatory homeostasis-associated molecular pattern receptors (HAMPRs). Our results have provided a novel insight on NRs as therapeutic targets in metabolic diseases, inflammations, and malignancies. Electronic supplementary material The online version of this article (10.1186/s13045-017-0526-8) contains supplementary material, which is available to authorized users.
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- 2017
32. Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways
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Ying Shao, Xiongwen Chen, Ramon Cueto, Ya-Feng Li, Luqiao Wang, Candice Johnson, Xiaofeng Yang, Wenhui Hu, Hangfei Fu, Xinyuan Li, Gayani Nanayakkara, Eric T. Choi, Jun Yu, Yu Sun, Jiali Cheng, and Hong Wang
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Male ,0301 basic medicine ,Cancer Research ,Inflammation and transcriptome ,Microarray ,Mice, Knockout, ApoE ,Microarray datasets ,Interleukin-1beta ,Datasets as Topic ,lcsh:RC254-282 ,Transcriptome ,Mice ,03 medical and health sciences ,Sirtuin 1 ,Animals ,Molecular Biology ,Transcription factor ,Gene ,Aorta ,Regulator gene ,Inflammation ,Genetics ,biology ,Microarray analysis techniques ,lcsh:RC633-647.5 ,Research ,Caspase 1 ,Interleukin-18 ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,Meta-analysis ,030104 developmental biology ,Adipose Tissue ,Gene Expression Regulation ,Liver ,Oncology ,Organ Specificity ,Tissue Array Analysis ,Caspase-1 ,biology.protein ,Signal transduction ,Energy Metabolism ,Signal Transduction - Abstract
Background It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1β, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the effects exerted by caspase-1 on transcriptome are mediated only by its well-known substrates. Therefore, we hypothesized that the effects of caspase-1 on transcriptome may be partially independent from IL-1β, IL-18, and Sirt-1. Methods To determine new global and tissue-specific gene regulatory effects of caspase-1, we took novel microarray data analysis approaches including Venn analysis, cooperation analysis, and meta-analysis methods. We used these statistical methods to integrate different microarray datasets conducted on different caspase-1 knockout tissues and datasets where caspase-1 downstream targets were manipulated. Results We made the following important findings: (1) Caspase-1 exerts its regulatory effects on the majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by sirtuin-1 during organ injury and inflammation in adipose tissue but not in the liver; (3) Caspase-1 cooperates with IL-1β in regulating less than half of the genes involved in cardiovascular disease, organismal injury, and cancer in mouse liver; (4) The meta-analysis identifies 40 caspase-1 globally regulated genes across tissues, suggesting that caspase-1 globally regulates many novel pathways; and (5) The meta-analysis identified new cooperatively and non-cooperatively regulated genes in caspase-1, IL-1β, IL-18, and Sirt-1 pathways. Conclusions Our findings suggest that caspase-1 regulates many new signaling pathways potentially via its known substrates and also via transcription factors and other proteins that are yet to be identified. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0406-2) contains supplementary material, which is available to authorized users.
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- 2017
33. MicroRNA-155 Deficiency Leads to Decreased Atherosclerosis, Increased White Adipose Tissue Obesity, and Non-alcoholic Fatty Liver Disease
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Hong Wang, Xinyuan Li, Hangfei Fu, Huimin Shan, Ying Shao, Michael G. Tordoff, Xiaohua Jiang, Jahaira Lopez-Pastrana, Ying Yin, Victor Rizzo, Xiaofeng Yang, Candice Johnson, Jietang Mai, Zsolt Bagi, Anthony Virtue, and Ya-Feng Li
- Subjects
0301 basic medicine ,Apolipoprotein E ,medicine.medical_specialty ,business.industry ,Leptin ,Fatty liver ,Inflammation ,Cell Biology ,White adipose tissue ,030204 cardiovascular system & hematology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,Resistin ,medicine.symptom ,business ,Molecular Biology ,Obesity paradox - Abstract
Obesity paradox (OP) describes a widely observed clinical finding of improved cardiovascular fitness and survival in some overweight or obese patients. The molecular mechanisms underlying OP remain enigmatic partly due to a lack of animal models mirroring OP in patients. Using apolipoprotein E knock-out (apoE−/−) mice on a high fat (HF) diet as an atherosclerotic obesity model, we demonstrated 1) microRNA-155 (miRNA-155, miR-155) is significantly up-regulated in the aortas of apoE−/− mice, and miR-155 deficiency in apoE−/− mice inhibits atherosclerosis; 2) apoE−/−/miR-155−/− (double knock-out (DKO)) mice show HF diet-induced obesity, adipocyte hypertrophy, and present with non-alcoholic fatty liver disease; 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin and increased expression of adipogenic transcription factors but lack glucose intolerance and insulin resistance. Our results are the first to present an OP model using DKO mice with features of decreased atherosclerosis, increased obesity, and non-alcoholic fatty liver disease. Our findings suggest the mechanistic role of reduced miR-155 expression in OP and present a new OP working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying OP and provide a new biomarker and novel therapeutic target for OP-related metabolic diseases.
- Published
- 2017
34. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study
- Author
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Ya-Feng Li, Jonathan Yi, Xiaofeng Yang, William Y. Yang, Gayani Nanayakkara, Hong Wang, Ying Shao, Eric T. Choi, Yanjie Xu, Hang Xi, Muriel Lavallee, Jiali Cheng, Fan Yang, Luqiao Wang, Candice Johnson, Hangfei Fu, Jun Yu, and Xiaoshu Cheng
- Subjects
0301 basic medicine ,Cancer Research ,Inflammasomes ,Caspase 1 ,Coronary Artery Disease ,Biology ,Exosome ,lcsh:RC254-282 ,03 medical and health sciences ,Gene expression ,Extracellular ,Animals ,Data Mining ,Humans ,Nuclear gene regulation ,Molecular Biology ,Cell Nucleus ,Inflammation ,Organelles ,Trafficking ,Cell Death ,Inflammation propagation ,lcsh:RC633-647.5 ,Research ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,Subcellular localization ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Chromatin ,Microvesicles ,3. Good health ,Cell biology ,Cytosol ,030104 developmental biology ,Gene Expression Regulation ,Oncology ,Caspase-1 - Abstract
Background Caspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named “inflammasomes” for proteolytic activation. However, it remains unclear whether the proteolytic activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1. Methods We conducted meticulous data analysis method s on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies. Results We made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation. Conclusions Our identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0351-5) contains supplementary material, which is available to authorized users.
- Published
- 2016
35. Increasing upstream chromatin long‐range interactions may favor induction of circular RNAs in lysoPC‐activated human aortic endothelial cells
- Author
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William Y. Yang, Yan Zhou, Yu Sun, Xiaofeng Yang, Hong Wang, Caijia Yu, Xinyuan Li, Candice Johnson, Angus Li, Wenhui Hu, Xiaohua Jiang, Daohai Yu, and Charles Drummer
- Subjects
Chemistry ,Range (biology) ,Genetics ,Biophysics ,Upstream (networking) ,Molecular Biology ,Biochemistry ,Biotechnology ,Chromatin - Published
- 2019
36. Increasing Upstream Chromatin Long-Range Interactions May Favor Induction of Circular RNAs in LysoPC-Activated Human Aortic Endothelial Cells
- Author
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Angus Li, Yu Sun, Charles Drummer, Yifan Lu, Daohai Yu, Yan Zhou, Xinyuan Li, Simone J. Pearson, Candice Johnson, Catherine Yu, William Y. Yang, Kevin Mastascusa, Xiaohua Jiang, Jianxin Sun, Thomas Rogers, Wenhui Hu, Hong Wang, and Xiaofeng Yang
- Subjects
0301 basic medicine ,Physiology ,lcsh:Physiology ,proatherogenic lipid lysophosphatidylcholine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Physiology (medical) ,chromatin long–range interaction ,microRNA ,RNA-Seq ,Gene ,lcsh:QP1-981 ,Chemistry ,human aortic endothelial cell activation ,Chromatin ,Cell biology ,Open reading frame ,030104 developmental biology ,Lysophosphatidylcholine ,030220 oncology & carcinogenesis ,RNA splicing ,lipids (amino acids, peptides, and proteins) ,circular RNAs ,Transforming growth factor - Abstract
Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC-induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; (3) Upregulation of 47 circRNAs is temporally associated with mRNAs-mediated LPC-upregulated cholesterol synthesis-SREBP2 pathway and LPC-downregulated TGF-β pathway; (4) Increase in upstream chromatin long-range interaction sites to circRNA related genes is associated with preferred circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long-range interaction sites from downstream to upstream may promote induction of a list of circRNAs in lysoPC-activated HAECs; (5) Six significantly changed circRNAs may have sponge functions for miRNAs; and (6) 74% significantly changed circRNAs contain open reading frames, suggesting that putative short proteins may interfere with the protein interaction-based signaling. Our findings have demonstrated for the first time that a new set of LPC-induced circRNAs may contribute to homeostasis in LPC-induced HAEC activation. These novel insights may lead to identifications of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations, and cancers.
- Published
- 2018
37. Co-signaling receptors regulate T-cell plasticity and immune tolerance
- Author
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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
38. 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
- Author
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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
39. Increased Expression of Resistin in MicroRNA-155-Deficient White Adipose Tissues May Be a Possible Driver of Metabolically Healthy Obesity Transition to Classical Obesity
- Author
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Hong Wang, Xiaofeng Yang, Lexy Singh, Miguel Hernandez, Charles Drummer, Anthony Virtue, Candice Johnson, Tracy Gao, and Susu Wu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,obesity ,Physiology ,Adipokine ,Adipose tissue ,lcsh:Physiology ,Proinflammatory cytokine ,miR-155 ,03 medical and health sciences ,Insulin resistance ,Physiology (medical) ,Diabetes mellitus ,Internal medicine ,Metabolically healthy obesity ,medicine ,Original Research ,resistin ,lcsh:QP1-981 ,diabetes ,business.industry ,Fatty liver ,medicine.disease ,3. Good health ,microRNAs ,miR-221 ,030104 developmental biology ,Endocrinology ,fatty liver disease ,Resistin ,atherosclerosis ,business - Abstract
We reported that microRNA-155 (miR-155) deficiency in ApoE-/- mice yields a novel metabolically healthy obese (MHO) model, which exhibits improved atherosclerosis but results in obesity, non-alcoholic fatty liver disease (NAFLD) without insulin resistance. Using experimental data mining approaches combined with experiments, we found that, among 109 miRNAs, miR-155, and miR-221 are significantly modulated in all four hyperlipidemia-related diseases (HRDs), namely atherosclerosis, NAFLD, obesity and type II diabetes (T2DM). MiR-155 is significantly upregulated in atherosclerosis and decreased in other HRDs. MiR-221 is increased in three HRDs but reduced in obesity. These findings led to our new classification of types I and II MHOs, which are regulated by miR-221 and miR-155, respectively. Western blots showed that the proinflammatory adipokine, resistin, is significantly increased in white adipose tissues (WAT) of the MHO mice, revealing our newly proposed, miR-155-suppressed “secondary wave inflammatory state (SWIS),” characteristic of MHO transition to classical obesity (CO). Taken together, we are first to show that MHO may have heterogeneity in comorbidities, and is therefore classified into type I, and type II MHOs; and that increased expression of resistin in miR-155-/- white adipose tissues may be a driver for SWIS in MHO transition to CO. Our findings provide novel insights into the pathogenesis of MHO, MHO transition to CO, hyperlipidemic pathways related to cancer, and new therapeutic targets.
- Published
- 2018
40. Mechanistic Study of Four Co‐Morbid Hyperlipidemia‐Related Pathologies Reveals NFκB and STAT3‐Mediated miR‐155 and miR‐221 Potentially Serve as Master Regulators, and Elucidates Metabolically Healthy Obese Model
- Author
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Candice Johnson, Hong Wang, Lexy Singh, Charles Drummer, Anthony Virtue, Tracy Gao, Xiaofeng Yang, and Miguel Hernandez
- Subjects
biology ,business.industry ,medicine.disease ,Biochemistry ,Co morbid ,miR-155 ,Hyperlipidemia ,Genetics ,Cancer research ,biology.protein ,Medicine ,business ,STAT3 ,Molecular Biology ,Biotechnology - Published
- 2018
41. Canonical and non‐canonical inflammasomes are differentially regulated in NAFLD, which may play important roles in sensing hyperlipidemic DAMPs and initiating the pathogenesis of the disease and liver inflammation
- Author
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Xiaofeng Yang, Candice Johnson, Charles Drummer, and Hong Wang
- Subjects
Pathogenesis ,Non canonical ,business.industry ,Immunology ,Genetics ,Medicine ,Inflammation ,Disease ,medicine.symptom ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2018
42. Abstract 518: Coronary Thrombus Leukocytes of Acute Coronary Syndrome Patients Trans-Differentiate Into Endothelial Cell-Like Angiogenic Cells
- Author
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Hong Wang, Nish Vadalia, Xiaofeng Yang, Hangfei Fu, Candice Johnson, Eric R. Xue, and Jun Yu
- Subjects
Acute coronary syndrome ,Pathology ,medicine.medical_specialty ,business.industry ,Angiogenesis ,Inflammation ,medicine.disease ,Thrombosis ,Endothelial stem cell ,Coronary thrombus ,Medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions; and how angiogenesis is regulated in various disease conditions. In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro-angiogenic, anti-angiogenic, and bi-functional C/Cs. We made the following findings: 1) human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; 2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; 3 ) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; 4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; 5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; 6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease. Our results demonstrate that thrombus-derived leukocytes are partially “hijacked” to become endothelial cell-like angiogenic cells that directly promote angiogenesis after myocardial infarction; and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others.
- Published
- 2017
43. Abstract 371: Deficiency in Microrna-155 Leads to Reduced Atherosclerosis, Increased Obesity and Nonalcoholic Fatty Liver Disease--A Novel Mouse Model of Metabolically Healthy Obesity
- Author
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Candice Johnson, Anthony Virtue, Jahaira Lopez-Pastraña, Ying Shao, Hangfei Fu, Xinyuan Li, Ya-Feng Li, Ying Yin, Jietang Mai, Victor Rizzo, Michael Tordoff, Zsolt Bagi, Huimin Shan, Xiaohua Jiang, Hong Wang, and Xiao-Feng Yang
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Metabolically healthy obesity (MHO) describes the phenomenon of overweight and obese patients paradoxically retaining a healthy metabolic profile. The molecular mechanisms underlying MHO remain enigmatic partly due to a dearth of animal models mirroring MHO in patients. Using apolipoprotein E knockout (ApoE -/- ) mice on high-fat (HF) diet as an atherosclerotic obesity model, we demonstrated: 1) microRNA-155 (miRNA-155, miR-155) is significantly upregulated in aortas of ApoE -/- mice; and miR-155 deficiency in ApoE -/- mice inhibits atherosclerosis; 2) ApoE -/- /miR-155 -/- (DKO) mice show HF diet-induced obesity, adipocyte hypertrophy and present with nonalcoholic fatty liver disease (NAFLD); 3) DKO mice demonstrate HF diet-induced elevations of plasma leptin, resistin, fed-state and fasting insulin, increased expression of adipogenic transcription factors, but lack glucose intolerance and insulin resistance. Our results are the first to present a metabolically healthy obesity (MHO) model using DKO mice with features of decreased atherosclerosis, increased obesity and NAFLD. Our findings suggest the mechanistic role of reduced miR-155 expression in MHO and present a new MHO working model based on a single miRNA deficiency in diet-induced obese atherogenic mice. Furthermore, our results serve as a breakthrough in understanding the potential mechanism underlying MHO and provide a new biomarker and novel therapeutic target for MHO-related metabolic diseases.
- Published
- 2017
44. Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study
- Author
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Nish Vadalia, Hangfei Fu, Jun Yu, Xiaofeng Yang, Luqiao Wang, Candice Johnson, Eric T. Choi, Claudette Sanchez, Hong Wang, Eric R. Xue, Qian Chen, Jun Nelson, William Y. Yang, and Jian Xing Ma
- Subjects
0301 basic medicine ,Cancer Research ,Chemokine ,Angiogenesis ,Myocardial Infarction ,Mice ,Neoplasms ,Angiogenic genes ,Leukocytes ,Data Mining ,Angiogenic Proteins ,Receptor ,Tissue expression of genes ,Hematology ,Neovascularization, Pathologic ,biology ,lcsh:Diseases of the blood and blood-forming organs ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Endothelial stem cell ,Vascular endothelial growth factor B ,Oncology ,Stem cell ,medicine.medical_specialty ,Angiogenic leukocytes ,Neovascularization, Physiologic ,lcsh:RC254-282 ,03 medical and health sciences ,SOX2 ,Internal medicine ,medicine ,Animals ,Humans ,Acute Coronary Syndrome ,Immune regulation of angiogenesis ,Pathological modulation of angiogenesis ,Molecular Biology ,lcsh:RC633-647.5 ,business.industry ,Research ,Endothelial Cells ,Thrombosis ,030104 developmental biology ,Cell Transdifferentiation ,Immunology ,biology.protein ,Cancer research ,Transcriptome ,business ,Biomarkers - Abstract
Background Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions and how angiogenesis is regulated in various disease conditions. Methods In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro-angiogenic, anti-angiogenic, and bi-functional C/Cs. Results We made the following findings: (1) the human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; (2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; (3) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; (4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; (5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; and (6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease. Conclusions Our results demonstrate that thrombus-derived leukocytes express more endothelial cell-specific angiogenic markers to directly promote angiogenesis after myocardial infarction and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0440-0) contains supplementary material, which is available to authorized users.
- Published
- 2017
45. Rapid and Sensitive Screening of 17β-Estradiol Estrogenicity Using Fourier Transform Infrared Imaging Spectroscopy (FT-IRIS)
- Author
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Mohan P. Achary, Rominder P.S. Suri, Nancy Pleshko, and Candice Johnson
- Subjects
Population ,Cell ,symbols.namesake ,Spectroscopy, Fourier Transform Infrared ,medicine ,Animals ,Humans ,Environmental Chemistry ,education ,Incubation ,EC50 ,Cell Nucleus ,Principal Component Analysis ,education.field_of_study ,Chromatography ,Estradiol ,Chemistry ,Mucin ,General Chemistry ,Imaging spectroscopy ,Fourier transform ,medicine.anatomical_structure ,MCF-7 Cells ,symbols ,IRIS (biosensor) ,Subcellular Fractions - Abstract
It is important to develop rapid and sensitive screening assays to assess the biological effects of emerging contaminants. In this contribution, the ability to determine the molecular level effects of 17β-estradiol on single MCF-7 cells using Fourier transform infrared imaging spectroscopy (FT-IRIS) was investigated. The use of FT-IRIS enabled subcellular imaging of the cells and determination of a dose dependent response in mucin concentration at 24 and 48 h of incubation. The 48 h increase in mucin was comparable to increases in cellular proliferation (Pearson R = 0.978). The EC50 values for the E-screen and FT-IRIS assays were 2.29 and 2.56 ppt, respectively, indicating that the molecular changes, which are observed at the single cell level using FT-IRIS, are reflective of physiological changes that are observed as the cell population responds to 17ß-estradiol. The FT-IRIS method, when combined with principal component analysis, enabled differentiation and grouping of cells exposed to varying concentrations of 17ß-estradiol. The FT-IRIS method shows potential to be used as a rapid and sensitive screening technique for the detection of biological responses to different emerging contaminants in relevant cells or tissues.
- Published
- 2014
46. Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells – Novel qualification markers for chronic disease risk factors and conditional DAMPs
- Author
-
Candice Johnson, Ruijing Zhang, Xiaohua Jiang, Yifan Lu, Jun Yu, Fatma Saaoud, Hong Wang, Daohai Yu, Xiaofeng Yang, Charles Drummer, Gayani Nanayakkara, Yu Sun, Ying Shao, Xinyuan Li, William Y. Yang, and Eric T. Choi
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Inflammation ,Adaptive Immunity ,Biology ,Models, Biological ,Biochemistry ,Histones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Risk Factors ,medicine ,Humans ,lcsh:QH301-705.5 ,Transcription factor ,Aorta ,chemistry.chemical_classification ,lcsh:R5-920 ,Genes, Essential ,Effector ,Organic Chemistry ,Endothelial Cells ,Lysophosphatidylcholines ,Acetylation ,Atherosclerosis ,Cell biology ,030104 developmental biology ,Enzyme ,Histone ,Lysophosphatidylcholine ,Gene Expression Regulation ,lcsh:Biology (General) ,chemistry ,Chronic Disease ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Disease Susceptibility ,medicine.symptom ,lcsh:Medicine (General) ,Biomarkers ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Research Paper ,Signal Transduction - Abstract
To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245). Keywords: Trained immunity, Human aortic endothelial cell activation, Proatherogenic lipids lysophosphatidycholine (LPC), RNA-Seq, Chromatin long range interaction
- Published
- 2019
47. Impaired blood pressure control in children with obstructive sleep apnea
- Author
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Scott A. Sands, Stephanie Yiallourou, Margot J Davey, Rosemary S.C. Horne, Lisa M. Walter, Gillian M. Nixon, John Trinder, Anna Vlahandonis, Candice Johnson, and Adrian M. Walker
- Subjects
Male ,Blood pressure control ,medicine.medical_specialty ,Elevated bp ,Polysomnography ,Blood Pressure ,Baroreflex ,Autonomic Nervous System ,Severity of Illness Index ,Heart Rate ,Internal medicine ,Humans ,Medicine ,Spectral analysis ,Child ,Sleep Apnea, Obstructive ,medicine.diagnostic_test ,business.industry ,Snoring ,Sleep apnea ,General Medicine ,medicine.disease ,nervous system diseases ,respiratory tract diseases ,Obstructive sleep apnea ,Blood pressure ,Anesthesia ,Hypertension ,Cardiology ,Female ,Sleep Stages ,business - Abstract
Background: Obstructive sleep apnea (OSA) in adults has been associated with hypertension, low baroreflex sensitivity (BRS), a delayed heart rate response to changing blood pressure (heart period delay [HPD]), and increased blood pressure variability (BPV). Poor BRS may contribute to hypertension by impairing the control of blood pressure (BP), with increased BPV and HPD. Although children with OSA have elevated BP, there are scant data on BRS, BPV, or HPD in this group. Methods: 105 children ages 7–12 years referred for assessment of OSA and 36 nonsnoring controls were studied. Overnight polysomnography (PSG) was performed with continuous BP monitoring. Subjects were assigned to groups according to their obstructive apnea–hypopnea index (OAHI): primary snoring (PS) (OAHI 61 event/h), mild OSA (OAHI > 1–65 events/h) and moderate/severe (MS) OSA (OAHI > 5 events/h). BRS and HPD were calculated using cross spectral analysis and BPV using power spectral analysis. Results: Subjects with OSA had significantly lower BRS (p < .05 for both) and a longer HPD (PS and MS OSA, p < .01; mild OSA, p < .05) response to spontaneous BP changes compared with controls. In all frequencies of BPV, the MS group had higher power compared with the control and PS groups (low frequency [LF], p < .05; high frequency [HF], p < .001). Conclusions: Our study demonstrates reduced BRS, longer HPD, and increased BPV in subjects with OSA compared to controls. This finding suggests that children with OSA have altered baroreflex function. Longitudinal studies are required to ascertain if this dampening of the normal baroreflex response can be reversed with treatment.
- Published
- 2013
48. An Interaction Model for Estimating In Vitro Estrogenic and Androgenic Activity of Chemical Mixtures
- Author
-
Mohan P. Achary, Candice Johnson, and Rominder P.S. Suri
- Subjects
Chromatography ,Chemistry ,Estrogens ,Interaction model ,Biological activity ,General Chemistry ,Complex Mixtures ,In Vitro Techniques ,Models, Theoretical ,In vitro ,Chemical mixtures ,Computational chemistry ,Additive function ,Androgens ,Molecular targets ,Environmental Chemistry ,Bioassay ,Interaction index - Abstract
There is a need to better understand and predict the biological activity and interaction of chemical constituents in mixtures. Many existing methods assume that the mixture components are additive, and in the case of endocrine disruption, deviation from additivity may occur and render predictions inconclusive. In this study, an alternate index, aRP, which enables the quantification of an antagonistic interaction from analytically derived concentrations of chemical constituents within a mixture that act upon the same molecular target is described. The index is calculated by measuring the degree to which the test compound modulates the activity of a standard hormone as a function of mixture proportions. The aRP was shown to be valid for additive mixtures. It theoretically estimates the product of the relative potential and the interaction index inverse for nonadditive mixtures. The aRP values were computed for agonists and antagonists of both the estrogen and androgen receptors by using yeast-based methods (YES and YAS). The resulting aRP estimates were then validated using higher order mixtures of agonists and antagonists. The use of aRP led to improved predictions compared to estimates based on the toxicity equivalent factor (TEF) approach. The aRP model yielded estimates that were statistically indistinguishable (α = 0.01) from the measured responses in 75% of the 32 mixtures tested. By the same criteria, the TEF approach successfully predicted 34% of the mixtures. Both the aRP and TEF approach correlated well with the observed responses (Pearson R = 0.98 and 0.84, respectively); however, the TEF estimates produced higher percent errors, particularly in mixtures with higher proportions of antagonists. It is suggested that the use of the aRP index allows for a better approximation of the net activity captured by the bioassays through the use of chemically derived concentrations.
- Published
- 2013
49. Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--'Sand Out and Gold Stays'
- Author
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Yi Zhang, Candice Johnson, Xuebin Qin, Ying Shao, Hong Wang, Eric T. Choi, Valeria Chernaya, William Y. Yang, Ramon Cueto, Jianxin Sun, Xiaofeng Yang, and Xiaojin Sha
- Subjects
0301 basic medicine ,Pharmaceutical Science ,Methylation ,Gene Expression Regulation, Enzymologic ,Article ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Metabolic Diseases ,Histone methylation ,Histone H2A ,Databases, Genetic ,Genetics ,Histone code ,Animals ,Data Mining ,Humans ,Epigenetics ,RNA, Messenger ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,biology ,Histone deacetylase 2 ,Gene Expression Profiling ,Acetylation ,Enzymes ,Histone Code ,030104 developmental biology ,Histone ,Biochemistry ,030220 oncology & carcinogenesis ,Histone methyltransferase ,biology.protein ,Molecular Medicine ,Cardiology and Cardiovascular Medicine - Abstract
To determine whether the expression of histone modification enzymes is regulated in physiological and pathological conditions, we took an experimental database mining approach pioneered in our labs to determine a panoramic expression profile of 164 enzymes in 19 human and 17 murine tissues. We have made the following significant findings: (1) Histone enzymes are differentially expressed in cardiovascular, immune, and other tissues; (2) our new pyramid model showed that heart and T cells are among a few tissues in which histone acetylation/deacetylation, and histone methylation/demethylation are in the highest varieties; and (3) histone enzymes are more downregulated than upregulated in metabolic diseases and regulatory T cell (Treg) polarization/ differentiation, but not in tumors. These results have demonstrated a new working model of "Sand out and Gold stays," where more downregulation than upregulation of histone enzymes in metabolic diseases makes a few upregulated enzymes the potential novel therapeutic targets in metabolic diseases and Treg activity.
- Published
- 2015
50. Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation
- Author
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Hangfei Fu, Huimin Shan, Xiaohua Jiang, Ya-Feng Li, Xiaofeng Yang, Walter J. Koch, Candice Johnson, Jianxin Sun, Andrew J. Andrews, Gayani Nanayakkara, Muniswamy Madesh, Nicholas E. Hoffman, Yin-Ming Kuo, Xinyuan Li, Pu Fang, Daohai Yu, Hong Wang, Fuyong Du, and Satoru Eguchi
- Subjects
0301 basic medicine ,Time Factors ,Aortic Diseases ,Inflammation ,Hyperlipidemias ,Mitochondrion ,Biology ,Antioxidants ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Apolipoproteins E ,medicine ,Animals ,Humans ,Metabolomics ,Genetic Predisposition to Disease ,Calcium Signaling ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Membrane Potential, Mitochondrial ,Mice, Knockout ,Oxidase test ,Reactive oxygen species ,Gene Expression Profiling ,Endothelial Cells ,Lysophosphatidylcholines ,Atherosclerosis ,Intercellular Adhesion Molecule-1 ,Cell biology ,Mitochondria ,Endothelial stem cell ,Mice, Inbred C57BL ,Transcription Factor AP-1 ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Lysophosphatidylcholine ,Phenotype ,chemistry ,Gene Expression Regulation ,Knockout mouse ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Reactive Oxygen Species ,Oxidation-Reduction ,Nicotinamide adenine dinucleotide phosphate - Abstract
Objective— Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here, we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. Approach and Results— Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0, and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0, and 18:1 induced mtROS in primary human aortic ECs, independently of the activities of nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, using confocal microscopy and Seahorse XF mitochondrial analyzer, we showed that LPC induced mtROS via unique calcium entry–mediated increase of proton leak and mitochondrial O 2 reduction. In addition, we found that mtROS contributed to LPC-induced EC activation by regulating nuclear binding of activator protein-1 and inducing intercellular adhesion molecule-1 gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in apolipoprotein E knockout mice using intravital microscopy and flow cytometry methods. Conclusions— ATP synthesis–uncoupled, but proton leak-coupled, mtROS increase mediates LPC-induced EC activation during early atherosclerosis. These results indicate that mitochondrial antioxidants are promising therapies for vascular inflammation and cardiovascular diseases.
- Published
- 2015
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