64 results on '"William Y. Yang"'
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2. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms
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Ying Shao, William Y. Yang, Fatma Saaoud, Charles Drummer IV, Yu Sun, Keman Xu, Yifan Lu, Huimin Shan, Ethan M. Shevach, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Cardiology ,Inflammation ,Medicine - Abstract
Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE–/– mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35–deficient (IL-35P35–deficient) mice on an ApoE–/– background and found Treg reduction in the spleen and aorta compared with ApoE–/– controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE–/– Tregs, and we have validated higher CCR5 expression in ApoE–/– Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE–/– have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
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- 2021
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3. Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators
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Ming Liu, Na Wu, Keman Xu, Fatma Saaoud, Eleni Vasilopoulos, Ying Shao, Ruijing Zhang, Jirong Wang, Haitao Shen, William Y. Yang, Yifan Lu, Yu Sun, Charles Drummer, Lu Liu, Li Li, Wenhui Hu, Jun Yu, Domenico Praticò, Jianxin Sun, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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organelle crosstalk ,inflammation ,cancers and tumors ,viral infections ,endothelial cell activation ,Treg ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
To examine whether the expressions of 260 organelle crosstalk regulators (OCRGs) in 16 functional groups are modulated in 23 diseases and 28 tumors, we performed extensive -omics data mining analyses and made a set of significant findings: (1) the ratios of upregulated vs. downregulated OCRGs are 1:2.8 in acute inflammations, 1:1 in metabolic diseases, 1:1.2 in autoimmune diseases, and 1:3.8 in organ failures; (2) sepsis and trauma-upregulated OCRG groups such as vesicle, mitochondrial (MT) fission, and mitophagy but not others, are termed as the cell crisis-handling OCRGs. Similarly, sepsis and trauma plus organ failures upregulated seven OCRG groups including vesicle, MT fission, mitophagy, sarcoplasmic reticulum–MT, MT fusion, autophagosome–lysosome fusion, and autophagosome/endosome–lysosome fusion, classified as the cell failure-handling OCRGs; (3) suppression of autophagosome–lysosome fusion in endothelial and epithelial cells is required for viral replications, which classify this decreased group as the viral replication-suppressed OCRGs; (4) pro-atherogenic damage-associated molecular patterns (DAMPs) such as oxidized low-density lipoprotein (oxLDL), lipopolysaccharide (LPS), oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), and interferons (IFNs) totally upregulated 33 OCRGs in endothelial cells (ECs) including vesicle, MT fission, mitophagy, MT fusion, endoplasmic reticulum (ER)–MT contact, ER– plasma membrane (PM) junction, autophagosome/endosome–lysosome fusion, sarcoplasmic reticulum–MT, autophagosome–endosome/lysosome fusion, and ER–Golgi complex (GC) interaction as the 10 EC-activation/inflammation-promoting OCRG groups; (5) the expression of OCRGs is upregulated more than downregulated in regulatory T cells (Tregs) from the lymph nodes, spleen, peripheral blood, intestine, and brown adipose tissue in comparison with that of CD4+CD25− T effector controls; (6) toll-like receptors (TLRs), reactive oxygen species (ROS) regulator nuclear factor erythroid 2-related factor 2 (Nrf2), and inflammasome-activated regulator caspase-1 regulated the expressions of OCRGs in diseases, virus-infected cells, and pro-atherogenic DAMP-treated ECs; (7) OCRG expressions are significantly modulated in all the 28 cancer datasets, and the upregulated OCRGs are correlated with tumor immune infiltrates in some tumors; (8) tumor promoter factor IKK2 and tumor suppressor Tp53 significantly modulate the expressions of OCRGs. Our findings provide novel insights on the roles of upregulated OCRGs in the pathogenesis of inflammatory diseases and cancers, and novel pathways for the future therapeutic interventions for inflammations, sepsis, trauma, organ failures, autoimmune diseases, metabolic cardiovascular diseases (CVDs), and cancers.
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- 2021
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4. Reply to Comment on Shen H, et al. 'Co-signaling receptors regulate T-cell plasticity and immune tolerance'. Frontiers in Bioscience-Landmark. 2019; 24: 96–132
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Haitao Shen, Na Wu, Gayani Nanayakkara, Hangfei Fu, Qian Yang, William Y. Yang, Angus Li, Yu Sun, Charles Drummer IV, Candice Johnson, Ying Shao, Luqiao Wang, Keman Xu, Wenhui Hu, Marion Chan, Vincent Tam, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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Biochemistry ,QD415-436 ,Biology (General) ,QH301-705.5 - Published
- 2021
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5. ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes
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Yu Sun, Yifan Lu, Jason Saredy, Xianwei Wang, Charles Drummer IV, Ying Shao, Fatma Saaoud, Keman Xu, Ming Liu, William Y. Yang, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Reactive oxygen species (ROS) ,A sensing network for metabolic stress ,Inflammation ,Trained immunity ,Nuclear signaling ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).
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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. Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells
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Xinyuan Li, Pu Fang, Yu Sun, Ying Shao, William Y. Yang, Xiaohua Jiang, Hong Wang, and Xiaofeng Yang
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
It has been shown that anti-inflammatory cytokines interleukin-35 (IL-35) and IL-10 could inhibit acute endothelial cell (EC) activation, however, it remains unknown if and by what pathways IL-35 and IL-10 could block atherogenic lipid lysophosphatidylcholine (LPC)-induced sustained EC activation; and if mitochondrial reactive oxygen species (mtROS) can differentiate mediation of EC activation from trained immunity (innate immune memory). Using RNA sequencing analyses, biochemical assays, as well as database mining approaches, we compared the effects of IL-35 and IL-10 in LPC-treated human aortic ECs (HAECs). Principal component analysis revealed that both IL-35 and IL-10 could similarly and partially reverse global transcriptome changes induced by LPC. Gene set enrichment analyses showed that while IL-35 and IL-10 could both block acute EC activation, characterized by upregulation of cytokines/chemokines and adhesion molecules, IL-35 is more potent than IL-10 in suppressing innate immune signatures upregulated by LPC. Surprisingly, LPC did not induce the expression of trained tolerance itaconate pathway enzymes but induced trained immunity enzyme expressions; and neither IL-35 nor IL-10 was found to affect LPC-induced trained immunity gene signatures. Mechanistically, IL-35 and IL-10 could suppress mtROS, which partially mediate LPC-induced EC activation and innate immune response. Therefore, anti-inflammatory cytokines could reverse mtROS-mediated acute and innate immune trans-differentiation responses in HAECs, but it could spare metabolic reprogramming and trained immunity signatures, which may not fully depend on mtROS. Our characterizations of anti-inflammatory cytokines in blocking mtROS-mediated acute and prolonged EC activation, and sparing trained immunity are significant for designing novel strategies for treating cardiovascular diseases, other inflammatory diseases, and cancers. Keywords: Interleukin-35, Interleukin-10, Endothelial cell activation, Mitochondrial ROS, Trained immunity, Atherosclerosis
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- 2020
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9. Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling
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Wen Shen, Chao Gao, Ramon Cueto, Lu Liu, Hangfei Fu, Ying Shao, William Y. Yang, Pu Fang, Eric T. Choi, Qinghua Wu, Xiaofeng Yang, and Hong Wang
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection. Keywords: Homocysteine-methionine cycle, Metabolic sensor, SAM/SAH-dependent methylation
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- 2020
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10. 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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11. Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile – Novel hypothesis establishment
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Ramon Cueto, Lixiao Zhang, Hui Min Shan, Xiao Huang, Xinyuan Li, Ya-feng Li, Jahaira Lopez, William Y. Yang, Muriel Lavallee, Catherine Yu, Yong Ji, Xiaofeng Yang, and Hong Wang
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24–14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59–33 nmol/g), moderate in lung/heart/brain (7–4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42–18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7–0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction. Keywords: Database mining, Tissue expression profile, Homocysteine metabolism
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- 2018
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12. 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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13. 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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14. 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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15. Experimental Data-Mining Analyses Reveal New Roles of Low-Intensity Ultrasound in Differentiating Cell Death Regulatome in Cancer and Non-cancer Cells via Potential Modulation of Chromatin Long-Range Interactions
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Jiwei Wang, Bin Lai, Gayani Nanayakkara, Qian Yang, Yu Sun, Yifan Lu, Ying Shao, Daohai Yu, William Y. Yang, Ramon Cueto, Hangfei Fu, Huihong Zeng, Wen Shen, Susu Wu, Chunquan Zhang, Yanna Liu, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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ultrasound ,cell death regulators ,inflammatory pathways ,cancer therapy ,chromatin long-range interaction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The mechanisms underlying low intensity ultrasound (LIUS) mediated suppression of inflammation and tumorigenesis remain poorly determined.Methods: We used microarray datasets from NCBI GEO Dataset databases and conducted a comprehensive data mining analyses, where we studied the gene expression of 299 cell death regulators that regulate 13 different cell death types (cell death regulatome) in cells treated with LIUS.Results: We made the following findings: (1) LIUS exerts a profound effect on the expression of cell death regulatome in cancer cells and non-cancer cells. Of note, LIUS has the tendency to downregulate the gene expression of cell death regulators in non-cancer cells. Most of the cell death regulator genes downregulated by LIUS in non-cancer cells are responsible for mediating inflammatory signaling pathways; (2) LIUS activates different cell death transcription factors in cancer and non-cancer cells. Transcription factors TP-53 and SRF- were induced by LIUS exposure in cancer cells and non-cancer cells, respectively; (3) As two well-accepted mechanisms of LIUS, mild hyperthermia and oscillatory shear stress induce changes in the expression of cell death regulators, therefore, may be responsible for inducing LIUS mediated changes in gene expression patterns of cell death regulators in cells; (4) LIUS exposure may change the redox status of the cells. LIUS may induce more of antioxidant effects in non-cancer cells compared to cancer cells; and (5) The genes modulated by LIUS in cancer cells have distinct chromatin long range interaction (CLRI) patterns to that of non-cancer cells.Conclusions: Our analysis suggests novel molecular mechanisms that may be 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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- 2019
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16. 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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17. 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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18. DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses—Inflammations and Cancers Can Have High Genomic Risks
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Huihong Zeng, Gayani K. Nanayakkara, Ying Shao, Hangfei Fu, Yu Sun, Ramon Cueto, William Y. Yang, Qian Yang, Haitao Sheng, Na Wu, Luqiao Wang, Wuping Yang, Hongping Chen, Lijian Shao, Jianxin Sun, Xuebin Qin, Joon Y. Park, Konstantinos Drosatos, Eric T. Choi, Qingxian Zhu, Hong Wang, and Xiaofeng Yang
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DNA damage checkpoint and repair factors ,inflammation ,cancers ,genomic instability ,danger associated molecular patterns (DAMPs) ,Physiology ,QP1-981 - Abstract
Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA DDCFs and 42 DNA DDRFs in 21 human and 20 mouse tissues in physiological/pathological conditions. We made the following significant findings: (1) Few DDCFs and DDRFs are ubiquitously expressed in tissues while many are differentially regulated.; (2) the expression of DDCFs and DDRFs are modulated not only in cancers but also in sterile inflammatory disorders and metabolic diseases; (3) tissue methylation status, pro-inflammatory cytokines, hypoxia regulating factors and tissue angiogenic potential can determine the expression of DDCFs and DDRFs; (4) intracellular organelles can transmit the stress signals to the nucleus, which may modulate the cell death by regulating the DDCF and DDRF expression. Our results shows that sterile inflammatory disorders and cancers increase genomic instability, therefore can be classified as pathologies with a high genomic risk. We also propose a new concept that as parts of cellular sensor cross-talking network, DNA checkpoint and repair factors serve as nuclear sensors for intracellular organelle stresses. Further, this work would lead to identification of novel therapeutic targets and new biomarkers for diagnosis and prognosis of metabolic diseases, inflammation, tissue damage and cancers.
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- 2018
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19. GATA3, HDAC6, and BCL6 Regulate FOXP3+ Treg Plasticity and Determine Treg Conversion into Either Novel Antigen-Presenting Cell-Like Treg or Th1-Treg
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Keman Xu, William Y. Yang, Gayani Kanchana Nanayakkara, Ying Shao, Fan Yang, Wenhui Hu, Eric T. Choi, Hong Wang, and Xiaofeng Yang
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CD4+ T helper subset differentiation ,CD4+ FOXP3+ regulatory T cells ,metabolic cardiovascular diseases ,Th1-like Treg ,APC-like Treg ,Immunologic diseases. Allergy ,RC581-607 - Abstract
We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset-promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg. Our data implies that while HDAC6 and Bcl6 are important regulators of Treg plasticity, GATA3 determine the fate of plastic Tregby controlling whether it will convert in to either Th1-Treg or APC-T-reg. Our results have provided novel insights on Treg plasticity into APC-Treg and Th1-Treg, and new therapeutic targets in metabolic diseases, autoimmune diseases, and inflammatory disorders.
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- 2018
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20. 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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21. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms
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Fatma Saaoud, Keman Xu, Xiaohua Jiang, Ying Shao, Yu Sun, Xiaofeng Yang, Hong Wang, Huimin Shan, William Y. Yang, Ethan M. Shevach, Yifan Lu, and Charles Drummer
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CD4-Positive T-Lymphocytes ,Receptors, CCR5 ,Mice, Knockout, ApoE ,Programmed Cell Death 1 Receptor ,Cardiology ,chemical and pharmacologic phenomena ,Spleen ,Inflammation ,Biology ,T-Lymphocytes, Regulatory ,Mice ,Chemokine receptor ,TIGIT ,Cell Movement ,medicine ,Animals ,Receptors, Immunologic ,Receptor ,Aorta ,Mice, Knockout ,Interleukins ,TOR Serine-Threonine Kinases ,FOXP3 ,RNA ,Forkhead Transcription Factors ,hemic and immune systems ,Cellular immune response ,General Medicine ,Atherosclerosis ,Phenotype ,Interleukin-10 ,medicine.anatomical_structure ,Cancer research ,Cytokines ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article - Abstract
Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE–/– mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35–deficient (IL-35P35–deficient) mice on an ApoE–/– background and found Treg reduction in the spleen and aorta compared with ApoE–/– controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE–/– Tregs, and we have validated higher CCR5 expression in ApoE–/– Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE–/– have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
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- 2021
22. ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes
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Fatma Saaoud, Xiaohua Jiang, Xiaofeng Yang, Ying Shao, William Y. Yang, Yifan Lu, Ming Liu, Charles Drummer, Keman Xu, Hong Wang, Yu Sun, Jason Saredy, and Xianwei Wang
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0301 basic medicine ,Mitochondrial ROS ,Programmed cell death ,Clinical Biochemistry ,Review Article ,Trained immunity ,Mitochondrion ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,A sensing network for metabolic stress ,Organelle ,medicine ,Homeostasis ,lcsh:QH301-705.5 ,Cell Nucleus ,chemistry.chemical_classification ,Inflammation ,Reactive oxygen species ,lcsh:R5-920 ,Organic Chemistry ,Reactive oxygen species (ROS) ,Inflammasome ,Mitochondria ,Cell biology ,Nuclear signaling ,Cytosol ,Metabolic pathway ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,Reactive Oxygen Species ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).
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- 2020
23. 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
24. 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
25. Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile – Novel hypothesis establishment
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Hui Min Shan, Catherine Yu, Muriel Lavallee, Ya-Feng Li, Hong Wang, Xiaofeng Yang, Xiao Huang, Xinyuan Li, Ramon Cueto, William Y. Yang, Lixiao Zhang, Yong Ji, and Jahaira Lopez
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0301 basic medicine ,S-Adenosylmethionine ,medicine.medical_specialty ,Hyperhomocysteinemia ,Homocysteine ,Clinical Biochemistry ,Spleen ,Mitochondrion ,Biology ,Kidney ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Risk Factors ,Internal medicine ,Gene expression ,medicine ,Animals ,Humans ,Lung ,lcsh:QH301-705.5 ,Regulation of gene expression ,lcsh:R5-920 ,Organic Chemistry ,medicine.disease ,Mitochondria ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Electron Transport Chain Complex Proteins ,Gene Expression Regulation ,lcsh:Biology (General) ,chemistry ,Cardiovascular Diseases ,Organ Specificity ,lcsh:Medicine (General) ,Pancreas - Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) which has been implicated in matochondrial (Mt) function impairment. In this study, we characterized Hcy metabolism in mouse tissues by using LC-ESI-MS/MS analysis, established tissue expression profiles for 84 nuclear-encoded Mt electron transport chain complex (nMt-ETC-Com) genes in 20 human and 19 mouse tissues by database mining, and modeled the effect of HHcy on Mt-ETC function. Hcy levels were high in mouse kidney/lung/spleen/liver (24–14 nmol/g tissue) but low in brain/heart (~5 nmol/g). S-adenosylhomocysteine (SAH) levels were high in the liver/kidney (59–33 nmol/g), moderate in lung/heart/brain (7–4 nmol/g) and low in spleen (1 nmol/g). S-adenosylmethionine (SAM) was comparable in all tissues (42–18 nmol/g). SAM/SAH ratio was as high as 25.6 in the spleen but much lower in the heart/lung/brain/kidney/liver (7–0.6). The nMt-ETC-Com genes were highly expressed in muscle/pituitary gland/heart/BM in humans and in lymph node/heart/pancreas/brain in mice. We identified 15 Hcy-suppressive nMt-ETC-Com genes whose mRNA levels were negatively correlated with tissue Hcy levels, including 11 complex-I, one complex-IV and two complex-V genes. Among the 11 Hcy-suppressive complex-I genes, 4 are complex-I core subunits. Based on the pattern of tissue expression of these genes, we classified tissues into three tiers (high/mid/low-Hcy responsive), and defined heart/eye/pancreas/brain/kidney/liver/testis/embryonic tissues as tier 1 (high-Hcy responsive) tissues in both human and mice. Furthermore, through extensive literature mining, we found that most of the Hcy-suppressive nMt-ETC-Com genes were suppressed in HHcy conditions and related with Mt complex assembly/activity impairment in human disease and experimental models. We hypothesize that HHcy inhibits Mt complex I gene expression leading to Mt dysfunction. Keywords: Database mining, Tissue expression profile, Homocysteine metabolism
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- 2018
26. 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
27. 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
28. Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells
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Tracy Gao, William Y. Yang, Xiaofeng Yang, Muriel Lavallee, Keman Xu, Hong Wang, Pu Fang, Kylie Chan, and Xinyuan Li
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0301 basic medicine ,Pharmacology ,Mitochondrial ROS ,chemistry.chemical_classification ,Reactive oxygen species ,Cell signaling ,ATP synthase ,biology ,Physiology ,medicine.medical_treatment ,T cell ,General Medicine ,Cell biology ,Endothelial activation ,03 medical and health sciences ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,chemistry ,Physiology (medical) ,Immunology ,biology.protein ,medicine ,Pathological - Abstract
Mitochondrial reactive oxygen species (mtROS) are signaling molecules, which drive inflammatory cytokine production and T cell activation. In addition, cardiovascular diseases, cancers, and autoimmune diseases all share a common feature of increased mtROS level. Both mtROS and ATP are produced as a result of electron transport chain activity, but it remains enigmatic whether mtROS could be generated independently from ATP synthesis. A recent study shed light on this important question and found that, during endothelial cell (EC) activation, mtROS could be upregulated in a proton leak-coupled, but ATP synthesis-uncoupled manner. As a result, EC could upregulate mtROS production for physiological EC activation without compromising mitochondrial membrane potential and ATP generation, and consequently without causing mitochondrial damage and EC death. Thus, a novel pathophysiological role of proton leak in driving mtROS production was uncovered for low grade EC activation, patrolling immunosurveillance cell trans-endothelial migration and other signaling events without compromising cellular survival. This new working model explains how mtROS could be increasingly generated independently from ATP synthesis and endothelial damage or death. Mapping the connections among mitochondrial metabolism, physiological EC activation, patrolling cell migration, and pathological inflammation is significant towards the development of novel therapies for inflammatory diseases and cancers.
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- 2017
29. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study
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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
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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.
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- 2016
30. HDL subclass proteomic analysis and functional implication of protein dynamic change during HDL maturation
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Yuling Zhang, Hang Xi, William Y. Yang, Merlin Abner Paz, Jason Saredy, Xiaofeng Yang, Jingfeng Wang, Mohsin Khan, Alan T. Remaley, Runlu Sun, Hong Wang, Scott M. Gordon, and Seungbum Choi
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0301 basic medicine ,Apolipoprotein E ,Male ,Proteomics ,medicine.medical_specialty ,Proteome ,Clinical Biochemistry ,Biochemistry ,Models, Biological ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Liver X receptor ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Chemistry ,Cholesterol ,Organic Chemistry ,Cholesterol, HDL ,Acute-phase protein ,nutritional and metabolic diseases ,Computational Biology ,Lipid metabolism ,Lipid Metabolism ,PON1 ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,lipids (amino acids, peptides, and proteins) ,lcsh:Medicine (General) ,Lipoproteins, HDL ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Research Paper - Abstract
Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation. Keywords: Cardiovascular disease, Lipids and cholesterol, Proteomics, Metabolism, Risk factors
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- 2019
31. BCL6 inhibits CD4+Foxp3+ regulatory T cell trans‐differentiation into macrophage‐like cells via modulation of chromatin long‐range interactions
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Alexander M. Fagenson, Hangfei Fu, Honglang Li, Yu Sun, William Y. Yang, Jiwei Wang, Kevin Mastascusa, Hong Wang, Fatma Saaoud, Xiaofeng Yang, Peiqian Zhu, Daohai Yu, Bin Lai, Ramon Cueto, Susu Wu, and Ying Shao
- Subjects
Regulatory T cell ,Chemistry ,FOXP3 ,BCL6 ,Biochemistry ,Trans differentiation ,Cell biology ,Chromatin ,medicine.anatomical_structure ,Genetics ,medicine ,Macrophage ,Molecular Biology ,Biotechnology - Published
- 2019
32. Lysophosphatidylcholine promotes trained immunity of human aortic endothelial cells via histone 3 lysine 14 acetylation‐dependent and independent gene modulation
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Yifan Lu, Hangfei Fu, William Y. Yang, Ramon Cueto, Fatma Saaoud, Ying Shao, Hong Wang, Xiaofeng Yang, Yu Sun, and Daohai Yu
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Therapeutic gene modulation ,biology ,Lysine ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,Histone ,Lysophosphatidylcholine ,chemistry ,Immunity ,Acetylation ,Genetics ,biology.protein ,Molecular Biology ,Biotechnology - Published
- 2019
33. Increasing upstream chromatin long‐range interactions may favor induction of circular RNAs in lysoPC‐activated human aortic endothelial cells
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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
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Chemistry ,Range (biology) ,Genetics ,Biophysics ,Upstream (networking) ,Molecular Biology ,Biochemistry ,Biotechnology ,Chromatin - Published
- 2019
34. Low‐intensity ultrasound differentially upregulates cell death regulators in cancer cells, and downregulates inflammatory pathways in non‐cancer cells via oxidative stresschromatin long‐range interaction signaling
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Xiaofeng Yang, Chunquan Zhang, William Y. Yang, Yu Sun, Ying Shao, Hong Wang, Daohai Yu, Jiwei Wang, Yanna Liu, Bin Lai, and Qiao Yang
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Programmed cell death ,Range (biology) ,Chemistry ,Low intensity ultrasound ,Cancer cell ,Non cancer ,Genetics ,Cancer research ,Inflammatory pathways ,Oxidative phosphorylation ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2019
35. 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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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.
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- 2018
36. Co-signaling receptors regulate T-cell plasticity and immune tolerance
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Gayani Nanayakkara, Marion M. Chan, Vincent H. Tam, William Y. Yang, Keman Xu, Wenhui Hu, Xiaofeng Yang, Haitao Shen, Hong Wang, Ying Shao, Luqiao Wang, Candice Johnson, Angus Li, Hangfei Fu, Qian Yang, Na Wu, Charles Drummer, Eric T. Choi, and Yu Sun
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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.
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- 2018
37. Reply to Comment on Shen H, et al. 'Co-signaling receptors regulate T-cell plasticity and immune tolerance'. Frontiers in Bioscience-Landmark. 2019; 24: 96–132
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Xiaofeng Yang, Haitao Shen, Charles Drummer, Yu Sun, Ying Shao, Na Wu, Wenhui Hu, Luqiao Wang, Candice Johnson, Marion M. Chan, Keman Xu, Angus Li, Hong Wang, Vincent H. Tam, Qian Yang, Hangfei Fu, William Y. Yang, Eric T. Choi, and Gayani Nanayakkara
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T cell plasticity ,General Immunology and Microbiology ,Biology ,Receptor ,Neuroscience ,General Biochemistry, Genetics and Molecular Biology ,Immune tolerance - Published
- 2021
38. Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling
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Hangfei Fu, Chao Gao, Ying Shao, William Y. Yang, Xiaofeng Yang, Wen Shen, Li Liu, Eric T. Choi, Pu Fang, Ramon Cueto, Qinghua Wu, and Hong Wang
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0301 basic medicine ,Hyperhomocysteinemia ,Methyltransferase ,Homocysteine ,Short Communication ,Clinical Biochemistry ,Methylation ,Biochemistry ,SAM/SAH-dependent methylation ,Histones ,03 medical and health sciences ,chemistry.chemical_compound ,Cytosol ,Methionine ,0302 clinical medicine ,Histone methylation ,medicine ,Humans ,Gene Regulatory Networks ,Protein Interaction Maps ,lcsh:QH301-705.5 ,Homocysteine-methionine cycle ,lcsh:R5-920 ,biology ,Organic Chemistry ,medicine.disease ,Molecular biology ,3. Good health ,Metabolic sensor ,Protein Transport ,030104 developmental biology ,Histone ,lcsh:Biology (General) ,chemistry ,DNA methylation ,biology.protein ,lcsh:Medicine (General) ,030217 neurology & neurosurgery - Abstract
Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection. Keywords: Homocysteine-methionine cycle, Metabolic sensor, SAM/SAH-dependent methylation
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- 2020
39. Abstract 029: Interleukin-35 Suppresses Endothelial Activation by Inhibiting Mitochondrial Reactive Oxygen Species Mediated Site-specific Acetylation of Histone 3 Lysine 14
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William Y. Yang, Xiaofeng Yang, Pu Fang, Ya-Feng Li, Hong Wang, Xinyuan Li, Xiaojin Sha, Yin-Ming Kuo, Massimo Maddaloni, Xiaohua Jiang, Ying Shao, David W. Pascual, Jin Jun Luo, and Andrew J Andrews
- Subjects
chemistry.chemical_classification ,Reactive oxygen species ,biology ,Chemistry ,medicine.medical_treatment ,Lysine ,Cell biology ,Endothelial activation ,Cytokine ,Histone ,Acetylation ,Interleukin 35 ,medicine ,biology.protein ,HAMP ,Cardiology and Cardiovascular Medicine - Abstract
Recently we reported that IL-35 is an inflammation-induced ant-inflammatory cytokine; thus, function as a HAMP (homeostasis associated molecular patterns). However, whether IL-35 affects endothelial cell activation and subsequent development of atherosclerosis is not known. Hence, we studied the expression of IL-35 during early atherosclerosis; and its roles and mechanisms in suppressing EC activation. Initially, we analyzed whether endogenous IL-35 levels and its receptor expression was increased in early atherosclerosis. Our data revealed that IL-35 level was significantly increased in the plasma of hyperlipidemic patients and apolipoprotein E (ApoE-/-) deficient mice. Further, the expression of IL-35 receptor components were increased in ApoE-/- mouse aortas. IL-35 inhibited monocyte recruitment on to human aortic endothelial cells (EC) activated by pro-atherogenic lysophosphatidylcholine (LPC). Furthermore, our RNA-Seq analysis showed that IL-35 selectively inhibited ICAM-1 expression that mediates EC activation. Further analysis by flowcytometry and electron spin resonance analysis revealed that IL-35 blocked LPC-mediated mitochondrial-reactive oxygen species (mtROS) production. The subsequent mass spectrometry, ChIP-Seq analysis and EMSA showed that LPC-mediated mtROS promotes acetylation of histone 3 lysine 14 (H3K14). Acetylation of histones facilitate the transcription of EC activation-related genes. We found that acetylated H3K14 increased the binding of pro-inflammatory transcription factor Ap-1 on to ICAM-1 promoter region and induction of ICAM-1 gene transcription. IL-35 mediated Inhibition of mtROS attenuated H3K14 acetylation, inhibited AP-1 binding to ICAM-1 promoter and suppressed ICAM-1 transcription. Finally, IL-35 cytokine treatment inhibited the progression and development of atherosclerosis in ApoE-/- mice. Our study concluded that IL-35 is induced during atherosclerosis and plays an anti-atherogenic role by suppressing EC activation through mtROS and H3K14 acetylation dependent mechanism.
- Published
- 2018
40. Increased Plasticity of FOXP3+ Treg under Pathological Conditions Convert Treg into Either Novel Treg or Th1‐Treg
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Gayani Nanayakkara, Wenhui Hu, Hong Wang, Eric T. Choi, Ying Shao, Keman Xu, Fan Yang, Xiaofeng Yang, and William Y. Yang
- Subjects
Immunology ,Genetics ,FOXP3 ,Biology ,Plasticity ,Molecular Biology ,Biochemistry ,Pathological ,Biotechnology - Published
- 2018
41. STAT1 (Signal Transducer and Activator of Transcription 1) Deficiency in T Cells Upregulates MHC Class II and Co‐stimulation Receptors, Suggesting that STAT1 deficiency in T Cells May Increase the Plasticity and Convert in to Atypical Antigen Presenting Cells
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Wenhui Hu, Hangfei Fu, Gayani Nanayakkara, Xiaofeng Yang, Haitao Shen, Charles Drummer, Ying Shao, Luqiao Wang, Qian Yang, Na Wu, Hong Wang, Keman Xu, William Y. Yang, and Eric T. Choi
- Subjects
MHC class II ,biology ,Chemistry ,Plasticity ,Biochemistry ,Cell biology ,Co-stimulation ,Genetics ,biology.protein ,STAT protein ,STAT1 ,Receptor ,Antigen-presenting cell ,Molecular Biology ,Biotechnology - Published
- 2018
42. Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury
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Xiaofeng Yang, Joon-Young Park, William Y. Yang, Gayani Nanayakkara, Hong Wang, Jiali Cheng, Ying Shao, and Ramon Cueto
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0301 basic medicine ,Damp ,Physiology ,Clinical Biochemistry ,Inflammation ,Endogeny ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Receptor ,Molecular Biology ,General Environmental Science ,G protein-coupled receptor ,Innate immune system ,Pattern recognition receptor ,food and beverages ,Cell Biology ,respiratory system ,Forum Review Articles ,Cell biology ,body regions ,030104 developmental biology ,030220 oncology & carcinogenesis ,biological sciences ,General Earth and Planetary Sciences ,sense organs ,medicine.symptom ,Signal transduction - Abstract
Significance: We proposed lysophospholipids (LPLs) and LPL-G-protein-coupled receptors (GPCRs) as conditional danger-associated molecular patterns (DAMPs) and conditional DAMP receptors as a paradigm shift to the widely accepted classical DAMP and DAMP receptor model. Recent Advances: The aberrant levels of LPLs and GPCRs activate pro-inflammatory signal transduction pathways, trigger innate immune response, and lead to tissue oxidative and inflammatory injury. Critical Issues: Classical DAMP model specifies only the endogenous metabolites that are released from damaged/dying cells as DAMPs, but fails to identify elevated endogenous metabolites secreted from viable/live cells during pathologies as DAMPs. The current classification of DAMPs also fails to clarify the following concerns: (i) Are molecules, which bind to pattern recognition receptors (PRRs), the only DAMPs contributing to inflammation and tissue injury? (ii) Are all DAMPs acting only via classical PRRs during cellular stress? To answer these questions, we reviewed the molecular characteristics and signaling mechanisms of LPLs, a group of endogenous metabolites and their specific receptors and analyzed the significant progress achieved in characterizing oxidative stress mechanisms of LPL mediated tissue injury. Future Directions: Further LPLs and LPL-GPCRs may serve as potential therapeutic targets for the treatment of pathologies induced by sterile inflammation. Antioxid. Redox Signal. 28, 973–986.
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- 2018
43. Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation
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Eric T. Choi, Wei Mao, Xiaofeng Yang, Jin Dai, Hong Wang, Yong Ji, Pu Fang, Cueto Ramon, Jason Saredy, Hang Xi, and William Y. Yang
- Subjects
0301 basic medicine ,Cancer Research ,Metabolic risk factors ,T cell ,animal diseases ,Inflammation ,chemical and pharmacologic phenomena ,Review ,Biology ,Lymphocyte Activation ,lcsh:RC254-282 ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,CD40 Antigens ,Molecular Biology ,lcsh:RC633-647.5 ,Metabolism-associated danger signal ,NFAT ,Reverse-immune checkpoint ,Cell Differentiation ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,biochemical phenomena, metabolism, and nutrition ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Acquired immune system ,CD40+ MC ,Immune checkpoint ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Monocyte differentiation ,Immunology ,bacteria ,medicine.symptom ,Signal transduction ,Signal Transduction - Abstract
Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response. We classify immune checkpoint into two categories: one-way immune checkpoint for forward signaling towards TC only, and two-way immune checkpoint for both forward and reverse signaling towards TC and APC, respectively. Recently, we and others provided evidence suggesting that metabolic risk factors (RF) activate innate and adaptive immunity, involving the induction of immune checkpoint molecules. We summarize these findings and suggest a novel theory, metabolism-associated danger signal (MADS) recognition, by which metabolic RF activate innate and adaptive immunity. We emphasize that MADS activates the reverse immune checkpoint which leads to APC inflammation in innate and adaptive immunity. Our recent evidence is shown that metabolic RF, such as uremic toxin or hyperhomocysteinemia, induced immune checkpoint molecule CD40 expression in monocytes (MC) and elevated serum soluble CD40 ligand (sCD40L) resulting in CD40+ MC differentiation. We propose that CD40+ MC is a novel pro-inflammatory MC subset and a reliable biomarker for chronic kidney disease severity. We summarize that CD40:CD40L immune checkpoint can induce TC and APC activation via forward stimulatory, reverse stimulatory, and TC contact-independent immune checkpoints. Finally, we modeled metabolic RF-induced two-way stimulatory immune checkpoint amplification and discussed potential signaling pathways including AP-1, NF-κB, NFAT, STAT, and DNA methylation and their contribution to systemic and tissue inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0504-1) contains supplementary material, which is available to authorized users.
- Published
- 2017
44. IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14)
- Author
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Xiaohua Jiang, Xiaofeng Yang, Ya-Feng Li, Massimo Maddaloni, Yin-Ming Kuo, Xinyuan Li, Ying Shao, David W. Pascual, Pu Fang, Hong Wang, Xiaojin Sha, Andrew J. Andrews, Jin Jun Luo, and William Y. Yang
- Subjects
0301 basic medicine ,Male ,Mice, Knockout, ApoE ,medicine.medical_treatment ,Aortic Diseases ,Article ,Proinflammatory cytokine ,Histones ,03 medical and health sciences ,medicine ,Animals ,Humans ,Transcription factor ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,Chemistry ,Monocyte ,Interleukins ,Lysine ,Endothelial Cells ,Lysophosphatidylcholines ,Acetylation ,Receptors, Interleukin ,Atherosclerosis ,Intercellular Adhesion Molecule-1 ,Cell biology ,Mitochondria ,Endothelial stem cell ,Mice, Inbred C57BL ,Transcription Factor AP-1 ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Knockout mouse ,Interleukin 35 ,Female ,Cardiology and Cardiovascular Medicine ,Reactive Oxygen Species ,Protein Processing, Post-Translational - Abstract
Objective— IL-35 (interleukin-35) is an anti-inflammatory cytokine, which inhibits immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. It remains unknown whether atherogenic stimuli induce IL-35 and whether IL-35 inhibits atherogenic lipid-induced endothelial cell (EC) activation and atherosclerosis. EC activation induced by hyperlipidemia stimuli, including lysophosphatidylcholine is considered as an initiation step for monocyte recruitment and atherosclerosis. In this study, we examined the expression of IL-35 during early atherosclerosis and the roles and mechanisms of IL-35 in suppressing lysophosphatidylcholine-induced EC activation. Approach and Results— Using microarray and ELISA, we found that IL-35 and its receptor are significantly induced during early atherosclerosis in the aortas and plasma of ApoE (apolipoprotein E) knockout mice—an atherosclerotic mouse model—and in the plasma of hypercholesterolemic patients. In addition, we found that IL-35 suppresses lysophosphatidylcholine-induced monocyte adhesion to human aortic ECs. Furthermore, our RNA-sequencing analysis shows that IL-35 selectively inhibits lysophosphatidylcholine-induced EC activation-related genes, such as ICAM-1 (intercellular adhesion molecule-1). Mechanistically, using flow cytometry, mass spectrometry, electron spin resonance analyses, and chromatin immunoprecipitation-sequencing analyses, we found that IL-35 blocks lysophosphatidylcholine-induced mitochondrial reactive oxygen species, which are required for the induction of site-specific H3K14 (histone 3 lysine 14) acetylation, increased binding of proinflammatory transcription factor AP-1 in the promoter of ICAM-1, and induction of ICAM-1 transcription in human aortic EC. Finally, IL-35 cytokine therapy suppresses atherosclerotic lesion development in ApoE knockout mice. Conclusions— IL-35 is induced during atherosclerosis development and inhibits mitochondrial reactive oxygen species-H3K14 acetylation-AP-1–mediated EC activation.
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- 2017
45. 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.
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- 2017
46. Endocytosis and membrane receptor internalization: implication of F-BAR protein Carom
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Cueto Ramon, William Y. Yang, Xiaoshu Cheng, Xianxian Zhao, Xiaofeng Yang, Dingwen He, Xinyu Xiong, Hong Wang, Luqiao Wang, Suxuan Liu, Yanjie Xu, Jixiang Xia, Lixiao Zhang, Hang Xi, and Sam Stein
- Subjects
0301 basic medicine ,media_common.quotation_subject ,Endocytic cycle ,Receptors, Cell Surface ,Endocytosis ,Clathrin ,Models, Biological ,Article ,Cell membrane ,03 medical and health sciences ,Lysosome ,medicine ,Humans ,Internalization ,media_common ,biology ,Chemistry ,Membrane Proteins ,Receptor-mediated endocytosis ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Membrane protein ,biology.protein ,Carrier Proteins ,Protein Binding - Abstract
Endocytosis is a cellular process mostly responsible for membrane receptor internalization. Cell membrane receptors bind to their ligands and form a complex which can be internalized. We previously proposed that F-BAR protein initiates membrane curvature and mediates endocytosis via their binding partners. However, F-BAR protein partners involved in membrane receptor endocytosis and the regulatory mechanism remain unknown. In this study, we established a group of database mining strategies to explore mechanisms underlying receptor-related endocytosis. We identified 34 endocytic membrane receptors and 10 regulating proteins for vesicle formation in clathrin-dependent endocytosis (CDE), a major process of membrane receptor internalization. We found that F-BAR protein FCHSD2 (Carom) may facilitate endocytosis via 9 endocytic partners. Carom is highly expressed, along with highly expressed endocytic membrane receptors and partners, in endothelial cells and macrophages. We established 3 models of Carom-receptor complex and their intracellular trafficking based on protein-protein interaction and subcellular localization. We conclude that Carom may mediate receptor endocytosis and transport endocytic receptors to the cytoplasm for receptor signaling and lysosome/proteasome degradation, or to the nucleus for RNA processing, gene transcription and DNA repair.
- Published
- 2017
47. Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases
- Author
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Ying Shao, William Y. Yang, Ye Tian, Jiali Cheng, Ramon Cueto, Luqiao Wang, Hong Wang, Gayani Nanayakkara, and Xiaofeng Yang
- Subjects
0301 basic medicine ,Mitochondrial ROS ,Pathology ,medicine.medical_specialty ,Mitochondrion ,medicine.disease_cause ,Article ,Mitochondria, Heart ,Pathogenesis ,Electron Transport ,03 medical and health sciences ,0302 clinical medicine ,Adenosine Triphosphate ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Inner mitochondrial membrane ,chemistry.chemical_classification ,Membrane Potential, Mitochondrial ,Reactive oxygen species ,Chemistry ,Electron transport chain ,Cell biology ,Oxidative Stress ,030104 developmental biology ,Mitochondrial respiratory chain ,Electron Transport Chain Complex Proteins ,Cardiovascular Diseases ,Protons ,Energy Metabolism ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Oxidative stress ,Signal Transduction - Abstract
Mitochondrial proton leak is the principal mechanism that incompletely couples substrate oxygen to ATP generation. This chapter briefly addresses the recent progress made in understanding the role of proton leak in the pathogenesis of cardiovascular diseases. Majority of the proton conductance is mediated by uncoupling proteins (UCPs) located in the mitochondrial inner membrane. It is evident that the proton leak and reactive oxygen species (ROS) generated from electron transport chain (ETC) in mitochondria are linked to each other. Increased ROS production has been shown to induce proton conductance, and in return, increased proton conductance suppresses ROS production, suggesting the existence of a positive feedback loop that protects the biological systems from detrimental effects of augmented oxidative stress. There is mounting evidence attributing to proton leak and uncoupling proteins a crucial role in the pathogenesis of cardiovascular disease. We can surmise the role of "uncoupling" in cardiovascular disorders as follows; First, the magnitude of the proton leak and the mechanism involved in mediating the proton leak determine whether there is a protective effect against ischemia-reperfusion (IR) injury. Second, uncoupling by UCP2 preserves vascular function in diet-induced obese mice as well as in diabetes. Third, etiology determines whether the proton conductance is altered or not during hypertension. And fourth, proton leak regulates ATP synthesis-uncoupled mitochondrial ROS generation, which determines pathological activation of endothelial cells for recruitment of inflammatory cells. Continue effort in improving our understanding in the role of proton leak in the pathogenesis of cardiovascular and metabolic diseases would lead to identification of novel therapeutic targets for treatment.
- Published
- 2017
48. IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases
- Author
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Hong Wang, Xiaofeng Yang, William Y. Yang, Xinyuan Li, and Pu Fang
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Regulatory B cells ,Immunology ,Inflammation ,Adaptive Immunity ,Biology ,Models, Biological ,T-Lymphocytes, Regulatory ,Biochemistry ,Article ,03 medical and health sciences ,Immune system ,Hepcidins ,Sepsis ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,Receptor ,Molecular Biology ,B-Lymphocytes, Regulatory ,Effector ,Interleukins ,Hematology ,Atherosclerosis ,Immunity, Innate ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Cytokine ,Cancer research ,Cytokines ,HAMP ,medicine.symptom ,Signal transduction - Abstract
IL-35 is a new anti-inflammatory cytokine identified in 2007, which inhibits inflammation and immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. The unique initiator and effector anti-inflammatory properties of IL-35 bring tremendous interest in investigating its role during cardiovascular disease (CVD) development, in which inflammatory processes are firmly established as central to its development and complications. In this review, we update recent understanding of how IL-35 is produced and regulated in the cells. In addition, we outline the signaling pathways affected by IL-35 in different cell types. Furthermore, we summarize the roles of IL-35 in atherosclerosis, diabetes, and sepsis. We propose a new working model that IL-35 and its receptors are novel homeostasis-associated molecular pattern (HAMP) and HAMP receptors, respectively, which explains the complex nature of IL-35 signaling as an anti-inflammatory initiator, effector and blocker. Thorough understanding of this topic is significant towards development of new anti-inflammatory therapies against CVDs and other diseases. (total words: 163)
- Published
- 2019
49. 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
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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
50. Lysophospholipid Receptors, as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation - Novel Paradigm and Therapeutic Potential
- Author
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Xiaofeng Yang, Ya-Feng Li, Hong Wang, Jun Yu, Ramon Cueto, William Y. Yang, Xin Wang, Gayani Nanayakkara, Ying Shao, Bin Liang, Lauren Cole, and Xinyuan Li
- Subjects
0301 basic medicine ,Damp ,Pharmaceutical Science ,Inflammation ,Endogeny ,Biology ,Article ,03 medical and health sciences ,Mice ,Databases, Genetic ,Genetics ,medicine ,Animals ,Data Mining ,Homeostasis ,Humans ,Receptor ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Mechanism (biology) ,Gene Expression Profiling ,Computational Biology ,Cell biology ,Gene expression profiling ,Lysophospholipid receptor ,Disease Models, Animal ,030104 developmental biology ,Receptors, Lysophospholipid ,Molecular Medicine ,medicine.symptom ,Signal transduction ,Lysophospholipids ,Cardiology and Cardiovascular Medicine ,Protein Binding ,Signal Transduction - Abstract
There are limitations in the current classification of danger-associated molecular patterns (DAMP) receptors. To overcome these limitations, we propose a new paradigm by using endogenous metabolites lysophospholipids (LPLs) as a prototype. By utilizing a data mining method we pioneered, we made the following findings: (1) endogenous metabolites such as LPLs at basal level have physiological functions; (2) under sterile inflammation, expression of some LPLs is elevated. These LPLs act as conditional DAMPs or anti-inflammatory homeostasis-associated molecular pattern molecules (HAMPs) for regulating the progression of inflammation or inhibition of inflammation, respectively; (3) receptors for conditional DAMPs and HAMPs are differentially expressed in human and mouse tissues; and (4) complex signaling mechanism exists between pro-inflammatory mediators and classical DAMPs that regulate the expression of conditional DAMPs and HAMPs. This novel insight will facilitate identification of novel conditional DAMPs and HAMPs, thus promote development of new therapeutic targets to treat inflammatory disorders.
- Published
- 2016
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