Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism DOI Creative Commons
Ying Shao, Jason Saredy, Keman Xu

и другие.

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июнь 25, 2021

To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined 28 EC microarray datasets with 7 monocyte as controls. We made following findings: The majority IGs are upregulated first 12 hours post-infection (PI), maintained until 48 PI human microvascular middle east respiratory syndrome-coronavirus (MERS-CoV) (an model for COVID-19). modulated 21 various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia oxLDL. Upregulation many such nucleic acid sensors shared between ECs MERS-CoV those PAMPs DAMPs. Human heart mouse aortic express all four types coronavirus receptors ANPEP, CEACAM1, ACE2, DPP4 virus entry facilitator TMPRSS2 (heart EC); most replication-transcription protein complexes expressed HMEC, which contribute to viremia, thromboembolism, cardiovascular comorbidities COVID-19. have novel trained immunity (TI), subsequent inflammation is enhanced. Upregulated proinflammatory cytokines TNFα, IL6, CSF1 CSF3 TI marker IL-32 well metabolic enzymes epigenetic indicate function HMEC MERS-CoV, may drive cytokine storms. demonstrate a promoting myelopoiesis. Mechanistically, ER stress ROS, together decreased mitochondrial OXPHOS complexes, facilitate response TI. Additionally, an increase regulators mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis upregulation pro-thrombogenic factors thromboembolism potential. Finally, NRF2-suppressed ROS regulate responses, TI, thrombosis, death. These results provide insights on roles infections COVID-19, diseases (CVD), inflammation, transplantation, autoimmune disease cancers.

Язык: Английский

Circular RNAs are a novel type of non-coding RNAs in ROS regulation, cardiovascular metabolic inflammations and cancers DOI

Fatma Saaoud,

Charles Drummer I.V.,

Ying Shao

и другие.

Pharmacology & Therapeutics, Год журнала: 2020, Номер 220, С. 107715 - 107715

Опубликована: Окт. 24, 2020

Язык: Английский

Процитировано

89
Trained Immunity and Reactivity of Macrophages and Endothelial Cells DOI Open Access
Charles Drummer,

Fatma Saaoud,

Ying Shao

и другие.

Arteriosclerosis Thrombosis and Vascular Biology, Год журнала: 2020, Номер 41(3), С. 1032 - 1046

Опубликована: Дек. 31, 2020

Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads an altered towards a second challenge after the return nonactivated state. This phenomenon is known as trained immunity (TI). TI not only important for host defense vaccine but also chronic inflammations such cardiovascular metabolic diseases atherosclerosis. occur in innate monocytes/macrophages, natural killer cells, endothelial (ECs), nonimmune fibroblast. In this review, we analyze significance of ECs, are considered addition macrophages. be induced by variety stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), oxLDL (oxidized low-density lipoprotein), defined risk factors diseases. Furthermore, ECs functional inflammation effectiveness transition inflammation. Rewiring cellular metabolism takes place during induction TI, increased glycolysis, glutaminolysis, accumulation tricarboxylic acid cycle metabolites acetyl-coenzyme A production, well mevalonate synthesis. Subsequently, epigenetic remodeling, resulting changes chromatin architecture that enables gene transcription enhanced proinflammatory response. However, pathways separated ensure memory stays when undergoes resolution. Additionally, reactive oxygen species play context-dependent roles TI. Therefore, plays significant EC macrophage pathology further characterization macrophages would provide novel insights into disease pathogenesis new therapeutic targets. Graphic Abstract: graphic abstract available article.

Язык: Английский

Процитировано

77
The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases DOI
Liliana M. Almeida, Brígida R. Pinho, Michael R. Duchen

и другие.

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Год журнала: 2022, Номер 97(5), С. 1737 - 1748

Опубликована: Апрель 26, 2022

ABSTRACT Protein kinase RNA‐like ER (PERK) is an endoplasmic reticulum (ER) stress sensor that responds to the accumulation of misfolded proteins. Once activated, PERK initiates signalling pathways halt general protein production, increase efficiency quality control, and maintain redox homeostasis. activation also protects mitochondrial homeostasis during stress. The location at contact sites between mitochondria creates a PERK–mitochondria axis allows detect in both organelles, adapt their functions prevent apoptosis. During stress, triggers hyperfusion, preventing premature apoptotic fragmentation mitochondria. increases formation cristae assembly respiratory supercomplexes, enhancing cellular ATP‐generating capacity. strengthens control by promoting expression chaperones proteases increasing biogenesis mitophagy, resulting renewal network. But how does mediate all these changes homeostasis? In addition classic PERK–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription 4 (ATF4) pathway, can activate other protective – PERK– O ‐linked N‐acetyl‐glucosamine transferase (OGT), PERK–transcription EB (TFEB), PERK–nuclear erythroid 2‐related 2 (NRF2) contributing broader regulation dynamics, metabolism, control. pharmacological models neurodegenerative metabolic diseases, such as Huntington's disease, progressive supranuclear palsy obesity, while inhibition was Parkinson's prion diseases diabetes. this review, we address molecular mechanisms which regulates metabolism discuss therapeutic potential targeting diseases.

Язык: Английский

Процитировано

66
Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways DOI Creative Commons

Fatma Saaoud,

Lu Liu, Keman Xu

и другие.

JCI Insight, Год журнала: 2022, Номер 8(1)

Опубликована: Ноя. 17, 2022

We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into N-oxide (TMAO) in nonliver tissues and TMAO promotes inflammation via trained immunity (TI). found that endoplasmic reticulum (ER) stress genes were coupregulated with MitoCarta chronic kidney diseases (CKD); upregulated 190 human aortic endothelial cells (HAECs); synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed mouse aortas; transdifferentiated HAECs innate immune cells; phosphorylated 12 kinases cytosol its receptor PERK CREB, integrated pathways; inhibitors suppressed TMAO-induced ICAM-1. mitochondrial genes, downregulated inhibitor DARS2, induced mitoROS, mitoTEMPO inhibited β-Glucan priming, followed by restimulation, TNF-α inducing metabolic reprogramming, glycolysis Our results have provided potentially novel insights regarding roles EC activation transdifferentiation reprogramming TI for enhanced vascular inflammation, they new therapeutic targets treating cardiovascular (CVD), CKD-promoted CVD, transplantation, aging, cancer.

Язык: Английский

Процитировано

64
Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism DOI Creative Commons
Ying Shao, Jason Saredy, Keman Xu

и другие.

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июнь 25, 2021

To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined 28 EC microarray datasets with 7 monocyte as controls. We made following findings: The majority IGs are upregulated first 12 hours post-infection (PI), maintained until 48 PI human microvascular middle east respiratory syndrome-coronavirus (MERS-CoV) (an model for COVID-19). modulated 21 various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia oxLDL. Upregulation many such nucleic acid sensors shared between ECs MERS-CoV those PAMPs DAMPs. Human heart mouse aortic express all four types coronavirus receptors ANPEP, CEACAM1, ACE2, DPP4 virus entry facilitator TMPRSS2 (heart EC); most replication-transcription protein complexes expressed HMEC, which contribute to viremia, thromboembolism, cardiovascular comorbidities COVID-19. have novel trained immunity (TI), subsequent inflammation is enhanced. Upregulated proinflammatory cytokines TNFα, IL6, CSF1 CSF3 TI marker IL-32 well metabolic enzymes epigenetic indicate function HMEC MERS-CoV, may drive cytokine storms. demonstrate a promoting myelopoiesis. Mechanistically, ER stress ROS, together decreased mitochondrial OXPHOS complexes, facilitate response TI. Additionally, an increase regulators mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis upregulation pro-thrombogenic factors thromboembolism potential. Finally, NRF2-suppressed ROS regulate responses, TI, thrombosis, death. These results provide insights on roles infections COVID-19, diseases (CVD), inflammation, transplantation, autoimmune disease cancers.

Язык: Английский

Процитировано

58