Ramadan A. Ali

Ain Shams University

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Jason S. Knight

University of Michigan–Ann Arbor

Srilakshmi Yalavarthi

University of Michigan–Ann Arbor

Alex A. Gandhi

University of Michigan–Ann Arbor

Yogendra Kanthi

National Heart Lung and Blood Institute

Katherine A. Wall

University of Toledo

Gautam Sule

University of Michigan–Ann Arbor

James T. Slama

University of Toledo

David R. Giovannucci

University of Toledo

Shanea K. Estes

University of Michigan–Ann Arbor

Yu Zuo

Third Xiangya Hospital

Cooperative Institutions

University of Michigan–Ann Arbor

Michigan United

University of Toledo

Michigan Medicine

Center for Rheumatology

Ain Shams University

University of Toledo Medical Center

Shanghai Jiao Tong University

Regional West Medical Center

National Institutes of Health

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Taxifolin inhibits NETosis through activation of Nrf2 and provides protective effects in models of lupus and antiphospholipid syndrome

Lara D. Veeken (2023)

Christine E. Rysenga Linda Zhang M Zahavi Jason S. Knight Ramadan A. Ali

Abstract Objectives Taxifolin (dihydroquercetin) is a bioactive plant flavonoid that exhibits anti-inflammatory and anti-oxidative properties. We hypothesized that taxifolin might be an effective dietary supplement to ameliorate symptoms arising from thrombo-inflammatory diseases such as lupus and APS. Methods We used in vitro assays and a mouse model to determine mechanisms by which taxifolin inhibits neutrophil extracellular trap (NET) formation (i.e. NETosis) and venous thrombosis in lupus and APS. Results At doses ranging from 0.1 to 1 µg/ml, taxifolin inhibited NETosis from control neutrophils stimulated with autoantibodies isolated from lupus and APS patients, and its suppressive effects were mitigated by blocking the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2–related factor 2). Furthermore, taxifolin at a dose as low as 20 mg/kg/day reduced in vivo NETosis in thrombo-inflammatory mouse models of lupus and APS while also significantly attenuating autoantibody formation, inflammatory cytokine production and large-vein thrombosis. Conclusion Our study is the first to demonstrate the protective effects of taxifolin in the context of lupus and APS. Importantly, our study also suggests a therapeutic potential to neutralize neutrophil hyperactivity and NETosis that could have relevance to a variety of thrombo-inflammatory diseases.

Neutrophil Extracellular Traps

Taxifolin

10.1093/rheumatology/kead547

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Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

medRxiv (Cold Spring Harbor Laboratory) (2021)

Hui Shi Alex A. Gandhi Stephanie A. Smith Qiuyu Wang Diane Chiang

Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro , defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo , defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

Defibrotide

Neutrophil Extracellular Traps

10.1101/2021.02.21.21252160

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NAADP evokes calcium signals and plays a critical role in downstream physiological responses in naïve T cells (1013.5)

The FASEB Journal (2014)

Ramadan A. Ali Christina Camick Katherine Wiles James T. Slama David R. Giovannucci

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca 2+ mobilizing second messenger discovered to date and has been implicated in Ca 2+ signaling in human Jurkat lymphoma T cells via ryanodine receptor activation. In contrast the role of NAADP in Ca 2+ signaling or the identity of the Ca 2+ stores targeted by NAADP in conventional naïve T cells has not been investigated. In the current study, we demonstrated for the first time to our knowledge the importance of NAADP in the generation of Ca 2+ signals in murine conventional naïve T cells. Combining live‐cell imaging methods and a pharmacological approach using the NAADP antagonist Ned‐19, we addressed the impact of NAADP on the generation of Ca 2+ signals evoked by TCR stimulation and the role of this signal in downstream physiological endpoints such as proliferation, cytokine production, and other responses to stimulation of murine naïve T cells. Moreover, we demonstrated that acidic stores in addition to the endoplasmic reticulum are the relevant Ca 2+ stores that were sensitive to NAADP in naïve T cells. Grant Funding Source : Supported by NIH GM100444

Jurkat cells

Second messenger system

Calcium Signaling

10.1096/fasebj.28.1_supplement.1013.5

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Prothrombotic antiphospholipid antibodies in COVID-19

medRxiv (Cold Spring Harbor Laboratory) (2020)

Yu Zuo Shanea K. Estes Ramadan A. Ali Alex A. Gandhi Srilakshmi Yalavarthi

ABSTRACT Patients with coronavirus disease 19 ( COVID-19 ) are at high risk for thrombotic arterial and venous occlusions. At the same time, lung histopathology often reveals fibrin-based occlusion in the small vessels of patients who succumb to the disease. Antiphospholipid syndrome ( APS ) is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies ( aPL ) targeting phospholipids and phospholipid-binding proteins. Case series have recently detected aPL in patients with COVID-19. Here, we measured eight types of aPL [anticardiolipin IgG/IgM/IgA, anti-beta-2 glycoprotein I IgG/IgM/IgA, and anti-phosphatidylserine/prothrombin ( aPS/PT ) IgG/IgM] in the sera of 172 patients hospitalized with COVID-19. We detected aPS/PT IgG in 24%, anticardiolipin IgM in 23%, and aPS/PT IgM in 18%. Any aPL was present in 52% of patients using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 units). Higher levels of aPL were associated with neutrophil hyperactivity (including the release of neutrophil extracellular traps/ NETs ), higher platelet count, more severe respiratory disease, and lower glomerular filtration rate. Similar to patients with longstanding APS, IgG fractions isolated from patients with COVID-19 promoted NET release from control neutrophils. Furthermore, injection of these COVID-19 IgG fractions into mice accelerated venous thrombosis. Taken together, these studies suggest that a significant percentage of patients with COVID-19 become at least transiently positive for aPL and that these aPL are potentially pathogenic.

Neutrophil Extracellular Traps

Lupus anticoagulant

Immunoglobulin M

10.1101/2020.06.15.20131607

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Citations (67)

NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP

Ramadan A. Ali

Source

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Deletion Of pl6 AND p15 Genes In Schistosomiasis-Associated Bladder Cancer (SABC)

Biochemical Society Transactions (2000)

Sanaa Eissa Ramadan A. Ali Amani E. Khalifa

Conference Abstract| October 01 2000 Deletion Of pl6 AND p15 Genes In Schistosomiasis-Associated Bladder Cancer (SABC) Sanaa Eissa; Sanaa Eissa 1Oncology Diagnostic Unit, Biochemistry Department, Ain Shams Faculty of Medicine Search for other works by this author on: This Site PubMed Google Scholar R. Ali; R. Ali 1Oncology Diagnostic Unit, Biochemistry Department, Ain Shams Faculty of Medicine Search for other works by this author on: This Site PubMed Google Scholar A. Khalifa A. Khalifa 1Oncology Diagnostic Unit, Biochemistry Department, Ain Shams Faculty of Medicine Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2000) 28 (5): A221. https://doi.org/10.1042/bst028a221 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Sanaa Eissa, R. Ali, A. Khalifa; Deletion Of pl6 AND p15 Genes In Schistosomiasis-Associated Bladder Cancer (SABC). Biochem Soc Trans 1 October 2000; 28 (5): A221. doi: https://doi.org/10.1042/bst028a221 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2000 Biochemical Society2000 Article PDF first page preview Close Modal You do not currently have access to this content.

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10.1042/bst028a221

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Cancer and Thrombosis: The Platelet Perspective

Frontiers in Cell and Developmental Biology (2017)

Claire K. Meikle Clare A. Kelly Priyanka Garg Leah M. Wuescher Ramadan A. Ali

Platelets are critical to hemostatic and immunological function, and are key players in cancer progression, metastasis, and cancer-related thrombosis. Platelets interact with immune cells to stimulate anti-tumor responses and can be activated by immune cells and tumor cells. Platelet activation can lead to complex interactions between platelets and tumor cells. Platelets facilitate cancer progression and metastasis by: 1) forming aggregates with tumor cells; 2) inducing tumor growth, epithelial-mesenchymal transition, and invasion; 3) shielding circulating tumor cells from immune surveillance and killing; 4) facilitating tethering and arrest of circulating tumor cells; and 5) promoting angiogenesis and tumor cell establishment at distant sites. Tumor cell-activated platelets also predispose cancer patients to thrombotic events. Tumor cells and tumor-derived microparticles lead to thrombosis by secreting procoagulant factors, resulting in platelet activation and clotting. Platelets play a critical role in cancer progression and thrombosis, and markers of platelet-tumor cell interaction are candidates as biomarkers for cancer progression and thrombosis risk.

Tumor progression

10.3389/fcell.2016.00147

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Citations (113)

NAADP mediated calcium release from acidic stores plays a critical role in downstream physiological responses of naïve CD4 and CD8 T cells (IRM10P.757)

The Journal of Immunology (2014)

Ramadan A. Ali Christina Camick Katherine Wiles James T. Slama Daivd Giovannucci

Abstract Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing second messenger discovered to date and has been implicated in Ca2+ signaling in human Jurkat lymphoma T cells via ryanodine receptor activation. In contrast, the role of NAADP in Ca2+ signaling or the identity of the Ca2+ stores targeted by NAADP in conventional naïve T cells has not been investigated. In the current study, we demonstrated for the first time to our knowledge the importance of NAADP in the generation of Ca2+ signals in murine conventional naïve T cells. Combining live-cell imaging methods and a pharmacological approach using the NAADP antagonist Ned-19, we addressed the impact of NAADP on the generation of Ca2+ signals evoked by TCR stimulation and the role of this signal in downstream physiological endpoints such as proliferation, cytokine production, and other responses to stimulation of murine naïve T cells. Moreover, we demonstrated that acidic stores in addition to the endoplasmic reticulum are the relevant Ca2+ stores that were sensitive to NAADP in naïve T cells.

Jurkat cells

Second messenger system

Calcium Signaling

10.4049/jimmunol.192.supp.129.24

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Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines

Molecular & Cellular Toxicology (2020)

Mai G. Awad Ramadan A. Ali Dalia Demerdash Abd El Monem Hafez Mohammed A. El‐Magd

Malondialdehyde

MTT assay

10.1007/s13273-020-00092-8