23 results on '"Tal, Sharon"'
Search Results
2. Impact of airborne algicidal bacteria on marine phytoplankton blooms.
- Author
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Lang-Yona N, Flores JM, Nir-Zadock TS, Nussbaum I, Koren I, and Vardi A
- Subjects
- Ecosystem, Oceans and Seas, Bacteria genetics, Phytoplankton physiology, Seawater microbiology
- Abstract
Ocean microbes are involved in global processes such as nutrient and carbon cycling. Recent studies indicated diverse modes of algal-bacterial interactions, including mutualism and pathogenicity, which have a substantial impact on ecology and oceanic carbon sequestration, and hence, on climate. However, the airborne dispersal and pathogenicity of bacteria in the marine ecosystem remained elusive. Here, we isolated an airborne algicidal bacterium, Roseovarius nubinhibens, emitted to the atmosphere as primary marine aerosol (referred also as sea spray aerosols) and collected above a coccolithophore bloom in the North Atlantic Ocean. The aerosolized bacteria retained infective properties and induced lysis of Gephyrocapsa huxleyi cultures.This suggests that the transport of marine bacteria through the atmosphere can effectively spread infection agents over vast oceanic regions, highlighting its significance in regulating the cell fate in algal blooms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)
- Published
- 2024
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3. CD300b regulates intestinal inflammation and promotes repair in colitis.
- Author
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Avlas S, Kassis H, Itan M, Reichman H, Dolitzky A, Hazut I, Grisaru-Tal S, Gordon Y, Tsarfaty I, Karo-Atar D, Rozenberg P, Bitton A, and Munitz A
- Subjects
- Humans, Mice, Animals, Intestinal Mucosa, Inflammation metabolism, Colitis chemically induced, Colitis genetics, Inflammatory Bowel Diseases metabolism
- Abstract
Chronic inflammation is a hallmark charataristic of various inflammatory diseases including inflammatory bowel disease. Subsequently, current therapeutic approaches target immune-mediated pathways as means for therapeutic intervention and promotion of mucosal healing and repair. Emerging data demonstrate important roles for CD300 receptor family members in settings of innate immunity as well as in allergic and autoimmune diseases. One of the main pathways mediating the activities of CD300 family members is via promotion of resolution through interactions with ligands expressed by viruses, bacteria, or dead cells (e.g., phospholipids such as PtdSer and/or ceramide). We have recently shown that the expression of CD300a, CD300b and CD300f were elevated in patients with IBD and that CD300f (but not CD300a) regulates colonic inflammation in response to dextran sodium sulphate (DSS)-induced colitis. Whether CD300b has a role in colitis or mucosal healing is largely unknown. Herein, we demonstrate a central and distinct role for CD300b in colonic inflammation and subsequent repair. We show that Cd300b
-/- mice display defects in mucosal healing upon cessation of DSS treatment. Cd300b-/- mice display increased weight loss and disease activity index, which is accompanied by increased colonic histopathology, increased infiltration of inflammatory cells and expression of multiple pro-inflammatory upon cessation of DSS cytokines. Furthermore, we demonstrate that soluble CD300b (sCD300b) is increased in the colons of DSS-treated mice and establish that CD300b can bind mouse and human epithelial cells. Finally, we show that CD300b decreases epithelial EpCAM expression, promotes epithelial cell motility and wound healing. These data highlight a key role for CD300b in colonic inflammation and repair processes and suggest that CD300b may be a future therapeutic target in inflammatory GI diseases., Competing Interests: Author AM is a consultant for Electra-TAU, Glaxo Smith Kline, Astra Zeneca, Sanofi, Oravax, Sartorious, Chemomab and is an inventor of patents owned by the Tel Aviv University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Avlas, Kassis, Itan, Reichman, Dolitzky, Hazut, Grisaru-Tal, Gordon, Tsarfaty, Karo-Atar, Rozenberg, Bitton and Munitz.)- Published
- 2023
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4. Epithelial cell-expressed type II IL-4 receptor mediates eosinophilic esophagitis.
- Author
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Avlas S, Shani G, Rhone N, Itan M, Dolitzky A, Hazut I, Grisaru-Tal S, Gordon Y, Shoda T, Ballaban A, Ben-Baruch NM, Rochman M, Diesendruck Y, Nahary L, Bitton A, Halpern Z, Benhar I, Varol C, Rothenberg ME, and Munitz A
- Subjects
- Humans, Mice, Animals, Interleukin-13 Receptor alpha1 Subunit metabolism, Interleukin-4 genetics, Interleukin-4 metabolism, Interleukin-13 metabolism, Epithelial Cells metabolism, Eosinophilic Esophagitis pathology
- Abstract
Background: Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease, characterized by eosinophil-rich inflammation in the esophagus. The histopathological and clinical features of EoE have been attributed to overproduction of the type 2 cytokines IL-4 and IL-13, which mediate profound alterations in the esophageal epithelium and neutralizing of their shared receptor component (IL-4Rα) with a human antibody drug (dupilumab) demonstrates clinical efficacy. Yet, the relative contribution of IL-4 and IL-13 and whether the type II IL-4 receptor (comprised of the IL-4Rα chain in association with IL-13Rα1) mediates this effect has not been determined., Methods: Experimental EoE was induced in WT, Il13ra1
-/- , and Krt14Cre /Il13ra1fl/fl mice by skin-sensitized using 4-ethoxymethylene-2-phenyl-2-oxazolin (OXA) followed by intraesophageal challenges. Esophageal histopathology was determined histologically. RNA was extracted and sequenced for transcriptome analysis and compared with human EoE RNAseq data., Results: Induction of experimental EoE in mice lacking Il13ra1 and in vivo IL-13 antibody-based neutralization experiments blocked antigen-induced esophageal epithelial and lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo targeted deletion of Il13ra1 in esophageal epithelial cells rendered mice protected from experimental EoE. Single-cell RNA sequencing analysis of human EoE biopsies revealed predominant expression of IL-13Rα1 in epithelial cells and that EoE signature genes correlated with IL-13 expression compared with IL-4., Conclusions: We demonstrate a definitive role for IL-13 signaling via IL-13Rα1 in EoE. These data provide mechanistic insights into the mode of action of current therapies in EoE and highlight the type II IL-4R as a future therapeutic target., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)- Published
- 2023
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5. T cell-eosinophil crosstalk-A new road for effective immune checkpoint blockade in breast cancer?
- Author
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Grisaru-Tal S and Munitz A
- Subjects
- Humans, Female, Immune Checkpoint Inhibitors therapeutic use, T-Lymphocytes, Eosinophils, Breast Neoplasms therapy
- Abstract
Immune checkpoint blockade (ICB) has revolutionized the landscape of cancer treatment. Nevertheless, most cancer patients still do not respond to ICB. In this issue of Cancer Cell, Blomberg et al. illustrate a critical cooperation between T cells and eosinophils, which jointly enhance effectiveness of ICB in breast cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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6. Differential regulation of Type 1 and Type 2 mouse eosinophil activation by apoptotic cells.
- Author
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Dolitzky A, Hazut I, Avlas S, Grisaru-Tal S, Itan M, Zaffran I, Levi-Schaffer F, Gerlic M, and Munitz A
- Subjects
- Mice, Animals, Cytokines metabolism, Interferon-gamma metabolism, Apoptosis, Eosinophils metabolism, Escherichia coli metabolism
- Abstract
Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis, host defense and cancer. Although eosinophils have been studied mostly in the context of Type 2 inflammatory responses, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Notably, both Type 1- and Type 2 inflammatory environments are characterized by tissue damage and cell death. Collectively, this raises the possibility that eosinophils can interact with apoptotic cells, which can alter eosinophil activation in the inflammatory milieu. Herein, we demonstrate that eosinophils can bind and engulf apoptotic cells. We further show that exposure of eosinophils to apoptotic cells induces marked transcriptional changes in eosinophils, which polarize eosinophils towards an anti-inflammatory phenotype that is associated with wound healing and cell migration. Using an unbiased RNA sequencing approach, we demonstrate that apoptotic cells suppress the inflammatory responses of eosinophils that were activated with IFN-γ + E. coli (e.g., Type 1 eosinophils) and augment IL-4-induced eosinophil activation (e.g., Type 2 eosinophils). These data contribute to the growing understanding regarding the heterogeneity of eosinophil activation patterns and highlight apoptotic cells as potential regulators of eosinophil polarization., Competing Interests: AM is a consultant for Glaxo Smith Kline, Astra Zeneca, Sanofi, Oravax, Sartorious and is an inventor of three patents owned by the Tel Aviv University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor YT declared a shared parent affiliation with the authors IZ and F-LS at the time of review., (Copyright © 2022 Dolitzky, Hazut, Avlas, Grisaru-Tal, Itan, Zaffran, Levi-Schaffer, Gerlic and Munitz.)
- Published
- 2022
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7. MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins.
- Author
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Hartal-Benishay LH, Saadi E, Toubiana S, Shaked L, Lalzar M, Abu Hatoum O, Tal S, Selig S, and Barki-Harrington L
- Abstract
Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hartal-Benishay, Saadi, Toubiana, Shaked, Lalzar, Abu Hatoum, Tal, Selig and Barki-Harrington.)
- Published
- 2022
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8. Mouse resident lung eosinophils are dependent on IL-5.
- Author
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Dolitzky A, Grisaru-Tal S, Avlas S, Hazut I, Gordon Y, Itan M, and Munitz A
- Subjects
- Animals, Antigens, Differentiation, Myelomonocytic, Leukocyte Count, Lung, Mice, Eosinophils, Interleukin-5
- Published
- 2022
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9. Eosinophil-lymphocyte interactions in the tumor microenvironment and cancer immunotherapy.
- Author
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Grisaru-Tal S, Rothenberg ME, and Munitz A
- Subjects
- Eosinophils, Humans, Immune Checkpoint Inhibitors, Immunity, Innate, Immunotherapy, Killer Cells, Natural pathology, Neoplasms, Tumor Microenvironment
- Abstract
Eosinophils are important effector cells and therapeutic targets in allergic diseases. Emerging data indicate that eosinophils infiltrate a variety of solid tumor types and have pleiotropic activities by at least two non-mutually exclusive mechanisms: direct interactions with tumor cells, and intricate cross-talk with lymphocytes. In light of the immune checkpoint inhibition revolution in cancer therapy, we review eosinophil-lymphocyte interactions in the tumor microenvironment. We also analyze potential interactions between eosinophils and lymphocyte subsets, including T cells, natural killer cells and innate lymphoid cells. We provide perspectives on the consequences of these interactions and how eosinophils are accessory cells that can affect the response to various forms of T cell-mediated immunotherapies and might be therapeutically targeted to improve cancer immunotherapy., (© 2022. Springer Nature America, Inc.)
- Published
- 2022
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10. Transcriptional Profiling of Mouse Eosinophils Identifies Distinct Gene Signatures Following Cellular Activation.
- Author
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Dolitzky A, Shapira G, Grisaru-Tal S, Hazut I, Avlas S, Gordon Y, Itan M, Shomron N, and Munitz A
- Subjects
- Animals, Biomarkers, Cell Plasticity genetics, Cell Plasticity immunology, Computational Biology methods, Cytokines genetics, Cytokines metabolism, Escherichia coli immunology, Gene Expression Profiling, Gene Ontology, High-Throughput Nucleotide Sequencing, Immune System Phenomena, Immunity, Inflammation Mediators, Lipopolysaccharides immunology, Macrophages immunology, Macrophages metabolism, Mice, Eosinophils immunology, Eosinophils metabolism, Gene Expression Regulation, Transcriptome
- Abstract
Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis to host defense and cancer. Eosinophils have been studied mostly in the context of Type 2 inflammatory responses such as those found in allergy. Nonetheless, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Recent data suggest that the pleotropic roles of eosinophils are due to heterogeneous responses to environmental cues. Despite this, the activation profile of eosinophils, in response to various stimuli is yet to be defined. To better understand the transcriptional spectrum of eosinophil activation, we exposed eosinophils to Type 1 (e.g. IFN-γ, E. coli ) vs. Type 2 (e.g. IL-4) conditions and subjected them to global RNA sequencing. Our analyses show that IL-4, IFN-γ, E. coli and IFN-γ in the presence of E. coli (IFN-γ/ E. coli )-stimulated eosinophils acquire distinct transcriptional profiles, which polarize them towards what we termed Type 1 and Type 2 eosinophils. Bioinformatics analyses using Gene Ontology based on biological processes revealed that different stimuli induced distinct pathways in eosinophils. These pathways were confirmed using functional assays by assessing cytokine/chemokine release (i.e. CXCL9, CCL24, TNF-α and IL-6) from eosinophils following activation. In addition, analysis of cell surface markers highlighted CD101 and CD274 as potential cell surface markers that distinguish between Type 1 and Type 2 eosinophils, respectively. Finally, the transcriptome signature of Type 1 eosinophils resembled that of eosinophils that were obtained from mice with experimental colitis whereas the transcriptome signature of Type 2 eosinophils resembled that of eosinophils from experimental asthma. Our data demonstrate that eosinophils are polarized to distinct "Type 1" and "Type 2" phenotypes following distinct stimulations. These findings provide fundamental knowledge regarding the heterogeneity of eosinophils and support the presence of transcriptional differences between Type 1 and Type 2 cells that are likely reflected by their pleotropic activities in diverse disease settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dolitzky, Shapira, Grisaru-Tal, Hazut, Avlas, Gordon, Itan, Shomron and Munitz.)
- Published
- 2021
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11. Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity.
- Author
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Grisaru-Tal S, Dulberg S, Beck L, Zhang C, Itan M, Hediyeh-Zadeh S, Caldwell J, Rozenberg P, Dolitzky A, Avlas S, Hazut I, Gordon Y, Shani O, Tsuriel S, Gerlic M, Erez N, Jacquelot N, Belz GT, Rothenberg ME, Davis MJ, Yu H, Geiger T, Madi A, and Munitz A
- Subjects
- Animals, Apoptosis, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation, Female, Humans, Lung Neoplasms metabolism, Lung Neoplasms secondary, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms immunology, CD8-Positive T-Lymphocytes immunology, Eosinophils immunology, Lung Neoplasms immunology, Receptors, CCR3 physiology, Tumor Microenvironment
- Abstract
The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein-coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ-activated eosinophils facilitated CD4
+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. SIGNIFICANCE: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer., (©2021 American Association for Cancer Research.)- Published
- 2021
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12. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.
- Author
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Jacquelot N, Seillet C, Wang M, Pizzolla A, Liao Y, Hediyeh-Zadeh S, Grisaru-Tal S, Louis C, Huang Q, Schreuder J, Souza-Fonseca-Guimaraes F, de Graaf CA, Thia K, Macdonald S, Camilleri M, Luong K, Zhang S, Chopin M, Molden-Hauer T, Nutt SL, Umansky V, Ciric B, Groom JR, Foster PS, Hansbro PM, McKenzie ANJ, Gray DHD, Behren A, Cebon J, Vivier E, Wicks IP, Trapani JA, Munitz A, Davis MJ, Shi W, Neeson PJ, and Belz GT
- Subjects
- Animals, Cell Line, Tumor, Chemotaxis, Leukocyte drug effects, Cytotoxicity, Immunologic drug effects, Eosinophils drug effects, Eosinophils immunology, Eosinophils metabolism, Female, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Humans, Lymphocytes immunology, Lymphocytes metabolism, Male, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Skin Neoplasms genetics, Skin Neoplasms immunology, Skin Neoplasms metabolism, Mice, Antibodies pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Immune Checkpoint Inhibitors pharmacology, Interleukin-33 pharmacology, Lymphocytes drug effects, Melanoma, Experimental drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Skin Neoplasms drug therapy
- Abstract
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
- Published
- 2021
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13. Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations.
- Author
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Grisaru-Tal S, Itan M, Grass DG, Torres-Roca J, Eschrich SA, Gordon Y, Dolitzky A, Hazut I, Avlas S, Jacobsen EA, Ziv-Baran T, and Munitz A
- Subjects
- Eosinophils, Female, Humans, Leukocyte Count, Mucous Membrane, Tumor Microenvironment, Eosinophilia, Neoplasms
- Abstract
Eosinophils are bone marrow-derived granulocytes that display key effector functions in allergic diseases. Nonetheless, recent data highlight important roles for eosinophils in the tumor microenvironment (TME). Eosinophils have been attributed with pleiotropic and perhaps conflicting functions, which may be attributed at least in part to variations in eosinophil quantitation in the TME. Thus, a reliable, quantitative, and robust method for the assessment of eosinophilic infiltration in the TME is required. This type of methodology could standardize the identification of these cells and promote the subsequent generation of hypothesis-driven mechanistic studies. To this end, we conducted a comprehensive analysis of multiple primary tumors from distinct anatomical sites using a standardized method. Bioinformatics analysis of 10,469 genomically profiled primary tumors revealed that eosinophil abundance within different tumors can be categorized into three groups representing tumors with high, intermediate, and low eosinophil levels. Consequently, eosinophil abundance, as well as spatial distribution, was determined in tissue tumor arrays of six tumors representing all three classifications (colon and esophagus - high; lung - intermediate; cervix, ovary, and breast - low). With the exception of breast cancer, eosinophils were mainly localized in the tumor stroma. Importantly, the tumor anatomical site was identified as the primary predictive factor of eosinophil stromal density highlighting a distinction between mucosal-barrier organs versus non-mucosal barrier organs. These findings enhance our understanding of eosinophil diversity in the TME and provide a compelling rationale for future experiments assessing the activity of these cells., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2020
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14. A new dawn for eosinophils in the tumour microenvironment.
- Author
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Grisaru-Tal S, Itan M, Klion AD, and Munitz A
- Subjects
- Animals, Biomarkers, Chemotaxis, Leukocyte genetics, Chemotaxis, Leukocyte immunology, Combined Modality Therapy, Disease Management, Disease Susceptibility, Eosinophils immunology, Eosinophils metabolism, Gene Expression Regulation, Neoplastic, Humans, Neoplasms etiology, Neoplasms metabolism, Neoplasms therapy, Signal Transduction, Eosinophils pathology, Neoplasms pathology, Tumor Microenvironment genetics, Tumor Microenvironment immunology
- Abstract
Eosinophils are evolutionarily conserved, pleotropic cells that display key effector functions in allergic diseases, such as asthma. Nonetheless, eosinophils infiltrate multiple tumours and are equipped to regulate tumour progression either directly by interacting with tumour cells or indirectly by shaping the tumour microenvironment (TME). Eosinophils can readily respond to diverse stimuli and are capable of synthesizing and secreting a large range of molecules, including unique granule proteins that can potentially kill tumour cells. Alternatively, they can secrete pro-angiogenic and matrix-remodelling soluble mediators that could promote tumour growth. Herein, we aim to comprehensively outline basic eosinophil biology that is directly related to their activity in the TME. We discuss the mechanisms of eosinophil homing to the TME and examine their diverse pro-tumorigenic and antitumorigenic functions. Finally, we present emerging data regarding eosinophils as predictive biomarkers and effector cells in immunotherapy, especially in response to immune checkpoint blockade therapy, and highlight outstanding questions for future basic and clinical cancer research.
- Published
- 2020
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15. Conserved statin-mediated activation of the p38-MAPK pathway protects Caenorhabditis elegans from the cholesterol-independent effects of statins.
- Author
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Goncalves IL, Tal S, Barki-Harrington L, and Sapir A
- Subjects
- Animals, Biomarkers, Gene Expression, Gene Expression Profiling, Gene Knockdown Techniques, Immunity, Innate, Macrophages immunology, Macrophages metabolism, Mevalonic Acid metabolism, Monomeric GTP-Binding Proteins genetics, Monomeric GTP-Binding Proteins metabolism, Phosphorylation, Stress, Physiological, Transcriptome, Unfolded Protein Response, p38 Mitogen-Activated Protein Kinases metabolism, Caenorhabditis elegans drug effects, Caenorhabditis elegans metabolism, Cholesterol metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, MAP Kinase Signaling System drug effects
- Abstract
Objective: Statins are a group of medications that reduce cholesterol synthesis by inhibiting the activity of HMG-CoA reductase, a key enzyme in the mevalonate pathway. The clinical use of statins to lower excess cholesterol levels has revolutionized the cardiovascular field and increased the survival of millions, but some patients have adverse side effects. A growing body of data suggests that some of the beneficial and adverse effects of statins, including their anti-inflammatory, anti-tumorigenic, and myopathic activities, are cholesterol-independent. However, the underlying mechanisms for these effects of statins are not well defined., Methods: Because Caenorhabditis elegans (C. elegans) lacks the cholesterol synthesis branch of the mevalonate pathway, this organism is a powerful system to unveil the cholesterol-independent effects of statins. We used genetic and biochemical approaches in C. elegans and cultured macrophage-derived murine cells to study the cellular response to statins., Results: We found that statins activate a conserved p38-MAPK (p38) cascade and that the protein geranylgeranylation branch of the mevalonate pathway links the effect of statins to the activation of this p38 pathway. We propose that the blockade of geranylgeranylation impairs the function of specific small GTPases we identified as upstream regulators of the p38 pathway. Statin-mediated p38 activation in C. elegans results in the regulation of programs of innate immunity, stress, and metabolism. In agreement with this regulation, knockout of the p38 pathway results in the hypersensitivity of C. elegans to statins. Treating cultured mammalian cells with clinical doses of statins results in the activation of the same p38 pathway, which upregulates the COX-2 protein, a major regulator of innate immunity in mammals., Conclusions: Statins activate an evolutionarily conserved p38 pathway to regulate metabolism and innate immunity. Our results highlight the cytoprotective role of p38 activation under statin treatment in vivo and propose that this activation underlies many of the critical cholesterol-independent effects of statins., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2020
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16. Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation.
- Author
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Saadi E, Sood R, Dromi I, Srouji R, Hatoum OA, Tal S, and Barki-Harrington L
- Subjects
- Animals, Cell Proliferation genetics, Chromatography, Liquid, Cyclooxygenase 2 genetics, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Neoplastic physiology, HEK293 Cells, Humans, Immunoblotting, Immunoprecipitation, Mice, Mice, Transgenic, Proteolysis, Tandem Mass Spectrometry, Cell Proliferation physiology, Cyclooxygenase 2 metabolism
- Abstract
Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis., Competing Interests: The authors declare no conflict of interest
- Published
- 2020
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17. Substrate-inactivated cyclooxygenase-2 is disposed of by exosomes through the ER-Golgi pathway.
- Author
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Saadi E, Tal S, and Barki-Harrington L
- Subjects
- Animals, Arachidonic Acid pharmacology, Cell Survival drug effects, Cell Survival physiology, Endoplasmic Reticulum drug effects, Exosomes drug effects, Golgi Apparatus drug effects, HEK293 Cells, Humans, Mice, RAW 264.7 Cells, Substrate Specificity drug effects, Substrate Specificity physiology, Cyclooxygenase 2 metabolism, Endoplasmic Reticulum metabolism, Exosomes metabolism, Golgi Apparatus metabolism
- Abstract
Catalysis of arachidonic acid (AA) by cyclooxygenase-2 (COX-2) gives rise to a single product that serves as a precursor for all prostaglandins, which are central mediators of inflammation. Rapid up-regulation of COX-2 expression in response to pro-inflammatory stimuli is a well-characterized means of generating the large pool of prostaglandins necessary for inflammation. However, an efficient inflammatory process must also terminate rapidly and thus requires cessation of COX-2 enzymatic activity and removal of excess protein from the cell. Previous studies showed that COX-2 that has not been exposed to AA ('naive') degrades in the cellular proteasome. However, continuous exposure to AA induces suicide inactivation of COX-2 and its elimination no longer occurs in neither the proteasomal nor lysosomal machineries. In the present study, we show that either overexpressed or endogenously induced COX-2 is secreted via exosomes through the endoplasmic reticulum-Golgi pathway. We further find that excretion of COX-2 is significantly enhanced by prolonged exposure to AA. Genetic or chemical inhibition of COX-2 enzymatic activity has no effect on its secretion in the absence of substrate, but prevents the additional activity-dependent secretion. Finally, transfer of COX-2 to target cells only occurs in the absence of AA stimulation. Together, these results suggest that exosomal secretion of AA-activated COX-2 constitutes a means to remove damaged inactive COX-2 from the cell., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2018
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18. Down-regulation of cyclooxygenase-2 by the carboxyl tail of the angiotensin II type 1 receptor.
- Author
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Sood R, Minzel W, Rimon G, Tal S, and Barki-Harrington L
- Published
- 2017
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19. Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity.
- Author
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Frenkel-Pinter M, Tal S, Scherzer-Attali R, Abu-Hussien M, Alyagor I, Eisenbaum T, Gazit E, and Segal D
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Animals, Animals, Genetically Modified, Disease Models, Animal, Drosophila melanogaster, Eye drug effects, Eye pathology, Peptide Fragments antagonists & inhibitors, Peptide Fragments metabolism, Tauopathies drug therapy, Tryptophan administration & dosage, Naphthalenes administration & dosage, Neuroprotective Agents administration & dosage, Tauopathies metabolism, Tryptophan analogs & derivatives, tau Proteins antagonists & inhibitors, tau Proteins metabolism
- Abstract
Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by Aβ-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered β-sheet oligomers and fibrils. Intervening in the toxic aggregation process is a promising therapeutic approach, but, to date, a disease-modifying therapy is neither available for AD nor for other tauopathies. Along these lines, we have previously demonstrated that a small naphthoquinone-tryptophan hybrid, termed NQTrp, is an effective modulator of tauopathy in vitro and in vivo. However, NQTrp is difficult to synthesize and is not very stable. Therefore, we tested whether a more stable and easier-to-synthesize modified version of NQTrp, containing a Cl ion, namely Cl-NQTrp, is also an effective inhibitor of tau aggregation in vitro and in vivo. Cl-NQTrp was previously shown to efficiently inhibit the aggregation of various amyloidogenic proteins and peptides. We demonstrate that Cl-NQTrp inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau, and alleviates tauopathy symptoms in a transgenic Drosophila model through the inhibition of tau aggregation-engendered toxicity. These results suggest that Cl-NQTrp could be a unique potential therapeutic for AD since it targets aggregation of both Aβ and tau., (© 2016 S. Karger AG, Basel.)
- Published
- 2017
- Full Text
- View/download PDF
20. Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity.
- Author
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Frenkel-Pinter M, Tal S, Scherzer-Attali R, Abu-Hussien M, Alyagor I, Eisenbaum T, Gazit E, and Segal D
- Subjects
- Animals, Disease Models, Animal, Drosophila, Drosophila Proteins genetics, Eye metabolism, Eye pathology, Eye ultrastructure, Female, Humans, Immunoprecipitation, In Vitro Techniques, Larva, Locomotion drug effects, Mice, Transgenic, Microscopy, Electron, Scanning, Naphthoquinones pharmacology, Neurotoxicity Syndromes pathology, Oligopeptides genetics, Protein Aggregates drug effects, Retinal Pigments metabolism, Tryptophan analogs & derivatives, Tryptophan pharmacology, tau Proteins genetics, Carrier Proteins metabolism, Naphthoquinones therapeutic use, Neurotoxicity Syndromes drug therapy, Oligopeptides metabolism, Tryptophan therapeutic use, tau Proteins metabolism
- Abstract
Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.
- Published
- 2016
- Full Text
- View/download PDF
21. Down-regulation of cyclooxygenase-2 by the carboxyl tail of the angiotensin II type 1 receptor.
- Author
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Sood R, Minzel W, Rimon G, Tal S, and Barki-Harrington L
- Subjects
- Amino Acid Motifs, Bacterial Proteins metabolism, Catalytic Domain, Cloning, Molecular, Gene Expression Regulation, Enzymologic, HEK293 Cells, Humans, Inflammation, Luminescent Proteins metabolism, Mutation, Proteasome Endopeptidase Complex metabolism, Radioimmunoassay, Signal Transduction, Cyclooxygenase 2 metabolism, Down-Regulation, Receptor, Angiotensin, Type 1 metabolism
- Abstract
The enzyme cyclooxygenase-2 (COX-2) plays an important role in the kidney by up-regulating the production of the vasoconstrictor hormone angiotensin II (AngII), which in turn down-regulates COX-2 expression via activation of the angiotensin II type 1 receptor (AT1) receptor. Chemical inhibition of the catalytic activity of COX-2 is a well-established strategy for treating inflammation but little is known of cellular mechanisms that dispose of the protein itself. Here we show that in addition to its indirect negative feedback on COX-2, AT1 also down-regulates the expression of the COX-2 protein via a pathway that does not involve G-protein or β-arrestin-dependent signaling. Instead, AT1 enhances the ubiquitination and subsequent degradation of the enzyme in the proteasome through elements in its cytosolic carboxyl tail (CT). We find that a mutant receptor that lacks the last 35 amino acids of its CT (Δ324) is devoid of its ability to reduce COX-2, and that expression of the CT sequence alone is sufficient to down-regulate COX-2. Collectively these results propose a new role for AT1 in regulating COX-2 expression in a mechanism that deviates from its canonical signaling pathways. Down-regulation of COX-2 by a short peptide that originates from AT1 may present as a basis for novel therapeutic means of eliminating excess COX-2 protein., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
22. Development of oral food-grade delivery systems: current knowledge and future challenges.
- Author
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Benshitrit RC, Levi CS, Tal SL, Shimoni E, and Lesmes U
- Subjects
- Administration, Oral, Animals, Drug Delivery Systems psychology, Drug Delivery Systems trends, Food Additives chemistry, Food Additives pharmacology, Humans, Knowledge, Pharmaceutical Preparations chemistry, Drug Delivery Systems methods, Drug Therapy psychology, Drug Therapy trends, Food Additives administration & dosage, Pharmaceutical Preparations administration & dosage
- Abstract
In recent years there has been an increasing interest in the development of new and efficient oral food delivery systems as tools to prevent disease and promote human health and well-being. Such vehicles are sought to protect bioactive ingredients added to food while controlling and targeting their release as they pass through the human gastrointestinal tract (GIT). This review aims to summarize the key concepts of food delivery systems, their characterization and evaluation. Particularly, evaluation of their performance within the human GIT is discussed. To this end an overview of several in vivo and in vitro methods currently applied for the study of such systems is given. Although considered to be still in its infancy, this promising field of research is likely to infiltrate into real products through rational design. In order for such efforts to materialize into real products some challenges still need to be met and are discussed herein. Overall, it seems that adopting a comprehensive pharmacological approach and relevant cutting edge tools are likely to facilitate innovations and help elucidate and perhaps tailor delivery systems' behavior in the human GIT.
- Published
- 2012
- Full Text
- View/download PDF
23. ArfGAP1 interacts with coat proteins through tryptophan-based motifs.
- Author
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Rawet M, Levi-Tal S, Szafer-Glusman E, Parnis A, and Cassel D
- Subjects
- Adaptor Protein Complex 1 metabolism, Adaptor Protein Complex 2 metabolism, Amino Acid Motifs, Amino Acid Sequence, Animals, GTPase-Activating Proteins genetics, Rats, Tryptophan genetics, Tryptophan metabolism, Coat Protein Complex I metabolism, GTPase-Activating Proteins metabolism
- Abstract
The Arf1 GTPase-activating protein ArfGAP1 regulates vesicular traffic through the COPI system. This protein consists of N-terminal catalytic domain, lipid packing sensors (the ALPS motifs) in the central region, and a carboxy part of unknown function. The carboxy part contains several diaromatic sequences that are reminiscent of motifs known to interact with clathrin adaptors. In pull-down experiments using GST-fused peptides from rat ArfGAP1, a peptide containing a (329)WETF sequence interacted strongly with clathrin adaptors AP1 and AP2, whereas a major coatomer-binding determinant was identified within the extreme carboxy terminal peptide ((405)AADEGWDNQNW). Mutagenesis and peptide competition experiments revealed that this determinant is required for coatomer binding to full-length ArfGAP1, and that interaction is mediated through the delta-subunit of the coatomer adaptor-like subcomplex. Evidence for a role of the carboxy motif in ArfGAP1-coatomer interaction in vivo is provided by means of a reporter fusion assay. Our findings point to mechanistic differences between ArfGAP1 and the other ArfGAPs known to function in the COPI system., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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