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Lan X, Zhang H, Chen ZY, Wang J, Zhang SC, Li Q, Ke JY, Wei W, Huang R, Tang X, Chen SP, Huang TT, Zhou YW. Suppressor of cytokine signaling 2 modulates regulatory T cell activity to suppress liver hepatocellular carcinoma growth and metastasis. World J Gastroenterol 2025; 31:100566. [PMID: 40248063 PMCID: PMC12001165 DOI: 10.3748/wjg.v31.i13.100566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/27/2024] [Accepted: 03/11/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Liver hepatocellular carcinoma (LIHC) is a highly aggressive cancer with poor prognosis due to its complex tumor microenvironment (TME) and immune evasion. Regulatory T cells (Tregs) play a critical role in tumor progression. Suppressor of cytokine signaling 2 (SOCS2), a key immune regulator, may modulate Treg activity and impact LIHC growth and metastasis. AIM To explore how the SOCS2 affects Treg activity in LIHC and its impact on tumor growth and metastasis. METHODS LIHC transcriptome data from The Cancer Genome Atlas database were analyzed using Gene Set Enrichment Analysis, Estimation of Stromal and Immune Cells in Malignant Tumors Using Expression Data, and Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts to evaluate immune pathways and Treg infiltration. Key prognostic genes were identified using Weighted Gene Co-expression Network Analysis and machine learning. In vitro, co-culture experiments, migration assays, apoptosis detection, and enzyme-linked immunosorbent assay were conducted. In vivo, tumor growth, metastasis, and apoptosis were assessed using subcutaneous and lung metastasis mouse models with hematoxylin and eosin staining, Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling, and immunohistochemistry analyses. RESULTS SOCS2 overexpression inhibited Treg cell activity, reducing LIHC cell migration and invasion while increasing apoptosis. In vivo, SOCS2 suppressed tumor growth and metastasis, confirming its therapeutic potential. CONCLUSION SOCS2 modulates CD4+ T function in the TME, contributing to LIHC progression. Targeting SOCS2 presents a potential therapeutic strategy for treating LIHC.
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Affiliation(s)
- Xi Lan
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Heng Zhang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Ze-Yan Chen
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Jing Wang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Shi-Chang Zhang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Qing Li
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Juan-Yu Ke
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Wei Wei
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Rong Huang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Xi Tang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Si-Ping Chen
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Ting-Ting Huang
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
| | - Yi-Wen Zhou
- Clinical Laboratory Center, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, Guangdong Province, China
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Cugudda A, La Manna S, Leone M, Vincenzi M, Marasco D. Design and functional studies of xylene-based cyclic mimetics of SOCS1 protein. Eur J Med Chem 2025; 282:117107. [PMID: 39608205 DOI: 10.1016/j.ejmech.2024.117107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 11/19/2024] [Accepted: 11/23/2024] [Indexed: 11/30/2024]
Abstract
Peptidomimetics of Suppressors of cytokine signaling 1 (SOCS1) protein demonstrated valid therapeutic potentials as anti-inflammatory agents. Indeed, SOCS1 has a small kinase inhibitory region (KIR) primarily involved in the inhibition of the JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway Herein, on the basis of previous investigations on a potent mimetic of KIR-SOCS1, named PS5, we designed and evaluated the SAR (Structure Activity Relationship) features of two xylene-based macrocycles analogues of PS5. These novel compounds bear thiol-xylene linkages with mono- and bi-cyclic scaffolds: they were in vitro functionally investigated toward JAK2 catalytic domain, as ligands with microscale thermophoresis (MST) and as inhibitors through LC-MS analyses. To evaluate structural properties Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies were employed along with serum stability assays. Results indicated that a monocycle scaffold is well-tolerated by PS5 sequence enhancing the affinity toward the kinase with a KD in the low micromolar range and providing consistent inhibitory effects of the catalytic activity, which were evaluated for the first time in the case of SOCS1 mimetics. Conformationally, the presence of xylene scaffold affects the flexibility of the compounds and their stabilities to proteases degradation. This study contributes to the understanding of the factors necessary for accurately mimicking the inhibitory mechanism of SOCS1 protein towards JAK2 and to the translation of proteomimetics into drugs.
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Affiliation(s)
- Alessia Cugudda
- Department of Pharmacy - University of Naples Federico II, 80131, Naples, Italy
| | - Sara La Manna
- Department of Pharmacy - University of Naples Federico II, 80131, Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging - CNR, 80131, Naples, Italy
| | - Marian Vincenzi
- Institute of Biostructures and Bioimaging - CNR, 80131, Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy - University of Naples Federico II, 80131, Naples, Italy; Institute of Biostructures and Bioimaging - CNR, 80131, Naples, Italy.
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3
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Benita BA, Koss KM. Peptide discovery across the spectrum of neuroinflammation; microglia and astrocyte phenotypical targeting, mediation, and mechanistic understanding. Front Mol Neurosci 2024; 17:1443985. [PMID: 39634607 PMCID: PMC11616451 DOI: 10.3389/fnmol.2024.1443985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/24/2024] [Indexed: 12/07/2024] Open
Abstract
Uncontrolled and chronic inflammatory states in the Central Nervous System (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan-rich scar tissue. Since the majority of neuroinflammation is exclusively based on the responses of said glia, their phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. Recently, research groups have focused on peptide discovery to identify these phenotypes, find novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. Several peptides targeting unique phenotypes of microglia and astroglia have been identified, along with several capable of mediating deleterious behaviors or promoting beneficial outcomes in the context of neuroinflammation. A comprehensive review of the peptides unique to microglia and astroglia will be provided along with their primary discovery methodologies, including top-down approaches using known biomolecules and naïve strategies using peptide and phage libraries.
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Affiliation(s)
| | - Kyle M. Koss
- Department of Surgery, University of Arizona, Tucson, AZ, United States
- Department of Neurobiology, University of Texas Medical Branch (UTMB) at Galvestion, Galvestion, TX, United States
- Sealy Institute for Drug Discovery (SIDD), University of Texas Medical Branch (UTMB) at Galvestion, Galvestion, TX, United States
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Yan M, Sun Z, Zhang S, Yang G, Jiang X, Wang G, Li R, Wang Q, Tian X. SOCS modulates JAK-STAT pathway as a novel target to mediate the occurrence of neuroinflammation: Molecular details and treatment options. Brain Res Bull 2024; 213:110988. [PMID: 38805766 DOI: 10.1016/j.brainresbull.2024.110988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/28/2024] [Accepted: 05/26/2024] [Indexed: 05/30/2024]
Abstract
SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis and related inflammatory diseases. SOCS act as inhibitors by regulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, thereby intervening in the pathogenesis of inflammation and autoimmune diseases. Recent studies have also demonstrated their involvement in central immunity and neuroinflammation, showing a dual functionality. However, the specific mechanisms of SOCS in the central nervous system remain unclear. This review thoroughly elucidates the specific mechanisms linking the SOCS-JAK-STAT pathway with the inflammatory manifestations of neurodegenerative diseases. Based on this, it proposes the theory that SOCS proteins can regulate the JAK-STAT pathway and inhibit the occurrence of neuroinflammation. Additionally, this review explores in detail the current therapeutic landscape and potential of targeting SOCS in the brain via the JAK-STAT pathway for neuroinflammation, offering insights into potential targets for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Min Yan
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Zhiyuan Sun
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Sen Zhang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Guangxin Yang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Xing Jiang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Guilong Wang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Ran Li
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
| | - Qinglu Wang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
| | - Xuewen Tian
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
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Cugudda A, La Manna S, Marasco D. Are peptidomimetics the compounds of choice for developing new modulators of the JAK-STAT pathway? Front Immunol 2024; 15:1406886. [PMID: 38983855 PMCID: PMC11232365 DOI: 10.3389/fimmu.2024.1406886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/12/2024] [Indexed: 07/11/2024] Open
Abstract
Protein-protein interactions (PPIs) play critical roles in a wide range of biological processes including the dysregulation of cellular pathways leading to the loss of cell function, which in turn leads to diseases. The dysfunction of several signaling pathways is linked to the insurgence of pathological processes such as inflammation, cancer development and neurodegeneration. Thus, there is an urgent need for novel chemical modulators of dysregulated PPIs to drive progress in targeted therapies. Several PPIs have been targeted by bioactive compounds, and, often, to properly cover interacting protein regions and improve the biological activities of modulators, a particular focus concerns the employment of macrocycles as proteomimetics. Indeed, for their physicochemical properties, they occupy an intermediate space between small organic molecules and macromolecular proteins and are prominent in the drug discovery process. Peptide macrocycles can modulate fundamental biological mechanisms and here we will focus on peptidomimetics active on the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways.
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Affiliation(s)
| | | | - Daniela Marasco
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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6
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Morelli M, Madonna S, Albanesi C. SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation. Front Immunol 2024; 15:1393799. [PMID: 38975347 PMCID: PMC11224294 DOI: 10.3389/fimmu.2024.1393799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/07/2024] [Indexed: 07/09/2024] Open
Abstract
SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.
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Affiliation(s)
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata - Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
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Cianciulli A, Calvello R, Porro C, Lofrumento DD, Panaro MA. Inflammatory Skin Diseases: Focus on the Role of Suppressors of Cytokine Signaling (SOCS) Proteins. Cells 2024; 13:505. [PMID: 38534350 PMCID: PMC10968894 DOI: 10.3390/cells13060505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Inflammatory skin diseases include a series of disorders characterized by a strong activation of the innate and adaptive immune system in which proinflammatory cytokines play a fundamental role in supporting inflammation. Skin inflammation is a complex process influenced by various factors, including genetic and environmental factors, characterized by the dysfunction of both immune and non-immune cells. Psoriasis (PS) and atopic dermatitis (AD) are the most common chronic inflammatory conditions of the skin whose pathogeneses are very complex and multifactorial. Both diseases are characterized by an immunological dysfunction involving a predominance of Th1 and Th17 cells in PS and of Th2 cells in AD. Suppressor of cytokine signaling (SOCS) proteins are intracellular proteins that control inflammatory responses by regulating various signaling pathways activated by proinflammatory cytokines. SOCS signaling is involved in the regulation and progression of inflammatory responses in skin-resident and non-resident immune cells, and recent data suggest that these negative modulators are dysregulated in inflammatory skin diseases such as PS and AD. This review focuses on the current understanding about the role of SOCS proteins in modulating the activity of inflammatory mediators implicated in the pathogenesis of inflammatory skin diseases such as PS and AD.
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Affiliation(s)
- Antonia Cianciulli
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
| | - Rosa Calvello
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, I-71100 Foggia, Italy;
| | - Dario Domenico Lofrumento
- Department of Biological and Environmental Sciences and Technologies, Section of Human Anatomy, University of Salento, I-73100 Lecce, Italy;
| | - Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Environment, University of Bari, I-70125 Bari, Italy; (A.C.); (R.C.)
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8
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Ilangumaran S, Gui Y, Shukla A, Ramanathan S. SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity. Front Immunol 2024; 15:1362224. [PMID: 38415248 PMCID: PMC10897024 DOI: 10.3389/fimmu.2024.1362224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 01/31/2024] [Indexed: 02/29/2024] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.
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Affiliation(s)
- Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Pandey R, Bakay M, Hakonarson H. SOCS-JAK-STAT inhibitors and SOCS mimetics as treatment options for autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis. Front Immunol 2023; 14:1271102. [PMID: 38022642 PMCID: PMC10643230 DOI: 10.3389/fimmu.2023.1271102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.
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Affiliation(s)
- Rahul Pandey
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Marina Bakay
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, United States
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10
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Jha A, Larkin J, Moore E. SOCS1-KIR Peptide in PEGDA Hydrogels Reduces Pro-Inflammatory Macrophage Activation. Macromol Biosci 2023; 23:e2300237. [PMID: 37337867 DOI: 10.1002/mabi.202300237] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Indexed: 06/21/2023]
Abstract
Macrophages modulate the wound healing cascade by adopting different phenotypes such as pro-inflammatory (M1) or pro-wound healing (M2). To reduce M1 activation, the JAK/STAT pathway can be targeted by using suppressors of cytokine signaling (SOCS1) proteins. Recently a peptide mimicking the kinase inhibitory region (KIR) of SOCS1 has been utilized to manipulate the adaptive immune response. However, the utilization of SOCS1-KIR to reduce pro-inflammatory phenotype in macrophages is yet to be investigated in a biomaterial formulation. This study introduces a PEGDA hydrogel platform to investigate SOCS1-KIR as a macrophage phenotype manipulating peptide. Immunocytochemistry, cytokine secretion assays, and gene expression analysis for pro-inflammatory macrophage markers in 2D and 3D experiments demonstrate a reduction in M1 activation due to SOCS1-KIR treatment. The retention of SOCS1-KIR in the hydrogel through release assays and diffusion tests is demonstrated. The swelling ratio of the hydrogel also remains unaffected with the entrapment of SOCS1-KIR. This study elucidates how SOCS1-KIR peptide in PEGDA hydrogels can be utilized as an effective therapeutic for macrophage manipulation.
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Affiliation(s)
- Aakanksha Jha
- J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Joseph Larkin
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, 32603, USA
| | - Erika Moore
- Fischell Department of Bioengineering, A. James Clark School of Engineering, University of Maryland, College Park, MD, 20742, USA
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11
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Monti A, Vitagliano L, Caporale A, Ruvo M, Doti N. Targeting Protein-Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches. Int J Mol Sci 2023; 24:7842. [PMID: 37175549 PMCID: PMC10178479 DOI: 10.3390/ijms24097842] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/22/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
Protein-protein interfaces play fundamental roles in the molecular mechanisms underlying pathophysiological pathways and are important targets for the design of compounds of therapeutic interest. However, the identification of binding sites on protein surfaces and the development of modulators of protein-protein interactions still represent a major challenge due to their highly dynamic and extensive interfacial areas. Over the years, multiple strategies including structural, computational, and combinatorial approaches have been developed to characterize PPI and to date, several successful examples of small molecules, antibodies, peptides, and aptamers able to modulate these interfaces have been determined. Notably, peptides are a particularly useful tool for inhibiting PPIs due to their exquisite potency, specificity, and selectivity. Here, after an overview of PPIs and of the commonly used approaches to identify and characterize them, we describe and evaluate the impact of chemical peptide libraries in medicinal chemistry with a special focus on the results achieved through recent applications of this methodology. Finally, we also discuss the role that this methodology can have in the framework of the opportunities, and challenges that the application of new predictive approaches based on artificial intelligence is generating in structural biology.
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Affiliation(s)
- Alessandra Monti
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Napoli, Italy; (A.M.); (L.V.); (M.R.)
| | - Luigi Vitagliano
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Napoli, Italy; (A.M.); (L.V.); (M.R.)
| | - Andrea Caporale
- Institute of Crystallography (IC), National Research Council (CNR), Strada Statale 14 km 163.5, Basovizza, 34149 Triese, Italy;
| | - Menotti Ruvo
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Napoli, Italy; (A.M.); (L.V.); (M.R.)
| | - Nunzianna Doti
- Institute of Biostructures and Bioimaging (IBB), National Research Council (CNR), 80131 Napoli, Italy; (A.M.); (L.V.); (M.R.)
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12
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La Manna S, Fortuna S, Leone M, Mercurio FA, Di Donato I, Bellavita R, Grieco P, Merlino F, Marasco D. Ad-hoc modifications of cyclic mimetics of SOCS1 protein: Structural and functional insights. Eur J Med Chem 2022; 243:114781. [PMID: 36152385 DOI: 10.1016/j.ejmech.2022.114781] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022]
Abstract
Suppressors of cytokine signaling 1 (SOCS1) protein, a negative regulator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that mimetics of KIR-SOCS1 can be potent therapeutics in several disorders (e.g., neurological, autoimmune or cardiovascular diseases). In this work, starting from a recently identified cyclic peptidomimetic of KIR-SOCS1, icPS5(Nal1), to optimize the peptide structure and improve its biological activity, we designed novel derivatives, containing crucial amino acids substitutions and/or modifications affecting the ring size. By combining microscale thermophoresis (MST), Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR) and computational studies, we showed that the cycle size plays a key role in the interaction with JAK2 and the substitution of native residues with un-natural building blocks is a valid tool to maintain low-micromolar affinity toward JAK2, greatly increasing their serum stability. These findings contribute to increase the structural knowledge required for the recognition of SOCS1/JAK2 and to progress towards their conversion into more drug-like compounds.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy
| | - Sara Fortuna
- CONCEPT Lab, Istituto Italiano di Tecnologia (IIT), Via E. Melen, 83, I-16152, Genova, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, CNR, 80145, Naples, Italy
| | - Flavia A Mercurio
- Institute of Biostructures and Bioimaging, CNR, 80145, Naples, Italy
| | - Ilaria Di Donato
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy
| | - Rosa Bellavita
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy
| | - Paolo Grieco
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy
| | - Francesco Merlino
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
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Open label safety and efficacy pilot to study mitigation of equine recurrent uveitis through topical suppressor of cytokine signaling-1 mimetic peptide. Sci Rep 2022; 12:7177. [PMID: 35505065 PMCID: PMC9065145 DOI: 10.1038/s41598-022-11338-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
Equine recurrent uveitis (ERU) is a painful and debilitating autoimmune disease and represents the only spontaneous model of human recurrent uveitis (RU). Despite the efficacy of existing treatments, RU remains a leading cause of visual handicap in horses and humans. Cytokines, which utilize Janus kinase 2 (Jak2) for signaling, drive the inflammatory processes in ERU that promote blindness. Notably, suppressor of cytokine signaling 1 (SOCS1), which naturally limits the activation of Jak2 through binding interactions, is often deficient in autoimmune disease patients. Significantly, we previously showed that topical administration of a SOCS1 peptide mimic (SOCS1-KIR) mitigated induced rodent uveitis. In this pilot study, we test the potential to translate the therapeutic efficacy observed in experimental rodent uveitis to equine patient disease. Through bioinformatics and peptide binding assays we demonstrate putative binding of the SOCS1-KIR peptide to equine Jak2. We also show that topical, or intravitreal injection of SOCS1-KIR was well tolerated within the equine eye through physical and ophthalmic examinations. Finally, we show that topical SOCS1-KIR administration was associated with significant clinical ERU improvement. Together, these results provide a scientific rationale, and supporting experimental evidence for the therapeutic use of a SOCS1 mimetic peptide in RU.
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14
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La Manna S, Leone M, Mercurio FA, Florio D, Marasco D. Structure-Activity Relationship Investigations of Novel Constrained Chimeric Peptidomimetics of SOCS3 Protein Targeting JAK2. Pharmaceuticals (Basel) 2022; 15:ph15040458. [PMID: 35455455 PMCID: PMC9031227 DOI: 10.3390/ph15040458] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 03/31/2022] [Accepted: 04/07/2022] [Indexed: 12/03/2022] Open
Abstract
SOCS3 (suppressor of cytokine signaling 3) protein suppresses cytokine-induced inflammation and its deletion in neurons or immune cells increases the pathological growth of blood vessels. Recently, we designed several SOCS3 peptidomimetics by assuming as template structures the interfacing regions of the ternary complex constituted by SOCS3, JAK2 (Janus Kinase 2) and gp130 (glycoprotein 130) proteins. A chimeric peptide named KIRCONG chim, including non-contiguous regions demonstrated able to bind to JAK2 and anti-inflammatory and antioxidant properties in VSMCs (vascular smooth muscle cells). With the aim to improve drug-like features of KIRCONG, herein we reported novel cyclic analogues bearing different linkages. In detail, in two of them hydrocarbon cycles of different lengths were inserted at positions i/i+5 and i/i+7 to improve helical conformations of mimetics. Structural features of cyclic compounds were investigated by CD (Circular Dichroism) and NMR (Nuclear Magnetic Resonance) spectroscopies while their ability to bind to catalytic domain of JAK2 was assessed through MST (MicroScale Thermophoresis) assay as well as their stability in biological serum. Overall data indicate a crucial role exerted by the length and the position of the cycle within the chimeric structure and could pave the way to the miniaturization of SOCS3 protein for therapeutic aims.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, Research Center on Bioactive Peptides (CIRPEB), University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.)
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging (CNR), 80145 Naples, Italy; (M.L.); (F.A.M.)
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging (CNR), 80145 Naples, Italy; (M.L.); (F.A.M.)
| | - Daniele Florio
- Department of Pharmacy, Research Center on Bioactive Peptides (CIRPEB), University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.)
| | - Daniela Marasco
- Department of Pharmacy, Research Center on Bioactive Peptides (CIRPEB), University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.)
- Correspondence: ; Tel.: +39-0812534607
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15
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La Manna S, Leone M, Iacobucci I, Annuziata A, Di Natale C, Lagreca E, Malfitano AM, Ruffo F, Merlino A, Monti M, Marasco D. Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide. Inorg Chem 2022; 61:3540-3552. [PMID: 35171608 PMCID: PMC9951207 DOI: 10.1021/acs.inorgchem.1c03540] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Neurodegenerative diseases are often caused by uncontrolled amyloid aggregation. Hence, many drug discovery processes are oriented to evaluate new compounds that are able to modulate self-recognition mechanisms. Herein, two related glycoconjugate pentacoordinate Pt(II) complexes were analyzed in their capacity to affect the self-aggregation processes of two amyloidogenic fragments, Aβ21-40 and Aβ25-35, of the C-terminal region of the β-amyloid (Aβ) peptide, the major component of Alzheimer's disease (AD) neuronal plaques. The most water-soluble complex, 1Ptdep, is able to bind both fragments and to deeply influence the morphology of peptide aggregates. Thioflavin T (ThT) binding assays, electrospray ionization mass spectrometry (ESI-MS), and ultraviolet-visible (UV-vis) absorption spectroscopy indicated that 1Ptdep shows different kinetics and mechanisms of inhibition toward the two sequences and demonstrated that the peptide aggregation inhibition is associated with a direct coordinative bond of the compound metal center to the peptides. These data support the in vitro ability of pentacoordinate Pt(II) complexes to inhibit the formation of amyloid aggregates and pave the way for the application of this class of compounds as potential neurotherapeutics.
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Affiliation(s)
- Sara La Manna
- Department
of Pharmacy, University of Naples “Federico
II”, 80131 Naples, Italy
| | - Marilisa Leone
- Institute
of Biostructures and Bioimaging - CNR, 80134 Naples, Italy
| | - Ilaria Iacobucci
- Department
of Chemical Sciences, University of Naples
“Federico II”, 80126 Naples, Italy
- CEINGE
Biotecnologie Avanzate S.c.a r.l., “University
of Naples Federico II”, 80131 Naples, Italy
| | - Alfonso Annuziata
- Department
of Chemical Sciences, University of Naples
“Federico II”, 80126 Naples, Italy
| | - Concetta Di Natale
- Interdisciplinary
Research Centre on Biomaterials (CRIB), Department of Ingegneria Chimica
del Materiali e della Produzione Industriale (DICMAPI), University “Federico II”, 80125 Naples, Italy
| | - Elena Lagreca
- Interdisciplinary
Research Centre on Biomaterials (CRIB), Department of Ingegneria Chimica
del Materiali e della Produzione Industriale (DICMAPI), University “Federico II”, 80125 Naples, Italy
| | - Anna Maria Malfitano
- Department
of Translational Medical Science, University
of Naples “Federico II”, 80131 Naples, Italy
| | - Francesco Ruffo
- Department
of Chemical Sciences, University of Naples
“Federico II”, 80126 Naples, Italy
| | - Antonello Merlino
- Department
of Chemical Sciences, University of Naples
“Federico II”, 80126 Naples, Italy
| | - Maria Monti
- Department
of Chemical Sciences, University of Naples
“Federico II”, 80126 Naples, Italy
- CEINGE
Biotecnologie Avanzate S.c.a r.l., “University
of Naples Federico II”, 80131 Naples, Italy
| | - Daniela Marasco
- Department
of Pharmacy, University of Naples “Federico
II”, 80131 Naples, Italy
- Institute
of Biostructures and Bioimaging - CNR, 80134 Naples, Italy
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16
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Chen H, Wu Y, Li K, Currie I, Keating N, Dehkhoda F, Grohmann C, Babon JJ, Nicholson SE, Sleebs BE. Optimization of Phosphotyrosine Peptides that Target the SH2 Domain of SOCS1 and Block Substrate Ubiquitination. ACS Chem Biol 2022; 17:449-462. [PMID: 34989544 DOI: 10.1021/acschembio.1c00884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Suppressor of cytokine signaling 1 (SOCS1) has emerged as a potential therapeutic target in inflammatory and viral diseases. SOCS1 operates via its kinase inhibitory region, Src homology 2 (SH2) domain, and SOCS box to negatively regulate the Janus kinase/signal transducers and activators of transcription signaling pathway. In this study, we utilized native phosphotyrosine peptide substrates as a starting point to iteratively explore the requirement of each amino acid position to target the SH2 domain of SOCS1. We show that Met, Thr, Thr, Val, and Asp in the respective -1, +1, +2, +3, and +5 positions within the peptide substrate are favored for binding to the SOCS1-SH2 domain and identifying several phosphotyrosine peptides that have potent SOCS1 binding affinity with IC50 values ranging from 20 to 70 nM and greater than 100-fold selectivity against the closely related SOCS family proteins, CIS, SOCS2, and SOCS3. The optimized phosphotyrosine peptide was shown to stabilize SOCS1 in a thermal shift assay using cell lysates and inhibited SOCS1-mediated ubiquitination of a target substrate in a biochemical assay. Collectively, these data provide the framework to develop cell-permeable peptidomimetics that further investigate the potential of the SOCS1-SH2 domain as a therapeutic target in inflammatory and viral diseases.
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Affiliation(s)
- Hao Chen
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Yuntong Wu
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Kunlun Li
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Iain Currie
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Narelle Keating
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Farhad Dehkhoda
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Christoph Grohmann
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Jeffrey J. Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Sandra E. Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
| | - Brad E. Sleebs
- The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
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La Manna S, De Benedictis I, Marasco D. Proteomimetics of Natural Regulators of JAK-STAT Pathway: Novel Therapeutic Perspectives. Front Mol Biosci 2022; 8:792546. [PMID: 35047557 PMCID: PMC8762217 DOI: 10.3389/fmolb.2021.792546] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/29/2021] [Indexed: 12/16/2022] Open
Abstract
The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein-protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK-STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.
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Affiliation(s)
| | | | - Daniela Marasco
- Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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18
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Thakur R, Suri CR, Kaur IP, Rishi P. Review. Crit Rev Ther Drug Carrier Syst 2022; 40:49-100. [DOI: 10.1615/critrevtherdrugcarriersyst.2022040322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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19
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Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1: Progress toward novel anti-inflammatory therapeutics. Eur J Med Chem 2021; 221:113547. [PMID: 34023736 DOI: 10.1016/j.ejmech.2021.113547] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/28/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023]
Abstract
Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs.
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20
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Manna SL, Florio D, Iacobucci I, Napolitano F, Benedictis ID, Malfitano AM, Monti M, Ravera M, Gabano E, Marasco D. A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications. Int J Mol Sci 2021; 22:ijms22063015. [PMID: 33809522 PMCID: PMC7998721 DOI: 10.3390/ijms22063015] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 01/21/2023] Open
Abstract
Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2'-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2':6',2''-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21-40) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ21-40 peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC50 values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ21-40 peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ21-40 with respect to the entire Aβ1-40 polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ21-40, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.); (I.D.B.)
| | - Daniele Florio
- Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.); (I.D.B.)
| | - Ilaria Iacobucci
- Department of Chemical Sciences, CEINGE Biotecnologie Avanzate S.c.a r.l., “University of Naples Federico II”, 80131 Naples, Italy; (I.I.); (M.M.)
| | - Fabiana Napolitano
- Department of Translational Medical Science, University of Naples “Federico II”, 80131 Naples, Italy; (F.N.); (A.M.M.)
| | - Ilaria De Benedictis
- Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.); (I.D.B.)
| | - Anna Maria Malfitano
- Department of Translational Medical Science, University of Naples “Federico II”, 80131 Naples, Italy; (F.N.); (A.M.M.)
| | - Maria Monti
- Department of Chemical Sciences, CEINGE Biotecnologie Avanzate S.c.a r.l., “University of Naples Federico II”, 80131 Naples, Italy; (I.I.); (M.M.)
| | - Mauro Ravera
- Department of Sciences and Technological Innovation (DiSIT), University of Piemonte Orientale “A. Avogadro”, 15121 Alessandria, Italy; (M.R.); (E.G.)
| | - Elisabetta Gabano
- Department of Sciences and Technological Innovation (DiSIT), University of Piemonte Orientale “A. Avogadro”, 15121 Alessandria, Italy; (M.R.); (E.G.)
| | - Daniela Marasco
- Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy; (S.L.M.); (D.F.); (I.D.B.)
- Correspondence: ; Tel.: +39-081-2534512; Fax: +39-081-2534574
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21
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Liu H, Wang W, Liu C. Increased expression of IFN-γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop. Exp Ther Med 2020; 21:112. [PMID: 33335575 PMCID: PMC7739872 DOI: 10.3892/etm.2020.9544] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
The weakening of extravillous trophoblast (EVT) invasion results in shallow placenta implantation. In HTR8/SVneo cells, IFN-γ can activate STAT1 and reduce cell invasion, and suppressor of cytokine signaling (SOCS) is an important negative regulatory protein in the Janus kinase (JAK)/STAT activator pathway and has a negative feedback function on JAK/STAT1. The aim of the present study was to elucidate how SOCS1 feedback regulates JAK/STAT1 and affects EVT cell invasion, which in turn affects the development of preeclampsia (PE). MTT and Annexin V/phosphatidylserine (PS) assays were performed to evaluate the viability and apoptosis of HTR8/SVneo cells treated with IFN-γ, respectively. Wound healing and invasion assays were also conducted to measure the migratory and invasive abilities of IFN-γ-treated HTR8/SVneo cells. The mRNA and protein expression levels of genes were detected using reverse transcription-quantitative PCR and western blot analysis. Small interfering RNA knockdown of SOCS1 was used to verify the role of feedback regulation in the IFN-γ-activated JAK/STAT1 signaling pathway. IFN-γ can inhibit HTR8/SVneo migration and invasion, and promote apoptosis by increasing the expression of phosphorylated (p)-JAK, p-STAT1 and caspase3, and reducing the expression of platelet-derived growth factor receptor A and Ezrin. Furthermore, SOCS1 may negatively regulate JAK/STAT1 and affect HTR-8/SVneo invasiveness. Evaluation of clinical samples demonstrated that the expression levels of SOCS1 and IFN-γ were higher in patients with PE compared with the healthy group. Collectively, the present results indicated that IFN-γ reduced the invasion of HTR-8/SVneo cells by activating JAK/STAT1, concurrently leading to an increase in SOCS1, which negatively regulates JAK/STAT1 and eliminates the pro-inflammatory effects of IFN-γ, thus forming a feedback loop.
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Affiliation(s)
- Huiqiang Liu
- Department of Gynecology and Obstetrics, Chaoyang Hospital Affiliated to Capital Medical University, Chaoyang, Beijing 100020, P.R. China.,Department of Gynecology and Obstetrics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Wenhao Wang
- Department of Gynecology and Obstetrics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
| | - Chongdong Liu
- Department of Gynecology and Obstetrics, Chaoyang Hospital Affiliated to Capital Medical University, Chaoyang, Beijing 100020, P.R. China
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22
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Di Natale C, Natale CF, Florio D, Netti PA, Morelli G, Ventre M, Marasco D. Effects of surface nanopatterning on internalization and amyloid aggregation of the fragment 264-277 of Nucleophosmin 1. Colloids Surf B Biointerfaces 2020; 197:111439. [PMID: 33137636 DOI: 10.1016/j.colsurfb.2020.111439] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/06/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022]
Abstract
The mechanical interpretation of the plethora of factors that governs cellular localization of amyloid aggregates is crucial for planning novel therapeutical interventions in neurodegenerative diseases since these aggregates exert a primary role in the proteostasis machinery. The uptake of Cell Penetrating Peptides (CPPs) conjugated with different amyloid polypeptides occurs via different endocytic processes regulated by cytoskeleton organization and cell morphology. Herein, we deepened the internalization of an amyloid system in cells cultured on nanopatterned surfaces that represent a powerful tool to shape cell and regulate its contractility. We analyzed the behavior of an amyloid model system, employing NPM1264-277 sequence, covalently conjugated to Tat fragment 48-60 as CPP. To investigate its internalization mechanism, we followed the formation of aggregates on two kinds of substrates: a flat and a nanopatterned surface. Herein, investigations during time were carried out by employing both confocal and second harmonic generation (SHG) microscopies. We showed that modifications of cellular environment affect peptide localization, its cytoplasmic translocation and the size of amyloid aggregates.
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Affiliation(s)
- Concetta Di Natale
- Department of Pharmacy, University of Naples "Federico II", Italy; Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy
| | - Carlo F Natale
- Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy
| | - Daniele Florio
- Department of Pharmacy, University of Naples "Federico II", Italy
| | - Paolo Antonio Netti
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy; Department of Chemical, Materials and Industrial Production Engineering (DICMAPI), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy
| | | | - Maurizio Ventre
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy; Department of Chemical, Materials and Industrial Production Engineering (DICMAPI), University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, University of Naples "Federico II", Italy
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23
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La Manna S, Lopez-Sanz L, Bernal S, Jimenez-Castilla L, Prieto I, Morelli G, Gomez-Guerrero C, Marasco D. Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis. Antioxidants (Basel) 2020; 9:antiox9080754. [PMID: 32824091 PMCID: PMC7465353 DOI: 10.3390/antiox9080754] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
| | - Laura Lopez-Sanz
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Susana Bernal
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Luna Jimenez-Castilla
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Ignacio Prieto
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain; (L.L.-S.); (S.B.); (L.J.-C.); (I.P.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Giancarlo Morelli
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
| | - Carmen Gomez-Guerrero
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
- Correspondence: (C.G.-G.); (D.M.)
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples “Federico II”, 80134 Naples, Italy; (S.L.M.); (G.M.)
- Correspondence: (C.G.-G.); (D.M.)
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Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes. Pharmaceuticals (Basel) 2020; 13:ph13080171. [PMID: 32751396 PMCID: PMC7464691 DOI: 10.3390/ph13080171] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 01/19/2023] Open
Abstract
Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264-277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.
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La Manna S, Lopez-Sanz L, Mercurio FA, Fortuna S, Leone M, Gomez-Guerrero C, Marasco D. Chimeric Peptidomimetics of SOCS 3 Able to Interact with JAK2 as Anti-inflammatory Compounds. ACS Med Chem Lett 2020; 11:615-623. [PMID: 32435361 DOI: 10.1021/acsmedchemlett.9b00664] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
The immunomodulatory effects of Suppressor of Cytokine Signaling (SOCS) proteins, that control the JAK/STAT pathway, indicate them as attractive candidates for immunotherapies. Recombinant SOCS3 protein suppresses the effects of inflammation, and its deletion in neurons or in immune cells increases pathological blood vessels growth. Recently, on the basis of the structure of the ternary complex among SOCS3, JAK2, and gp130, we focused on SOCS3 interfacing regions and designed several interfering peptides (IPs) that were able to mimic SOCS3 biological role in triple negative breast cancer (TNBC) models. Herein, to explore other protein regions involved in JAK2 recognition, several new chimeric peptides connecting noncontiguous SOCS3 regions and including a strongly aromatic fragment were investigated. Their ability to recognize the catalytic domain of JAK2 was evaluated through MST (microscale thermophoresis), and the most promising compound, named KIRCONG chim, exhibited a low micromolar value for dissociation constant. The conformational features of chimeric peptides were analyzed through circular dichroism and NMR spectroscopies, and their anti-inflammatory effects were assessed in cell cultures. Overall data suggest the importance of aromatic contribution in the recognition of JAK2 and that SOCS3 peptidomimetics could be endowed with a therapeutic potential in diseases with activated inflammatory cytokines.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134 Naples, Italy
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
| | - Laura Lopez-Sanz
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | | | - Sara Fortuna
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging - CNR, 80134 Naples, Italy
| | - Carmen Gomez-Guerrero
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134 Naples, Italy
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Di Natale C, La Manna S, Avitabile C, Florio D, Morelli G, Netti PA, Marasco D. Engineered β-hairpin scaffolds from human prion protein regions: Structural and functional investigations of aggregates. Bioorg Chem 2020; 96:103594. [PMID: 31991323 DOI: 10.1016/j.bioorg.2020.103594] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/14/2020] [Accepted: 01/18/2020] [Indexed: 12/16/2022]
Abstract
The investigation of conformational features of regions of amyloidogenic proteins are of great interest to deepen the structural changes and consequent self-aggregation mechanisms at the basis of many neurodegenerative diseases. Here we explore the effect of β-hairpin inducing motifs on regions of prion protein covering strands S1 and S2. In detail, we unveiled the structural and functional features of two model chimeric peptides in which natural sequences are covalently linked together by two dipeptides (l-Pro-Gly and d-Pro-Gly) that are known to differently enhance β-hairpin conformations but both containing N- and the C-terminal aromatic cap motifs to further improve interactions between natural strands. Spectroscopic investigations at solution state indicate that primary assemblies of the monomers of both constructs follow different aggregativemechanisms during the self-assembly: these distinctions, evidenced by CD and ThT emission spectroscopies, reflect into great morphological differences of nanostructures and suggest that rigid β-hairpin conformations greatly limit amyloid-like fibrillogenesis. Overall data confirm the important role exerted by the β-structure of regions S1 and S2 during the aggregation process and lead to speculate to its persistence even in unfolding conditions.
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Affiliation(s)
- Concetta Di Natale
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy; Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, 80125 Naples, Italy
| | - Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy
| | - Concetta Avitabile
- Institute of Biostructures and Bioimaging (IBB), National Research Council, Via Mezzocannone 16, 80134 Naples, Italy
| | - Daniele Florio
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy
| | - Giancarlo Morelli
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy
| | - Paolo Antonio Netti
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, 80125 Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II", Via Mezzocannone 16, 80134 Naples, Italy; Task force di Ateneo"METODOLOGIE ANALITICHE PER LA SALVAGUARDIA DEI BENI CULTURALI" MASBC, University of Naples "Federico II", Italy.
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Khan MGM, Ghosh A, Variya B, Santharam MA, Kandhi R, Ramanathan S, Ilangumaran S. Hepatocyte growth control by SOCS1 and SOCS3. Cytokine 2019; 121:154733. [PMID: 31154249 DOI: 10.1016/j.cyto.2019.154733] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/18/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023]
Abstract
The extraordinary capacity of the liver to regenerate following injury is dependent on coordinated and regulated actions of cytokines and growth factors. Whereas hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are direct mitogens to hepatocytes, inflammatory cytokines such as TNFα and IL-6 also play essential roles in the liver regeneration process. These cytokines and growth factors activate different signaling pathways in a sequential manner to elicit hepatocyte proliferation. The kinetics and magnitude of these hepatocyte-activating stimuli are tightly regulated to ensure restoration of a functional liver mass without causing uncontrolled cell proliferation. Hepatocyte proliferation can become deregulated under conditions of chronic inflammation, leading to accumulation of genetic aberrations and eventual neoplastic transformation. Among the control mechanisms that regulate hepatocyte proliferation, negative feedback inhibition by the 'suppressor of cytokine signaling (SOCS)' family proteins SOCS1 and SOCS3 play crucial roles in attenuating cytokine and growth factor signaling. Loss of SOCS1 or SOCS3 in the mouse liver increases the rate of liver regeneration and renders hepatocytes susceptible to neoplastic transformation. The frequent epigenetic repression of the SOCS1 and SOCS3 genes in hepatocellular carcinoma has stimulated research in understanding the growth regulatory mechanisms of SOCS1 and SOCS3 in hepatocytes. Whereas SOCS3 is implicated in regulating JAK-STAT signaling induced by IL-6 and attenuating EGFR signaling, SOCS1 is crucial for the regulation of HGF signaling. These two proteins also module the functions of certain key proteins that control the cell cycle. In this review, we discuss the current understanding of the functions of SOCS1 and SOCS3 in controlling hepatocyte proliferation, and its implications to liver health and disease.
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Affiliation(s)
- Md Gulam Musawwir Khan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Amit Ghosh
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Bhavesh Variya
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Madanraj Appiya Santharam
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Rajani Kandhi
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Sheela Ramanathan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Subburaj Ilangumaran
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
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Florio D, Malfitano AM, Di Somma S, Mügge C, Weigand W, Ferraro G, Iacobucci I, Monti M, Morelli G, Merlino A, Marasco D. Platinum(II) O, S Complexes Inhibit the Aggregation of Amyloid Model Systems. Int J Mol Sci 2019; 20:ijms20040829. [PMID: 30769904 PMCID: PMC6413125 DOI: 10.3390/ijms20040829] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/08/2019] [Accepted: 02/13/2019] [Indexed: 02/07/2023] Open
Abstract
Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.
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Affiliation(s)
- Daniele Florio
- Department of Pharmacy, University of Naples Federico II, Napoli 80134, Italy.
| | - Anna Maria Malfitano
- Department of Translational Medical Science, University of Naples Federico II, Napoli 80131, Italy.
| | - Sarah Di Somma
- Department of Translational Medical Science, University of Naples Federico II, Napoli 80131, Italy.
| | - Carolin Mügge
- Institute for Inorganic and Analytical Chemistry, University of Jena, Jena 07743, Germany.
- Department of Biology, Ruhr-University Bochum, Bochum 44801, Germany.
| | - Wolfgang Weigand
- Institute for Inorganic and Analytical Chemistry, University of Jena, Jena 07743, Germany.
| | - Giarita Ferraro
- Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
| | - Ilaria Iacobucci
- Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
- CEINGE Biotecnologie Avanzate s.c.a r.l., University of Naples Federico II, Napoli 80145, Italy.
| | - Maria Monti
- Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
- CEINGE Biotecnologie Avanzate s.c.a r.l., University of Naples Federico II, Napoli 80145, Italy.
| | - Giancarlo Morelli
- Department of Pharmacy, University of Naples Federico II, Napoli 80134, Italy.
| | - Antonello Merlino
- Department of Chemical Sciences, University of Naples Federico II, Napoli 80126, Italy.
| | - Daniela Marasco
- Department of Pharmacy, University of Naples Federico II, Napoli 80134, Italy.
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Peptides as Therapeutic Agents for Inflammatory-Related Diseases. Int J Mol Sci 2018; 19:ijms19092714. [PMID: 30208640 PMCID: PMC6163503 DOI: 10.3390/ijms19092714] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 09/07/2018] [Accepted: 09/09/2018] [Indexed: 01/08/2023] Open
Abstract
Inflammation is a physiological mechanism used by organisms to defend themselves against infection, restoring homeostasis in damaged tissues. It represents the starting point of several chronic diseases such as asthma, skin disorders, cancer, cardiovascular syndrome, arthritis, and neurological diseases. An increasing number of studies highlight the over-expression of inflammatory molecules such as oxidants, cytokines, chemokines, matrix metalloproteinases, and transcription factors into damaged tissues. The treatment of inflammatory disorders is usually linked to the use of unspecific small molecule drugs that can cause undesired side effects. Recently, many efforts are directed to develop alternative and more selective anti-inflammatory therapies, several of them imply the use of peptides. Indeed, peptides demonstrated as elected lead compounds toward several targets for their high specificity as well as recent and innovative synthetic strategies. Several endogenous peptides identified during inflammatory responses showed anti-inflammatory activities by inhibiting, reducing, and/or modulating the expression and activity of mediators. This review aims to discuss the potentialities and therapeutic use of peptides as anti-inflammatory agents in the treatment of different inflammation-related diseases and to explore the importance of peptide-based therapies.
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30
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La Manna S, Lee E, Ouzounova M, Di Natale C, Novellino E, Merlino A, Korkaya H, Marasco D. Mimetics of suppressor of cytokine signaling 3: Novel potential therapeutics in triple breast cancer. Int J Cancer 2018; 143:2177-2186. [DOI: 10.1002/ijc.31594] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/20/2018] [Accepted: 05/02/2018] [Indexed: 01/09/2023]
Affiliation(s)
- Sara La Manna
- Department of Pharmacy; University of Naples “Federico II”; Naples Italy
| | - Eunmi Lee
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta; Georgia
| | - Maria Ouzounova
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta; Georgia
| | - Concetta Di Natale
- Department of Pharmacy; University of Naples “Federico II”; Naples Italy
| | - Ettore Novellino
- Department of Pharmacy; University of Naples “Federico II”; Naples Italy
| | - Antonello Merlino
- Department of Chemical Sciences; University of Naples “Federico II”; Naples Italy
| | - Hasan Korkaya
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta; Georgia
| | - Daniela Marasco
- Department of Pharmacy; University of Naples “Federico II”; Naples Italy
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31
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Meng ZY, Kang HL, Duan W, Zheng J, Li QN, Zhou ZJ. MicroRNA-210 Promotes Accumulation of Neural Precursor Cells Around Ischemic Foci After Cerebral Ischemia by Regulating the SOCS1-STAT3-VEGF-C Pathway. J Am Heart Assoc 2018; 7:JAHA.116.005052. [PMID: 29478968 PMCID: PMC5866312 DOI: 10.1161/jaha.116.005052] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Neural precursor cell (NPC) migration toward lesions is key for neurological functional recovery. The neovasculature plays an important role in guiding NPC migration. MicroRNA‐210 (miR‐210) promotes angiogenesis and neurogenesis in the subventricular zone and hippocampus after cerebral ischemia; however, whether miR‐210 regulates NPC migration and the underlying mechanism is still unclear. This study investigated the role of miR‐210 in NPC migration. Methods and Results Neovascularization and NPC accumulation was detected around ischemic foci in a mouse model of middle cerebral artery occlusion (MCAO) and reperfusion. Bone marrow–derived endothelial progenitor cells (EPCs) were found to participate in neovascularization. miR‐210 was markedly upregulated after focal cerebral ischemia/reperfusion. Overexpressed miR‐210 enhanced neovascularization and NPC accumulation around the ischemic lesion and vice versa, strongly suggesting that miR‐210 might be involved in neovascularization and NPC accumulation after focal cerebral ischemia/reperfusion. In vitro experiments were conducted to explore the underlying mechanism. The transwell assay showed that EPCs facilitated NPC migration, which was further promoted by miR‐210 overexpression in EPCs. In addition, miR‐210 facilitated VEGF‐C (vascular endothelial growth factor C) expression both in vitro and in vivo. Moreover, the luciferase reporter assay demonstrated that miR‐210 directly targeted the 3′ untranslated region of SOCS1 (suppressor of cytokine signaling 1), and miR‐210 overexpression in HEK293 cells or EPCs decreased SOCS1 and increased STAT3 (signal transducer and activator of transcription 3) and VEGF‐C expression. When EPCs were simultaneously transfected with miR‐210 mimics and SOCS1, the expression of STAT3 and VEGF‐C was reversed. Conclusions miR‐210 promoted neovascularization and NPC migration via the SOCS1–STAT3–VEGF‐C pathway.
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Affiliation(s)
- Zhao-You Meng
- Department of Neurology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hua-Li Kang
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wei Duan
- Department of Neurology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jian Zheng
- Department of Neurology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qian-Ning Li
- Department of Neurology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhu-Juan Zhou
- Department of Neurology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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32
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La Manna S, Lopez-Sanz L, Leone M, Brandi P, Scognamiglio PL, Morelli G, Novellino E, Gomez-Guerrero C, Marasco D. Structure-activity studies of peptidomimetics based on kinase-inhibitory region of suppressors of cytokine signaling 1. Biopolymers 2017; 110. [PMID: 29154500 DOI: 10.1002/bip.23082] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/02/2017] [Accepted: 10/17/2017] [Indexed: 12/19/2022]
Abstract
Suppressors of Cytokine Signaling (SOCS) proteins are negative regulators of JAK proteins that are receptor-associated tyrosine kinases, which play key roles in the phosphorylation and subsequent activation of several transcription factors named STATs. Unlike the other SOCS proteins, SOCS1 and 3 show, in the N-terminal portion, a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence demonstrated promising in functional in vitro and in inflammatory animal models and we recently developed a peptidomimetic called PS5, as lead compound. Here, we investigated the cellular ability of PS5 to mimic SOCS1 biological functions in vascular smooth muscle cells and simultaneously we set up a new binding assay for the screening and identification of JAK2 binders based on a SPR experiment that revealed more robust with respect to previous ELISAs. On this basis, we designed several peptidomimetics bearing new structural constraints that were analyzed in both affinities toward JAK2 and conformational features through Circular Dichroism and NMR spectroscopies. Introduced chemical modifications provided an enhancement of serum stabilities of new sequences that could aid the design of future mimetic molecules of SOCS1 as novel anti-inflammatory compounds.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
| | - Laura Lopez-Sanz
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, 28040, Spain
| | - Marilisa Leone
- Institute of Biostructure and Bioimaging, National Research Council, Naples, 80134, Italy
| | - Paola Brandi
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
| | - Pasqualina Liana Scognamiglio
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
| | - Giancarlo Morelli
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
- Institute of Biostructure and Bioimaging, National Research Council, Naples, 80134, Italy
| | - Ettore Novellino
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
| | - Carmen Gomez-Guerrero
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, 28040, Spain
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi- University of Naples "Federico II,", Naples, 80134, Italy
- Institute of Biostructure and Bioimaging, National Research Council, Naples, 80134, Italy
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33
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Heppler LN, Frank DA. Targeting Oncogenic Transcription Factors: Therapeutic Implications of Endogenous STAT Inhibitors. Trends Cancer 2017; 3:816-827. [PMID: 29198438 DOI: 10.1016/j.trecan.2017.10.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 02/07/2023]
Abstract
Misregulation of transcription factors, including signal transducer and activator of transcription (STAT) proteins, leads to inappropriate gene expression patterns that can promote tumor initiation and progression. Under physiologic conditions, STAT signaling is stimulus dependent and tightly regulated by endogenous inhibitors, namely, suppressor of cytokine signaling (SOCS) proteins, phosphatases, and protein inhibitor of activated STAT (PIAS) proteins. However, in tumorigenesis, STAT proteins become constitutively active and promote the expression of progrowth and prosurvival genes. Although STAT activation has been widely implicated in cancer, therapeutic STAT inhibitors are still largely absent from the clinic. This review dissects the mechanisms of action of two families of endogenous STAT inhibitors, the SOCS and PIAS families, to potentially inform the development of novel therapeutic inhibitors.
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Affiliation(s)
- Lisa N Heppler
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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34
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La Manna S, Scognamiglio PL, Di Natale C, Leone M, Mercurio FA, Malfitano AM, Cianfarani F, Madonna S, Caravella S, Albanesi C, Novellino E, Marasco D. Characterization of linear mimetic peptides of Interleukin-22 from dissection of protein interfaces. Biochimie 2017; 138:106-115. [PMID: 28479106 DOI: 10.1016/j.biochi.2017.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 05/02/2017] [Indexed: 12/12/2022]
Abstract
Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology. The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses. The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases. In this study, we designed and characterized IL-22 derived peptides at protein interface regions: several sequences revealed able to interfere with the protein complex with IC50 in the micromolar range as evaluated through Surface Plasmon Resonance (SPR) experiments. Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition. Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Pasqualina Liana Scognamiglio
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Concetta Di Natale
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, CNR, 80134, Naples, Italy
| | | | - Anna Maria Malfitano
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Francesca Cianfarani
- Laboratory of Cellular and Molecular Biology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Sergio Caravella
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Cristina Albanesi
- Laboratory of Experimental Immunology, Fondazione "Luigi Maria Monti", Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Via Monti di Creta, 104, 00167, Rome, Italy
| | - Ettore Novellino
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy.
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Madonna S, Scarponi C, Morelli M, Sestito R, Scognamiglio PL, Marasco D, Albanesi C. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes. Oncotarget 2017; 8:24652-24667. [PMID: 28445952 PMCID: PMC5421877 DOI: 10.18632/oncotarget.15629] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 02/15/2017] [Indexed: 12/21/2022] Open
Abstract
Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.
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Affiliation(s)
- Stefania Madonna
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Claudia Scarponi
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Martina Morelli
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
| | - Rosanna Sestito
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
- Current address: Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Daniela Marasco
- Department of Pharmacy, CIRPEB, University of Naples “Federico II”, Naples, Italy
| | - Cristina Albanesi
- Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione “Luigi M. Monti” (FLMM), Rome, Italy
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Russo A, Manna SL, Novellino E, Malfitano AM, Marasco D. Molecular signaling involving intrinsically disordered proteins in prostate cancer. Asian J Androl 2017; 18:673-81. [PMID: 27212129 PMCID: PMC5000787 DOI: 10.4103/1008-682x.181817] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Investigations on cellular protein interaction networks (PINs) reveal that proteins that constitute hubs in a PIN are notably enriched in Intrinsically Disordered Proteins (IDPs) compared to proteins that constitute edges, highlighting the role of IDPs in signaling pathways. Most IDPs rapidly undergo disorder-to-order transitions upon binding to their biological targets to perform their function. Conformational dynamics enables IDPs to be versatile and to interact with a broad range of interactors under normal physiological conditions where their expression is tightly modulated. IDPs are involved in many cellular processes such as cellular signaling, transcriptional regulation, and splicing; thus, their high-specificity/low-affinity interactions play crucial roles in many human diseases including cancer. Prostate cancer (PCa) is one of the leading causes of cancer-related mortality in men worldwide. Therefore, identifying molecular mechanisms of the oncogenic signaling pathways that are involved in prostate carcinogenesis is crucial. In this review, we focus on the aspects of cellular pathways leading to PCa in which IDPs exert a primary role.
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Affiliation(s)
- Anna Russo
- Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy
| | - Sara La Manna
- Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy
| | - Ettore Novellino
- Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy
| | - Anna Maria Malfitano
- Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy
| | - Daniela Marasco
- Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy
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Recio C, Maione F, Iqbal AJ, Mascolo N, De Feo V. The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease. Front Pharmacol 2017; 7:526. [PMID: 28111551 PMCID: PMC5216031 DOI: 10.3389/fphar.2016.00526] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 12/19/2016] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity worldwide. Numerous therapies are currently under investigation to improve pathological cardiovascular complications, but yet, there have been very few new medications approved for intervention/treatment. Therefore, new approaches to treat CVD are urgently required. Attempts to prevent vascular complications usually involve amelioration of contributing risk factors and underlying processes such as inflammation, obesity, hyperglycaemia, or hypercholesterolemia. Historically, the development of peptides as therapeutic agents has been avoided by the Pharmaceutical industry due to their low stability, size, rate of degradation, and poor delivery. However, more recently, resurgence has taken place in developing peptides and their mimetics for therapeutic intervention. As a result, increased attention has been placed upon using peptides that mimic the function of mediators involved in pathologic processes during vascular damage. This review will provide an overview on novel targets and experimental therapeutic approaches based on peptidomimetics for modulation in CVD. We aim to specifically examine apolipoprotein A-I (apoA-I) and apoE mimetic peptides and their role in cholesterol transport during atherosclerosis, suppressors of cytokine signaling (SOCS)1-derived peptides and annexin-A1 as potent inhibitors of inflammation, incretin mimetics and their function in glucose-insulin tolerance, among others. With improvements in technology and synthesis platforms the future looks promising for the development of novel peptides and mimetics for therapeutic use. However, within the area of CVD much more work is required to identify and improve our understanding of peptide structure, interaction, and function in order to select the best targets to take forward for treatment.
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Affiliation(s)
- Carlota Recio
- Sir William Dunn School of Pathology, University of Oxford Oxford, UK
| | - Francesco Maione
- Department of Pharmacy, University of Naples Federico II Naples, Italy
| | - Asif J Iqbal
- Sir William Dunn School of Pathology, University of Oxford Oxford, UK
| | - Nicola Mascolo
- Department of Pharmacy, University of Naples Federico II Naples, Italy
| | - Vincenzo De Feo
- Department of Pharmacy, University of Salerno Salerno, Italy
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38
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SOCS1 in cancer: An oncogene and a tumor suppressor. Cytokine 2016; 82:87-94. [DOI: 10.1016/j.cyto.2016.01.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/11/2016] [Accepted: 01/12/2016] [Indexed: 01/24/2023]
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McCormick SM, Heller NM. Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins. Front Immunol 2015; 6:549. [PMID: 26579124 PMCID: PMC4621458 DOI: 10.3389/fimmu.2015.00549] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022] Open
Abstract
Macrophages are innate immune cells of dynamic phenotype that rapidly respond to external stimuli in the microenvironment by altering their phenotype to respond to and to direct the immune response. The ability to dynamically change phenotype must be carefully regulated to prevent uncontrolled inflammatory responses and subsequently to promote resolution of inflammation. The suppressor of cytokine signaling (SOCS) proteins play a key role in regulating macrophage phenotype. In this review, we summarize research to date from mouse and human studies on the role of the SOCS proteins in determining the phenotype and function of macrophages. We will also touch on the influence of the SOCS on dendritic cell (DC) and microglial phenotype and function. The molecular mechanisms of SOCS function in macrophages and DCs are discussed, along with how dysregulation of SOCS expression or function can lead to alterations in macrophage/DC/microglial phenotype and function and to disease. Regulation of SOCS expression by microRNA is discussed. Novel therapies and unanswered questions with regard to SOCS regulation of monocyte-macrophage phenotype and function are highlighted.
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Affiliation(s)
- Sarah M McCormick
- Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA
| | - Nicola M Heller
- Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA ; Anesthesiology and Critical Care Medicine, The Johns Hopkins University , Baltimore, MD , USA
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Carotenuto A, Auriemma L, Merlino F, Yousif AM, Marasco D, Limatola A, Campiglia P, Gomez-Monterrey I, Santicioli P, Meini S, Maggi CA, Novellino E, Grieco P. Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor. J Med Chem 2014; 57:5965-74. [DOI: 10.1021/jm500218x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Alfonso Carotenuto
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Luigia Auriemma
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Francesco Merlino
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Ali Munaim Yousif
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Daniela Marasco
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
- CIRPEB:
Centro Interuniversitario di Ricerca sui Peptidi Bioattivi , University of Naples “Federico II”, DFM-Scarl, Institute of Biostructures and Bioimaging-CNR, 80134, Naples, Italy
| | - Antonio Limatola
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Pietro Campiglia
- Department
of Pharmacy, University of Salerno, I-84084 Fisciano, Salerno Italy
| | | | - Paolo Santicioli
- Department
of Pharmacology, Menarini Ricerche, Via Rismondo 12/A, I-50131, Florence, Italy
| | - Stefania Meini
- Department
of Pharmacology, Menarini Ricerche, Via Rismondo 12/A, I-50131, Florence, Italy
| | - Carlo A. Maggi
- Department
of Pharmacology, Menarini Ricerche, Via Rismondo 12/A, I-50131, Florence, Italy
| | - Ettore Novellino
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
| | - Paolo Grieco
- Department
of Pharmacy, University of Naples “Federico II”, I-80131 Naples, Italy
- CIRPEB:
Centro Interuniversitario di Ricerca sui Peptidi Bioattivi , University of Naples “Federico II”, DFM-Scarl, Institute of Biostructures and Bioimaging-CNR, 80134, Naples, Italy
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Skjesol A, Liebe T, Iliev DB, Thomassen EIS, Tollersrud LG, Sobhkhez M, Lindenskov Joensen L, Secombes CJ, Jørgensen JB. Functional conservation of suppressors of cytokine signaling proteins between teleosts and mammals: Atlantic salmon SOCS1 binds to JAK/STAT family members and suppresses type I and II IFN signaling. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2014; 45:177-189. [PMID: 24582990 DOI: 10.1016/j.dci.2014.02.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 02/18/2014] [Accepted: 02/18/2014] [Indexed: 06/03/2023]
Abstract
Suppressor of cytokine signaling (SOCS) proteins are crucially involved in the control of inflammatory responses through their impact on various signaling pathways including the JAK/STAT pathway. Although all SOCS protein family members are identified in teleost fish, their functional properties in non-mammalian vertebrates have not been extensively studied. To gain further insight into SOCS functions in bony fish, we have identified and characterized the Atlantic salmon (Salmo salar) SOCS1, SOCS2 and CISH genes. These genes exhibited sequence conservation with their mammalian counterparts and they were ubiquitously expressed. SOCS1 in mammalian species has been recognized as a key negative regulator of interferon (IFN) signaling and recent data for the two model fish Tetraodon (Tetraodon nigroviridis) and zebrafish (Danio rerio) suggest that these functions are conserved from teleost to mammals. In agreement with this we here demonstrate a strong negative regulatory activity of salmon SOCS1 on type I and type II IFN signaling, while SOCS2a and b and CISH only moderately affected IFN responses. SOCS1 also inhibited IFNγ-induced nuclear localization of STAT1 and a direct interaction between SOCS1 and STAT1 and between SOCS1 and the Tyk2 kinase was found. Using SOCS1 mutants lacking either the KIR domain or the ESS, SH2 and SOCS box domains showed that all domains affected the ability of SOCS1 to inhibit IFN-mediated signaling. These results are the first to demonstrate that SOCS1 is a potent inhibitor of IFN-mediated JAK-STAT signaling in teleost fish.
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Affiliation(s)
- Astrid Skjesol
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
| | - Theresa Liebe
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway; Center for Molecular Biomedicine (CMB), Dept. of Biochemistry, University of Jena, D-07745 Jena, Germany
| | - Dimitar B Iliev
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
| | - Ernst I S Thomassen
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
| | - Linn Greiner Tollersrud
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
| | - Mehrdad Sobhkhez
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
| | | | - Christopher J Secombes
- Scottish Fish Immunology Research Centre, Institute of Biological and Environmental Sciences, University of Aberdeen, Tillydrone Avenue, Aberdeen AB24 2TZ, UK
| | - Jorunn B Jørgensen
- The Norwegian College of Fishery Science, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
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Zhang JJ, Fan YC, Zhao ZH, Yang Y, Dou CY, Gao S, Wang K. Prognoses of patients with acute-on-chronic hepatitis B liver failure are closely associated with altered SOCS1 mRNA expression and cytokine production following glucocorticoid treatment. Cell Mol Immunol 2014; 11:396-404. [PMID: 24727541 DOI: 10.1038/cmi.2014.23] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 02/13/2014] [Accepted: 02/13/2014] [Indexed: 12/28/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS) 1 plays a crucial role in the immune response and might contribute to the prognoses of liver failure treated with glucocorticoid. We recruited 47 acute-on-chronic hepatitis B liver failure (ACHBLF) patients receiving glucocorticoid treatment and 30 healthy controls to determine the potential effects of glucocorticoid on the transcriptional level of SOCS1 in peripheral blood mononuclear cells. On the third and twenty-eighth days of glucocorticoid treatment, SOCS1 expression was negatively correlated with model for end-stage liver disease (MELD) score. Interleukin-6 (IL-6) and tumor-necrosis factor-α (TNF-α) levels were statistically lower, while the SOCS1 transcription level was higher in survivors than non-survivors both in pre- and post-treatment ACHBLF patients. The methylation rate of the SOCS1 promoter in ACHBLF patients was higher than in healthy control patients as determined by methylation-specific polymerase chain reaction. The mRNA level of SOCS1 in methylated promoters was significantly lower than from patients with unmethylated SOCS1 promoters. interferon (IFN)-γ-responsive and STAT1-dependent gene expression was higher in survivors and was dramatically decreased with rising expression of SOCS1 after glucocorticoid treatment. Mortality rates were significantly higher in methylated patients than for those without methylation at the end of a 90-day follow-up. Furthermore, we found that five in six surviving patients displayed demethylated SOCS1 on the twenty-eighth day after treatment, while that number was 3 in 10 in the non-survivors. These findings suggested that ACHBLF patients without SOCS1 methylation may have a favorable response to corticosteroid treatment.
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Affiliation(s)
- Jian-Jun Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China
| | - Yu-Chen Fan
- 1] Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China [2] Institute of Hepatology, Shandong University, Ji'nan, China
| | - Ze-Hua Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China
| | - Yang Yang
- Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China
| | - Cheng-Yun Dou
- Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China
| | - Kai Wang
- 1] Department of Hepatology, Qilu Hospital of Shandong University, Ji'nan, China [2] Institute of Hepatology, Shandong University, Ji'nan, China
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Larkin J, Ahmed CM, Wilson TD, Johnson HM. Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells. Front Immunol 2013; 4:469. [PMID: 24391643 PMCID: PMC3866655 DOI: 10.3389/fimmu.2013.00469] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 12/04/2013] [Indexed: 01/17/2023] Open
Abstract
Regulatory T cells (Tregs) play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFNγ) mediated, lethal auto-immunity occurs (in both mice and humans) in their absence. In addition, Tregs have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFNγ signaling such as type 1 diabetes, lupus, and lipopolysaccharide (LPS) mediated endotoxemia. Notably, suppressor of cytokine signaling-1 deficient (SOCS1−/−) mice also succumb to a lethal auto-inflammatory disease, dominated by excessive IFNγ signaling and bearing similar disease course kinetics to Treg deficient mice. Moreover SOCS1 deficiency has been implicated in lupus progression, and increased susceptibility to LPS mediated endotoxemia. Although it has been established that Tregs and SOCS1 play a critical role in the regulation of IFNγ signaling, and the prevention of lethal auto-inflammatory disease, the role of Treg/SOCS1 cross-talk in the regulation of IFNγ signaling has been essentially unexplored. This is especially pertinent as recent publications have implicated a role of SOCS1 in the stability of peripheral Tregs. This review will examine the emerging research findings implicating a critical role of the intersection of the SOCS1 and Treg regulatory pathways in the control of IFN gamma signaling and immune system function.
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Affiliation(s)
- Joseph Larkin
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
| | - Chulbul M Ahmed
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
| | - Tenisha D Wilson
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
| | - Howard M Johnson
- Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA
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44
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Kubo M. Therapeutic hope for psoriasis offered by SOCS (suppressor of cytokine signaling) mimetic peptide. Eur J Immunol 2013; 43:1702-5. [PMID: 23828297 DOI: 10.1002/eji.201343748] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 06/04/2013] [Accepted: 06/13/2013] [Indexed: 01/21/2023]
Abstract
The cytokine network has a pivotal role in maintaining skin homeostasis, and the disturbance of this network can lead to skin pathogenesis. Evidence published in this issue of the European Journal of Immunology by Madonna et al. [Eur. J. Immunol. 2013. 43: 1883-1895], together with other recent data, focuses attention on a negative cytokine regulator, namely SOCS 1 (suppressor of cytokine signaling 1) in immune-mediated skin disease. In addition, Madonna et al. bring new perspectives regarding the therapeutic control of IFN-γ-mediated skin pathogenesis by use of a SOCS 1 mimetic peptide.
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Affiliation(s)
- Masato Kubo
- Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Chiba, Japan.
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45
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Stec W, Vidal O, Zeidler MP. Drosophila SOCS36E negatively regulates JAK/STAT pathway signaling via two separable mechanisms. Mol Biol Cell 2013; 24:3000-9. [PMID: 23885117 PMCID: PMC3771960 DOI: 10.1091/mbc.e13-05-0275] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The low-complexity Drosophila genome includes previously uncharacterized SOCS36E, an ancestral SOCS4/5 homologue. It is shown that SOCS36E suppresses JAK/STAT signaling through two separate mechanisms: via receptor stability, mediated by the conserved SOCS-box domain, and via suppression of receptor phosphorylation that requires the N-terminal domain. Conserved from humans to Drosophila, the Janus kinase/signal transducer and activators of transcription (JAK/STAT) signaling cascade is essential for multiple developmental and homeostatic processes, with regulatory molecules controlling pathway activity also highly conserved. We characterize the Drosophila JAK/STAT pathway regulator SOCS36E and show that it functions via two independent mechanisms. First, we show that Drosophila Elongin B/C and Cullin-5 act via the SOCS-box of SOCS36E to reduce pathway activity specifically in response to ligand stimulation—a process that involves endocytic trafficking and lysosomal degradation of the Domeless (Dome) receptor. Second, SOCS36E also suppresses both stimulated and basal pathway activity via an Elongin/Cullin-independent mechanism that is mediated by the N-terminus of SOCS36E, which is required for the physical interaction of SOCS36E with Dome. Although some human SOCS proteins contain N-terminal kinase-inhibitory domains, we do not identify such a region in SOCS36E and propose a model wherein the N-terminal of SOCS36E blocks access to tyrosine residues in Dome. Our biochemical analysis of a SOCS-family regulator from a lower organism highlights the fundamental conserved roles played by regulatory mechanisms in signal transduction.
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Affiliation(s)
- Wojciech Stec
- MRC Centre for Development and Biomedical Genetics and Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom
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46
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Madonna S, Scarponi C, Doti N, Carbone T, Cavani A, Scognamiglio PL, Marasco D, Albanesi C. Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses. Eur J Immunol 2013; 43:1883-95. [DOI: 10.1002/eji.201343370] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 03/08/2013] [Accepted: 04/12/2013] [Indexed: 01/09/2023]
Affiliation(s)
- Stefania Madonna
- Laboratory of Experimental Immunology; Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; Rome; Italy
| | - Claudia Scarponi
- Laboratory of Experimental Immunology; Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; Rome; Italy
| | - Nunzianna Doti
- Institute of Biostructures and Bioimaging, CNR; Naples; Italy
| | - Teresa Carbone
- Laboratory of Experimental Immunology; Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; Rome; Italy
| | - Andrea Cavani
- Laboratory of Experimental Immunology; Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; Rome; Italy
| | | | | | - Cristina Albanesi
- Laboratory of Experimental Immunology; Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; Rome; Italy
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47
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Abstract
Because of their genetically determined capacity to respond to pro-inflammatory stimuli, keratinocytes have a crucial role in the pathogenesis of psoriasis. Upon IFN-γ and TNF-α exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, and show aberrant hyperproliferation and terminal differentiation. The thickening of psoriasic skin also results from a peculiar resistance of keratinocytes to cytokine-induced apoptosis. In this study, we investigated on the molecular mechanisms concurring to the resistance of psoriatic keratinocytes to cell death, focusing on the role having suppressor of cytokine signaling (SOCS)1 and SOCS3, two molecules abundantly expressed in IFN-γ/TNF-α-activated psoriatic keratinocytes, in sustaining anti-apoptotic pathways. We found that SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT pathway in keratinocytes. The latter determines the activation of the anti-apoptotic NF-κB cascade and, in parallel, the inhibition of the pro-apoptotic BAD function in keratinocytes. For the first time, we report that phosphorylated AKT and phosphorylated BAD are strongly expressed in lesional psoriatic skin, compared with healthy or not lesional skin, and they strictly correlate to the high expression of SOCS1 and SOCS3 molecules in the psoriatic epidermis. Finally, the depletion of SOCS1 and SOCS3, as well as the chemical inactivation of PI3K activity in psoriatic keratinocytes, definitively unveils the role of PI3K/AKT cascade on the resistance of diseased keratinocytes to apoptosis.
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