Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis

Manna, Sara La; López-Sanz, Laura; Bernal, Susana; Prieto, Ignacio; Morelli, Giancarlo; Gómez-Guerrero, Carmen; Marasco, Daniela

doi:10.3390/antiox9080754

Cited by 18 publications

(11 citation statements)

References 63 publications

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“…Docking, molecular dynamics (MD), and in vitro binding assays suggested that even if van der Waals and electrostatic interactions mainly drive the recognition between JAK2 and internal PS5 cycles, the substitution of Phe/Nal1 allow a greater affinity toward protein target, conferring to aromatic interactions a crucial role for the formation of the complex as also confirmed by structural investigations, circular dichroism (CD), and nuclear magnetic resonance (NMR). In cellular contexts, such as VSMCs and macrophage cell line RAW 264.7, both PS5 cyclic analogs reduce STAT1 cellular migration at a longer extent with respect to Phe-internal cycle PS5, and this could have an impact on ongoing studies of their effects in plaque formation ( Charo and Taub, 2011 ; Demina et al, 2021 ) as well as for antioxidant properties ( La Manna et al, 2020b ), confirmed by PCR analysis, which demonstrated a drastic suppression of NADPH oxidase genes and increase in Sod1 and Cat .…”

Section: Proteomimetics Of Natural Inhibitors Of Jak-statmentioning

confidence: 75%

“…PS5 also displayed antioxidant and athero-protective properties in a mouse model of atherosclerosis, corroborating the therapeutic perspective for its in vivo application. Indeed, PS5 administration to atherosclerotic mice induced a reduction in 1) the size and extension of atheroma plaques, 2) the intraplaque lipid content, and 3) the accumulation of monocytes/macrophages ( La Manna et al, 2020b ).…”

Section: Proteomimetics Of Natural Inhibitors Of Jak-statmentioning

confidence: 99%

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Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Manna

Benedictis

Marasco

2022

Front. Mol. Biosci.

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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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Section: Proteomimetics Of Natural Inhibitors Of Jak-statmentioning

confidence: 75%

Section: Proteomimetics Of Natural Inhibitors Of Jak-statmentioning

confidence: 99%

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Manna

Benedictis

Marasco

2022

Front. Mol. Biosci.

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“…In the study, we first validated that E. coli K1 infection triggers JAK2/STAT5 activation in HBMECs, while AG490 (JAK2 inhibitor) pretreatment and CISH overexpression inhibited JAK2–STAT5 and attenuated BSM injuries. Published studies suggest that the suppressor of cytokine signaling proteins (SOCS) are the main regulators in the innate immune reaction induced by a microbial pathogen, especially participating in the cellular negative feedback regulation of JAK/STAT [ 34 ], avoiding excessive inflammation [ 35 ]. Recent studies have found that SOCS proteins can function as executors and contribute to the downregulation of pro-inflammatory factors associated with infection [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Alpha7 Nicotinic Acetylcholine Receptor Antagonists Prevent Meningitic Escherichia coli-Induced Blood–Brain Barrier Disruptions by Targeting the CISH/JAK2/STAT5b Axis

Gong

Gao

et al. 2022

Biomedicines

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Despite the availability of antibiotics over the last several decades, excessive antibiotic treatments for bacterial sepsis and meningitis (BSM) in children may result in several adverse outcomes. Hematogenous pathogens may directly induce permeability increases in human brain microvascular endothelial cells (HBMECs) and blood–brain barrier (BBB) dysfunctions. Our preliminary studies demonstrated that the alpha7 nicotinic acetylcholine receptor (α7nAChR) played an important role in the pathogenesis of BSM, accompanied by increasing cytokine-inducible SH2-containing protein (CISH) at the transcriptome level, but it has remained unclear how α7nAChR-CISH works mechanistically. The study aims to explore the underlying mechanism of α7nAChR and CISH during E. coli-induced BSM in vitro (HBMECs) and in vivo (α7nAChR-KO mouse). We found that in the stage of E. coli K1-induced BBB disruptions, α7nAChR functioned as the key regulator that affects the integrity of HBMECs by activating the JAK2–STAT5 signaling pathway, while CISH inhibited JAK2–STAT5 activation and exhibited protective effects against E. coli infection. Notably, we first validated that the expression of CISH could be regulated by α7nAChR in HBMECs. In addition, we determined the protective effects of MLA (methyllycaconitine citrate) and MEM (memantine hydrochloride) (functioning as α7nAChR antagonists) on infected HBMECs and suggested that the α7nAChR–CISH axis could explain the protective effects of the two small-molecule compounds on E. coli-induced HBMECs injuries and BBB disruptions. In conclusion, we dissected the α7nAChR/CISH/JAK2/STAT5 axis as critical for the pathogenesis of E. coli-induced brain microvascular leakage and BBB disruptions and provided novel evidence for the development of α7nAChR antagonists in the prevention of pediatric E. coli BSM.

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“…S1 peptide mimics of the unique SOCS1 KIR domain, is conjugated to a hydrophobic sequence and effectively enters into the cells to suppress JAK kinase activity and STAT activation (Jager et al, 2011; Recio et al, 2014). So far, the in vivo anti‐inflammatory effects of different SOCS1 derived sequences have been investigated in preclinical models of inflammatory diseases (Ahmed, Larkin, & Johnson, 2015; Jager et al, 2011; La Manna et al, 2020; Madonna et al, 2013) and diabetic complications (Lopez‐Sanz et al, 2018; Opazo‐Ríos et al, 2020; Recio et al, 2014; Recio et al, 2017). Herein, we demonstrate that S1 therapy suppresses STAT1/3 and downstream target genes in aorta and prevents elastase‐induced AAA formation.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

Bernal

López-Sanz

Prieto

et al. 2020

British J Pharmacology

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Background and Purpose: Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall. Targeting JAK/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculo-protective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental Approach: A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the wellestablished mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. Key Results: S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, down-regulated cytokines, metalloproteinases and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. Conclusion and Implications:This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA.

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Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis

Cited by 18 publications

References 63 publications

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Alpha7 Nicotinic Acetylcholine Receptor Antagonists Prevent Meningitic Escherichia coli-Induced Blood–Brain Barrier Disruptions by Targeting the CISH/JAK2/STAT5b Axis

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

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