scholarly journals The Novel Synthetic Peptide AESIS-1 Exerts a Preventive Effect on Collagen-Induced Arthritis Mouse Model via STAT3 Suppression

2020 ◽  
Vol 21 (2) ◽  
pp. 378
Author(s):  
Kyung Eun Kim ◽  
Suwon Jeon ◽  
Jisun Song ◽  
Tae Sung Kim ◽  
Min Kyung Jung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synthetic Peptide ◽  
Specific Inhibitor ◽  
Cytokine Signaling ◽  
The Novel ◽  
Collagen Induced Arthritis ◽  
Stat3 Phosphorylation ◽  
And Cartilage

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.

scholarly journals Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Maaria Palmroth ◽  
Krista Kuuliala ◽  
Ritva Peltomaa ◽  
Anniina Virtanen ◽  
Antti Kuuliala ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

scholarly journals Quercetin Preservesβ-Cell Mass and Function in Fructose-Induced Hyperinsulinemia through Modulating Pancreatic Akt/FoxO1 Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Jian-Mei Li ◽  
Wei Wang ◽  
Chen-Yu Fan ◽  
Ming-Xing Wang ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Serum Insulin ◽  
Cell Mass ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Akt Phosphorylation ◽  
High Fructose ◽  
Stat3 Phosphorylation ◽  
And Function

Fructose-induced hyperinsulinemia is associated with insulin compensative secretion and predicts the onset of type 2 diabetes. In this study, we investigated the preservation of dietary flavonoid quercetin on pancreaticβ-cell mass and function in fructose-treated rats and INS-1β-cells. Quercetin was confirmed to reduce serum insulin and leptin levels and blockade islet hyperplasia in fructose-fed rats. It also prevented fructose-inducedβ-cell proliferation and insulin hypersecretion in INS-1β-cells. High fructose increased forkhead box protein O1 (FoxO1) expressionsin vivoandin vitro, which were reversed by quercetin. Quercetin downregulated Akt and FoxO1 phosphorylation in fructose-fed rat islets and increased the nuclear FoxO1 levels in fructose-treated INS-1β-cells. The elevated Akt phosphorylation in fructose-treated INS-1β-cells was also restored by quercetin. Additionally, quercetin suppressed the expression of pancreatic and duodenal homeobox 1 (Pdx1) and insulin gene (Ins1 and Ins2)in vivoandin vitro. In fructose-treated INS-1β-cells, quercetin elevated the reduced janus kinase 2/signal transducers and activators of transcription 3 (Jak2/Stat3) phosphorylation and suppressed the increased suppressor of cytokine signaling 3 (Socs3) expression. These results demonstrate that quercetin protectsβ-cell mass and function under high-fructose induction through improving leptin signaling and preserving pancreatic Akt/FoxO1 activation.

scholarly journals Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 547
Author(s):  
Mariangela Garofalo ◽  
Laura Bertinato ◽  
Monika Staniszewska ◽  
Magdalena Wieczorek ◽  
Stefano Salmaso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enzyme Assay ◽  
Survival Rates ◽  
Oncolytic Adenovirus ◽  
The Novel ◽  
Anti Cancer ◽  
Check Point Inhibitors ◽  
Melanoma Therapy

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

Aberrant G-CSF- and IL-6-Induced Proliferation and Differentiation in Suppressor of Cytokine Signaling-3 (SOCS3)-Deficient Progenitor Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 821-821 ◽  
Author(s):  
Andrew W. Roberts ◽  
Ben A. Croker ◽  
Warren Alexander ◽  
Donald Metcalf
Keyword(s):  
Progenitor Cells ◽  
Negative Regulator ◽  
Cytokine Receptors ◽  
Cytokine Signaling ◽  
Littermate Control ◽  
Developmental Potential ◽  
Gm Csf ◽  
Stat3 Phosphorylation

Abstract Studies using mice with germline or tissue-specific deletion of SOCS3 indicate that SOCS3 is a negative regulator of IL-6, LIF, Leptin and G-CSF-induced STAT3 phosphorylation. We have investigated the physiological importance of SOCS3 in blood cells by creating conditionally-targeted mice with SOCS3-deficient hematopoiesis (Immunity2004; 20:153–65). These mice develop a fatal inflammatory disease in adulthood characterized by tissue infiltration with neutrophils and macrophages, and display hyper-responsiveness to G-CSF in vitro and in vivo, with the development of pathological myeloid cell-mediated tissue damage. In hepatocytes and macrophages stimulated with IL-6, we and others (Nature Immunol2003; 4:540–5, and 4:546–60) have found that SOCS3 is not only important for modulating the intensity of signalling from cytokine receptors, but also for the maintenance of specificity of the signal. Whether these qualitative changes revealed by microarray experiments have physiological significance remains to be proven. To investigate this issue in a more plastic system, we analyzed the consequences of SOCS3-deficiency in hematopoietic progenitor cells. We hypothesised that if SOCS3 was required to maintain the specificity, as well as intensity of signals arising from cytokine receptors, then changes in differentiation as well as proliferation would be observed. To exclude confounding effects from cytokine production by mature cells, and to minimize potential selection bias within the starting populations, purified SOCS3-deficient lin- kit+ progenitor cells from healthy young mice with SOCS3-deficent hematopoiesis, were compared with both littermate control and C57BL/6 lin- kit+ progenitor cells. Proliferation was monitored in liquid and agar cultures stimulated with SCF, IL-3, GM-CSF, G-CSF and IL-6 alone, or in combination with SCF. At the completion of the experiments ( 1–7 days), proportions of neutrophil, macrophage and precursors were determined by microscopy. The number of divisions progenitors underwent was monitored by clone-mapping experiments in agar and CFSE-labelling in liquid cultures. No differences between SOCS3-deficient and wild-type (WT) cells were observed after stimulation with SCF, IL-3, GM-CSF or combinations of these, suggesting that progenitor cells of each genotype were similar in their developmental potential. However, marked differences were observed for G-CSF and IL-6. G-CSF induced a 2-3-fold increase in cellular output in both liquid and agar cultures, and the distribution of CFSE-intensity was consistent with an additional division occurring over a 4 day timespan in SOCS3-deficient cells. With IL-6 stimulation, while SOCS3-deficient progenitor cells initiated 1.7-fold more colonies, the overall cellular output was no greater than that of WT progenitors. With WT progenitors for both stimuli, the vast majority of clones were neutrophil colonies and >90% of emergent cells at 7 days were neutrophils or their precursors. In contrast, SOCS3-deficient progenitors stimulated with IL-6 generated 43% granulocyte-macrophage colonies and 13% pure macrophage colonies with >70% of emergent cells being macrophages. For G-CSF, a similar, but less pronounced shift towards macrophage development was observed. We conclude that SOCS3 is required to maintain normal cellular proliferative and differentiative responses to G-CSF and IL-6. The precise perturbations in signalling responsible for these aberrations are being defined through microarray and biochemical experiments.

scholarly journals In vivo and in vitro evidence that chronic activation of the hexosamine biosynthetic pathway interferes with leptin-dependent STAT3 phosphorylation

2015 ◽  
Vol 308 (6) ◽  
pp. R543-R555 ◽  
Author(s):  
Arthur D. Zimmerman ◽  
Ruth B. S. Harris
Keyword(s):  
Biosynthetic Pathway ◽  
Sucrose Solution ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Hexosamine Biosynthetic Pathway ◽  
Stat3 Phosphorylation ◽  
New Evidence ◽  
Stimulation Of

We previously reported that a 2-day peripheral infusion of glucosamine caused leptin resistance in rats, suggesting a role for the hexosamine biosynthetic pathway (HBP) in the development of leptin resistance. Here we tested leptin responsiveness in mice in which HBP activity was stimulated by offering 30% sucrose solution in addition to chow and water or by infusing glucosamine. Mice were leptin resistant after 33 days of access to sucrose. Resistance was associated with increased activity of the HBP and with phosphorylation of transcription factor signal transducer and activator of transcription-3 Tyr705 [pSTAT3(Y705)] but inhibition of suppressor of cytokine signaling 3 in the liver and hypothalamus. Intravenous infusion of glucosamine for 3 h stimulated pSTAT3(Y705) but prevented leptin-induced phosphorylation of STAT3(S727). In an in vitro system, glucose, glucosamine, and leptin each dose dependently increased O-linked β- N-acetylglucosamine ( O-GlcNAc) protein and pSTAT3(Y705) in HepG2 cells. To test the effect of glucose on leptin responsiveness cells were incubated in 5.5 mM (LG) or 20 mM (HG) glucose for 18 h and were treated with 0 or 50 ng/ml leptin for 15 min. HG alone and LG + leptin produced similar increases in O-GlcNAc protein, glutamine fructose-6-phosphate amidotransferase (GFAT), and pSTAT3(Y705) compared with LG media. Leptin did not stimulate these proteins in HG cells, suggesting leptin resistance. Leptin-induced pSTAT3(S727) was prevented by HG media. Inhibition of GFAT with azaserine prevented LG + leptin and HG stimulation of pSTAT3. These data demonstrate development of leptin resistance in sucrose-drinking mice and provide new evidence of leptin-induced stimulation of the HBP.

scholarly journals Induction of SOCS Expression by EV71 Infection Promotes EV71 Replication

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Wenying Gao ◽  
Min Hou ◽  
Xin Liu ◽  
Zhaolong Li ◽  
Yongjun Yang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Enterovirus 71 ◽  
Ev71 Infection ◽  
Cytokine Signaling ◽  
Host Immune System ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Socs Proteins

Enterovirus 71 (EV71) is the causative pathogen of hand, foot, and mouth disease (HFMD). However, no effective antiviral therapy is currently available. Some viruses could escape the host’s innate immunity by upregulating suppressor of cytokine signaling (SOCS) proteins. Until now, whether EV71 evades the host immune system by regulating the expression of SOCS proteins remains unknown. In this study, we found that EV71 infection promoted SOCS expression at both mRNA and protein levels in vitro and in vivo. Consistently, the infectivity of EV71 was decreased significantly in the SOCS3 or SOCS1 knockdown cells, suggesting that SOCS1 and especially SOCS3 are crucial for EV71 infection. Further investigation showed that SOCS3 promoted virus infection by inhibiting interferon-induced STAT3 phosphorylation. SOCS1 and SOCS3 mRNA expressions were independent on virus-induced type I interferon expression but were blocked by the inhibitor of NF-κB. Therefore, EV71 infection stimulates the expression of SOCS proteins in an interferon-independent way and negatively regulates the JAK/STAT signaling pathway, thus escaping host immunity. All these results may add new information to the mechanism of EV71 in fighting against type I interferon responses.

scholarly journals Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Hongjian Zhao ◽  
Junjun Huang ◽  
Ming Chen ◽  
Baoru Li ◽  
Xinran Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Migration And Invasion ◽  
Cytokine Signaling ◽  
Cell Migration And Invasion ◽  
Stat3 Phosphorylation ◽  
Tripartite Motif ◽  
Tripartite Motif Protein

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with most mortalities being caused by metastases. However, the underlying molecular mechanism of CRC metastases remains largely unknown. Emerging evidence has shown the role of the tripartite motif family, especially tripartite motif protein 6 (TRIM6), in carcinogenesis. In this study, we used CRC cell lines with TRIM6 knockdown and overexpression to investigate the function of TRIM6 in CRC metastasis. We found that TRIM6 promotes CRC cell migration and invasion both in vitro and in vivo. TRIM6 knockdown slows down the migration and invasion processes, whereas TRIM6 overexpression accelerates CRC cell migration and invasion. TRIM6 is potentially the upstream regulatory factor for signal transducer and activator of transcription 3 (STAT3) via the suppressor of cytokine signaling 2 (SOCS2). A total of 70 samples from patients with CRC further confirmed that TRIM6 expression level is positively correlated with STAT3 phosphorylation and negatively correlated with SOCS2 expression. Therefore, TRIM6 could be a potential therapeutic target for CRC metastasis.

scholarly journals OP0236 RELEVANCE OF BIASED PAR2 INHIBITORS IN REDUCING INFLAMMATION AND CARTILAGE DEGRADATION IN IN VITRO AND IN VIVO MODELS OF RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 149.2-150
Author(s):  
T. Brugat ◽  
B. Rugeri ◽  
G. Hommet ◽  
A. Dumont ◽  
L. Baron ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oral Administration ◽  
Small Molecules ◽  
Signalling Pathways ◽  
Collagen Induced Arthritis ◽  
Cartilage Erosion ◽  
And Cartilage ◽  
Inflammatory Effect

Background:Protease-activated receptor-2 (PAR2) is a member of a family of G-protein-coupled receptors involved in multiple physiological mechanisms. Compelling evidences have unravelled the key roles of PAR2 in the pathology of both rheumatoid arthritis (RA) and osteoarthritis (OA)1. Indeed, in vitro, in vivo and ex vivo experiments showed that this receptor promotes inflammation, cartilage erosion (and subsequent bone degradation), and pain. However, the signalling pathways involved in these functions are not well understood2. This is of importance as some pathways can promote the pathogenesis3while others prevent it4. We developed a new series of small molecules as novel biased PAR2 inhibitors to treat rheumatic diseases.Objectives:To evaluate the efficacy and mechanism of action of new biased PAR2 inhibitors on cartilage erosion and inflammation.Methods:The potency of compounds to inhibit human PAR2 signalling was evaluated in vitro by FLIPR calcium assay in HEK293 cells. The same assay was used to determine their selectivity over human PAR1 and PAR4 as well as murine versions of PAR2. The effect of several PAR2 inhibitors on 9 signalling pathways (Gi2, GoB, Gz, Gq, G13, G14, G15, B arrestin 2, EPAC) was evaluated by the BRET-based bioSens-All™ technology. In vitro anti-hypertrophic effect was determined by measuring the mRNA level of type II collagen, aggrecan and MMP13 in rat chondrocytes after IL1β stimulation. In vitro anti-inflammatory effect was determined by measuring the secretion of IL6, IL8, IL1β, TNFα and IFNγ by human monocytes. In vivo, the pharmacodynamic of our small molecules was assessed after intravenous and oral administration. Therapeutic efficacy of a compound was then evaluated in a collagen-induced arthritis model in DBA1/J mice. In this model, measures of the arthritis index score, body weight, plasma level of TNFα, IL6, IL8 and IL1β and histological evaluation of cartilage erosion were performed.Results:Our new series of small molecules are potent PAR2 inhibitors (IC50<1nM in calcium assay) with some selectivity over PAR1 and PAR4. Our compounds significantly inhibited PAR2 mediated recruitment of Gz, Gq, G13, G14 and G15. However, surprisingly, these small molecules had no effect on B arrestin 2, EPAC, Gi2 and GoB demonstrating that they are biased inhibitors. The effect of our compounds on PAR2 signalling was clearly different from 3 already existing PAR2 inhibitors described in the literature (I-117, AZ3451 and P2pal-18s). We compared the in vitro anti-hypertrophic effect on chondrocyte and anti-inflammatory effect on monocytes of these compounds to determine the importance of PAR2 signalling pathways in these cellular functions. In vivo, our small molecules had good bioavailability after oral administration of 10mg/kg in mice (clearance = 0.038L/h/kg; T½ = 9.9h; AUC= 162564 ng.h/mL; Cmax = 9005 ng/mL). The in vivo therapeutic efficacy of a biased PAR2 inhibitor in a model of collagen-induced arthritis will be presented.Conclusion:Our results show the potency of biased PAR2 inhibitors to reduce both the inflammation and cartilage erosion in rheumatoid arthritis. They confirm the huge potential of PAR2 as a therapeutic target and unravel the relevance of biased antagonism of this receptor to treat rheumatic diseases.References:[1]McCulloch et al., Frontiers in Endocrinology, 2018;2Hollenberg et al., British Journal of Pharmacology, 2014;3Sharma et al., Genes and Immunity, 2015;4Rayees et al., Cell Reports, 2019Disclosure of Interests:Thibaut Brugat Employee of: Domain Therapeutics, Baptiste Rugeri Employee of: Domain Therapeutics, Gaël Hommet Employee of: Domain Therapeutics, Alexia Dumont Employee of: Domain Therapeutics, Luc Baron Employee of: Domain Therapeutics, Célia Halter Employee of: Domain Therapeutics, Meriem Sémache Employee of: Domain Therapeutics, Arturo Mancini Employee of: Domain Therapeutics, Camille Amalric Employee of: Domain Therapeutics, Marie Giambelluco Employee of: Domain Therapeutics, Nathalie Lenne Employee of: Domain Therapeutics, Marjorie Sidhoum Employee of: Domain Therapeutics, Christel Franchet Employee of: Domain Therapeutics, Stanislas Mayer Employee of: Domain Therapeutics, Xavier Leroy Employee of: Domain Therapeutics, Stephan Schann Employee of: Domain Therapeutics

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

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