The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design

Deftereos, Spyridon; Siasos, Gerasimos; Γιαννόπουλος, Γεώργιος; Vrachatis, Dimitrios; Angelidis, Christos; Giotaki, Sotiria G.; Gargalianos, Panagiotis; Giamarellou, Helen; Gogos, Charalampos; Daikos, Georgios; Lazanas, Marios; Λάγιου, Παγώνα; Saroglou, G.; Sipsas, Nikolaos V.; Tsiodras, Sotirios; Chatzigeorgiou, Dimitrios; Moussas, Nikolaos; Κοτανίδου, Αναστασία; Koulouris, Nikolaos; Oikonomou, Evangelos; Kaoukis, Andreas; Kossyvakis, Charalampos; Raisakis, Konstantinos; Fountoulaki, Katerina; Comis, Mihalis; Tsiachris, Dimitriοs; Sarri, Eleni; Theodorakis, Andreas; Dolz, Luis Martínez; Sanz‐Sánchez, Jorge; Reimers, Bernhard; Stefanini, Giulio G.; Cleman, Michael; Filippou, Dimitrios; Olympios, Christoforos; Pyrgakis, Vlasios; Goudevenos, John; Hahalis, George; Kolettis, Theofilos M.; Iliodromitis, Efstathios K.; Tousoulis, Dimitrios; Stefanadis, Christodoulos

doi:10.1016/j.hjc.2020.03.002

Cited by 135 publications

(144 citation statements)

References 31 publications

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“…Its mechanism of action is thought to be the inhibition of tubulin polymerization and microtubule generation and, possibly, effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome. Colchicine may inhibit activation of NLRP3 inflammasome and additionally may inhibit directly the synthesis of TNF-α and IL-6 [93]. Trials investigating the efficacy of conventional therapeutic doses of colchicine have been registered for the treatment of COVID-19 (NCT04322682, NCT04328480, NCT04326790).…”

Section: Colchicinementioning

confidence: 99%

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

2020

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IntroductionCoronaviruses (CoVs), mainly targeting human respiratory system, are responsible for health-threatening outbreaks including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and lastly coronavirus disease 2019 (COVID-19) [1]. In December 2019, in the Chinese Province of Wuhan the novel coronavirus has been identified in patients with atypical pneumonia characterized by fever, dry cough and progressive dyspnea [2]. Rapidly, this coronavirus, namely SARS-CoV-2 1 , has spread worldwide, leading to a serious lung inflammation, acute respiratory distress syndrome (ARDS), cardiac and renal injury, especially in patients with older age and comorbidities (diabetes mellitus, hypertension, and heart failure) [3][4][5]. According to disease progression, patients may be roughly divided into two groups; asymptomatic or mild cases that usually 2.The origin and structural features of SARS-CoV2CoVs belong to big family Coronaviridae which consists of two subfamilies: Orthocoronavirinae and Torovirinae.

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Section: Colchicinementioning

confidence: 99%

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

2020

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“…Chloroquine has some immunomodulatory effects, potentially suppressing the production and release of TNF-α and IL-6 13 . Colchicine has been shown to effectively suppress interleukin IL-1b, IL-18 and IL-6 in patients with acute coronary syndrome 40,41 and is now being trialed in COVID-19 ARDS, albeit it also has very signi cant side effects 37 .…”

Section: Resultsmentioning

confidence: 99%

Fighting the storm: novel anti- TNFα and anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19

Kovalchuk

Rodriguez-Juarez

Ilnytskyy

et al. 2020

Preprint

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The main aspects of severe COVID-19 disease pathogenesis include the increasing hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of the cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed that can efficiently and swiftly block TNFα, IL-6, and the inflammatory cytokine cascade in order to curb inflammation and prevent fibrosis, and lead to disease remission.Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of our novel C. sativa lines may be used to modulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. To analyze the anti-inflammatory effects of novel C. sativa lines, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis lines.We noted that out of seven studied extracts of novel C. sativa lines, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. Most importantly, one of the tested extracts had no effects at all, and one exerted effects that may be deleterious, signifying that cannabis is not generic and cultivar selection must be based on thorough pre-clinical studies.The observed pronounced inhibition of TNFα and IL-6 is the most important finding, as these molecules are currently considered to be the main actionable targets in COVID-19 cytokine storm and ARDS pathogenesis. Many currently trialed agents, such as anti-TNFα and anti-IL-6 biologics are expensive and cause an arrays of side effects. On the other hand, anti-TNFα and anti-IL-6 cannabis extracts that are generally regarded as safe (GRAS) modalities can be a useful addition to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

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“…Activating PAMP and DAMP signals for NLRP3 are famously diverse and include: K + efflux, Cl - efflux, Ca 2+ influx, mtDNA, alum, reactive oxygen species (ROS), implanted biomaterials or medical devices, asbestos, silica, calcium oxalate, and uric acid crystals, as well as a variety of metabolic components including cholesterol crystals and succinate accumulation [ 4 , 38 , 56 , 115 , 116 ]. Moreover, the NLRP3 inflammasome is thought to be a major pathophysiologic contributor to the cytokine storm observed in the clinical course of patients with COVID 19 [ 117 , 118 , 119 ]. There also exists a mechanism for non-canonical inflammasome activation involving caspase 4 and 5 in human, and caspase-11 (homologue) in mice [ 9 ].…”

Section: Atp-dependency For the Assembly And Activation Of Selectementioning

confidence: 99%

ATP-Binding and Hydrolysis in Inflammasome Activation

2020

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The prototypical model for NOD-like receptor (NLR) inflammasome assembly includesnucleotide-dependent activation of the NLR downstream of pathogen- or danger-associatedmolecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomericplatforms that lie upstream of inflammatory responses associated with innate immunity. Asmembers of the STAND ATPases, the NLRs are generally thought to share a similar model of ATPdependentactivation and effect. However, recent observations have challenged this paradigm toreveal novel and complex biochemical processes to discern NLRs from other STAND proteins. Inthis review, we highlight past findings that identify the regulatory importance of conserved ATPbindingand hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explorerecent breakthroughs that generate connections between NLR protein structure and function.Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectiveson the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations ofNLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctionsin nucleotide-binding domain topology with occupancy of ATP or ADP that are in turndisseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATPbindingand hydrolysis properties of NACHT domains in different NLRs integrate with signalingmodules and binding partners to control innate immune responses at the molecular level.

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The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design

Cited by 135 publications

References 31 publications

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

Fighting the storm: novel anti- TNFα and anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19

ATP-Binding and Hydrolysis in Inflammasome Activation

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