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1.
Rev Esp Quimioter ; 35 Suppl 3: 6-9, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2091721

ABSTRACT

In response to SARS-CoV-2 infection, the immune system physiologically upregulates to try to clear the virus from the body; failure to compensate for this inflammatory response with an anti-inflammatory response leads to dysregulation of the immune system that ultimately leads to a situation of uncontrolled hyperinflammation called cytokine storm. This cytokine storm can cause ARDS or multi-organ failure leading to patient death. This review exposes the different mechanisms of the inflammatory response in COVID-19 infection and the therapeutic options to treat this process.


Subject(s)
COVID-19 , Humans , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , SARS-CoV-2 , Cytokines , Anti-Inflammatory Agents/therapeutic use
2.
J Physiol Pharmacol ; 73(3)2022 Jun.
Article in English | MEDLINE | ID: covidwho-2091455

ABSTRACT

Systemic inflammation is a hallmark of severe coronavirus disease-19 (COVID-19). Anti-inflammatory therapy is considered crucial to modulate the hyperinflammatory response (cytokine storm) in hospitalized COVID-19 patients. There is currently no specific, conclusively proven, cost-efficient, and worldwide available anti-inflammatory therapy available to treat COVID-19 patients with cytokine storm. The present study aimed to investigate the treatment benefit of oral colchicine for hospitalized COVID-19 patients with suspected cytokine storm. Colchicine is an approved drug and possesses multiple anti-inflammatory mechanisms. This was a pilot, open-label randomized controlled clinical trial comparing standard of care (SOC) plus oral colchicine (colchicine arm) vs. SOC alone (control arm) in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. Colchicine treatment was initiated within first 48 hours of admission delivered at 1.5 mg loading dose, followed by 0.5 mg b.i.d. for next 6 days and 0.5 mg q.d. for the second week. A total of 96 patients were randomly allocated to the colchicine (n=48) and control groups (n=48). Both colchicine and control group patients experienced similar clinical outcomes by day 14 of hospitalization. Treatment outcome by day 14 in colchicine vs control arm: recovered and discharged alive: 36 (75.0%) vs. 37 (77.1%), remain admitted after 14-days: 4 (8.3%) vs. 5 (10.4%), ICU transferred: 4 (8.3%) vs. 3 (6.3%), and mortality: 4 (8.3%) vs. 3 (6.3%). The speed of improvement of COVID-19 acute symptoms including shortness of breath, fever, cough, the need of supplementary oxygen, and oxygen saturation level, was almost identical in the two groups. Length of hospitalization was on average 1.5 day shorter in the colchicine group. There was no evidence for a difference between the two groups in the follow-up serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, interleukin-6 (IL-6), high-sensitivity troponin T (hs-TnT) and N-terminal pro b-type natriuretic peptide (NT pro-BNP). According to the results of our study, oral colchicine does not appear to show clinical benefits in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. It is possible that the anti-inflammatory pathways of colchicine are not crucially involved in the pathogenesis of COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , SARS-CoV-2 , Cytokine Release Syndrome/drug therapy , Colchicine/therapeutic use , Hospitalization , Anti-Inflammatory Agents/therapeutic use , Treatment Outcome
3.
NPJ Syst Biol Appl ; 8(1): 38, 2022 10 10.
Article in English | MEDLINE | ID: covidwho-2062214

ABSTRACT

A major complication in COVID-19 infection consists in the onset of acute respiratory distress fueled by a dysregulation of the host immune network that leads to a run-away cytokine storm. Here, we present an in silico approach that captures the host immune system's complex regulatory dynamics, allowing us to identify and rank candidate drugs and drug pairs that engage with minimal subsets of immune mediators such that their downstream interactions effectively disrupt the signaling cascades driving cytokine storm. Drug-target regulatory interactions are extracted from peer-reviewed literature using automated text-mining for over 5000 compounds associated with COVID-induced cytokine storm and elements of the underlying biology. The targets and mode of action of each compound, as well as combinations of compounds, were scored against their functional alignment with sets of competing model-predicted optimal intervention strategies, as well as the availability of like-acting compounds and known off-target effects. Top-ranking individual compounds identified included a number of known immune suppressors such as calcineurin and mTOR inhibitors as well as compounds less frequently associated for their immune-modulatory effects, including antimicrobials, statins, and cholinergic agonists. Pairwise combinations of drugs targeting distinct biological pathways tended to perform significantly better than single drugs with dexamethasone emerging as a frequent high-ranking companion. While these predicted drug combinations aim to disrupt COVID-induced acute respiratory distress syndrome, the approach itself can be applied more broadly to other diseases and may provide a standard tool for drug discovery initiatives in evaluating alternative targets and repurposing approved drugs.


Subject(s)
COVID-19 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , COVID-19/drug therapy , Calcineurin , Cytokine Release Syndrome/drug therapy , Dexamethasone , Humans , SARS-CoV-2
4.
Eur J Med Chem ; 241: 114659, 2022 Nov 05.
Article in English | MEDLINE | ID: covidwho-2035972

ABSTRACT

Cytokine storm is a key feature of sepsis and severe stage of COVID-19, and the immunosuppression after excessive immune activation is a substantial hazard to human life. Both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by various pattern recognition receptors (PRRs), which lead to the immune response. A number of neolignan analogues were synthesized in this work and showed powerful anti-inflammation properties linked to the response to innate and adaptive immunity, as well as NP-7 showed considerable anti-inflammatory activity at 100 nM. On the sepsis model caused by cecum ligation and puncture (CLP) in C57BL/6J mice, NP-7 displayed a strong regulatory influence on cytokine release. Then a photo-affinity probe of NP-7 was synthesized and chemoproteomics based on stable isotope labeling with amino acids in cell cultures (SILAC) identified Immunity-related GTPase M (IRGM) as a target suppressing cytokine storm, which was verified by competitive pull-down, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulations.


Subject(s)
Anti-Inflammatory Agents , Cytokine Release Syndrome , GTP-Binding Proteins , Sepsis , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , COVID-19 , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Disease Models, Animal , GTP-Binding Proteins/metabolism , Humans , Mice , Mice, Inbred C57BL , Proteomics
5.
J Med Virol ; 94(11): 5574-5581, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1995545

ABSTRACT

Mortality in coronavirus disease 2019 (COVID-19) patients has been linked to the presence of a "cytokine storm" induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which involves elevated levels of circulating cytokines and immune-cell hyperactivation. Targeting cytokines during the management of COVID-19 patients has the potential to improve survival rates and reduce mortality. Although cytokine blockers and immune-host modulators are currently being tested in severely ill COVID-19 patients to cope with the overwhelming systemic inflammation, there is not too many successful cases, thus finding new cytokine blockers to attenuate the cytokine storm syndrome is meaningful. In this paper, we significantly attenuated the inflammatory responses induced by mouse hepatitis viruses A59 and SARS-CoV-2 through a soluble DR5-Fc (sDR5-Fc) chimeric protein that blocked the TNF-related apoptosis-inducing ligand-death receptor 5 (TRAIL-DR5) interaction. Our findings indicates that blocking the TRAIL-DR5 pathway through the sDR5-Fc chimeric protein is a promising strategy to treat COVID-19 severe patients requiring intensive care unit  admission or with chronic metabolic diseases.


Subject(s)
COVID-19 , Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology , SARS-CoV-2 , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Mice , Recombinant Fusion Proteins/genetics
6.
J Allergy Clin Immunol ; 150(4): 796-805, 2022 10.
Article in English | MEDLINE | ID: covidwho-1991092

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. OBJECTIVES: To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. METHODS: We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. RESULTS: We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. CONCLUSIONS: These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.


Subject(s)
COVID-19 , Inflammasomes , Anti-Inflammatory Agents , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , DNA, Complementary , Humans , Inflammasomes/metabolism , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Proteins , Receptors, Interleukin-1 , SARS-CoV-2
7.
BMC Infect Dis ; 22(1): 537, 2022 Jun 13.
Article in English | MEDLINE | ID: covidwho-1986768

ABSTRACT

BACKGROUND: Passive immunization against SARS-CoV-2 limits viral burden and death from COVID-19; however, it poses a theoretical risk of disease exacerbation through antibody-dependent enhancement (ADE). ADE after anti-SARS-CoV2 antibody treatment has not been reported, and therefore the potential risk and promoting factors remain unknown. CASE PRESENTATION: A 75-year-old female was admitted to the emergency room with recurrent, unexplained bruises and leukocytopenia, anemia, and thrombocytopenia. Evaluation of a bone marrow biopsy established the diagnosis of an acute promyelocytic leukemia (APL). SARS-CoV-2 RT-PCR testing of nasal and throat swabs on admission was negative. During the routine SARS-CoV-2 testing of inpatients, our patient tested positive for SARS-CoV-2 on day 14 after admission without typical COVID-19 symptoms. Due to disease- and therapy-related immunosuppression and advanced age conferring a high risk of progressing to severe COVID-19, casirivimab and imdevimab were administered as a preemptive approach. The patient developed immune activation and cytokine release syndrome (CRS) occurring within four hours of preemptive anti-SARS-CoV2 antibody (casirivimab/imdevimab) infusion. Immune activation and CRS were evidenced by a rapid increase in serum cytokines (IL-6, TNFα, IL-8, IL-10), acute respiratory insufficiency, and progressive acute respiratory distress syndrome. DISCUSSION AND CONCLUSION: The temporal relationship between therapeutic antibody administration and the rapid laboratory, radiological, and clinical deterioration suggests that CRS was an antibody-related adverse event, potentially exacerbated by APL treatment-mediated differentiation of leukemic blasts and promyelocytes. This case highlights the need for careful assessment of life-threatening adverse events after passive SARS-CoV-2 immunization, especially in the clinical context of patients with complex immune and hematological landscapes.


Subject(s)
COVID-19 , Leukemia, Promyelocytic, Acute , Respiratory Distress Syndrome , Aged , Antibodies, Monoclonal, Humanized , COVID-19/complications , COVID-19/diagnosis , COVID-19 Testing , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Female , Humans , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , SARS-CoV-2
8.
Inflammopharmacology ; 30(5): 1503-1516, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1982229

ABSTRACT

The Covid-19, a threatening pandemic, was originated from China in December 2019 and spread quickly to all over the world. The pathogenesis of coronavirus is linked with the disproportionate response of the immune system. This involves the systemic inflammatory reaction which is characterized by marked pro-inflammatory cytokine release commonly known as cytokine release storm (CRS). The pro inflammatory cytokines are involved in cascade of pulmonary inflammation, hyper coagulation and thrombosis which may be lethal for the individual. That's why, it is very important to have understanding of pro inflammatory cytokines and their pathological role in SARS-CoV-2. The pathogenesis of Covid is not the same in every individual, it can vary due to the presence of pre-existing comorbidities like suffering from already an inflammatory disease such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), an immune-compromised patients suffering from Diabetes Mellitus (DM) and Tuberculosis (TB) are more vulnerable morbidity and complications following COVID-19. This review is particularly related to COVID-19 patients having comorbidity of other inflammatory diseases. We have discussed the brief pathogenesis of COVID-19 and cytokines release storm with reference to other co-morbidities including RA, IBD, COPD, DM and TB. The available therapeutic regimens for COVID-19 including cytokine inhibitors, anti-viral, anti-biotic, bronchodilators, JAK- inhibitors, immunomodulators and anti-fibrotic agents have also been discussed briefly. Moreover, newly emerging medicines in the clinical trials have also been discussed which are found to be effective in treating Covid-19.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , Pulmonary Disease, Chronic Obstructive , Bronchodilator Agents/therapeutic use , COVID-19/drug therapy , Comorbidity , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Pulmonary Disease, Chronic Obstructive/drug therapy , SARS-CoV-2
9.
Phytomedicine ; 102: 154153, 2022 Jul 20.
Article in English | MEDLINE | ID: covidwho-1977720

ABSTRACT

BACKGROUND: The cytokine storm (CS) triggered by coronavirus disease 2019 (COVID-19) has caused serious harm to health of humanity and huge economic burden to the world, and there is a lack of effective methods to treat this complication. PURPOSE: In this research, we used network pharmacology and molecular docking to reveal the interaction mechanism in the glycyrrhetinic acid (GA) for the treatment of CS, and validated the effect of GA intervention CS by experiments. STUDY DESIGN: First, we screened corresponding target of GA and CS from online databases, and obtained the action target genes through the Venn diagram. Then, protein-protein interaction (PPI) network, Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of the action target genes were acquired by R language to predict its mechanism. Next, molecular docking was performed on core targets. Finally, experiments in which GA intervened in lipopolysaccharide (LPS)-induced CS were implemented. RESULTS: 84 action target genes were obtained from online database. The PPI network of target genes showed that TNF, IL6, MAPK3, PTGS2, ESR1 and PPARG were considered as the core genes. The results of GO and KEGG showed that action target genes were closely related to inflammatory and immune related signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, Human cytomegalovirus infection, PPAR signaling pathway and so on. Molecule docking results prompted that GA had fine affinity with IL6 and TNF proteins. Finally, in vivo and in vitro experimental results showed that GA could significantly inhibit LPS-induced CS. CONCLUSION: GA has a potential inhibitory effect on CS, which is worthy of further exploration.


Subject(s)
COVID-19 , Drugs, Chinese Herbal , Glycyrrhetinic Acid , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Drugs, Chinese Herbal/pharmacology , Glycyrrhetinic Acid/pharmacology , Glycyrrhetinic Acid/therapeutic use , Humans , Interleukin-6 , Lipopolysaccharides , Molecular Docking Simulation
10.
Am J Chin Med ; 50(4): 927-959, 2022.
Article in English | MEDLINE | ID: covidwho-1973869

ABSTRACT

Coronavirus disease 2019 (COVID-19) is currently a worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, there are no drugs that can specifically combat SARS-CoV-2. Besides, multiple SARS-CoV-2 variants are circulating globally. These variants may lead to immune escape or drug resistance. Natural products may be appropriate for this need due to their cost efficiency, fewer side effects, and antiviral activities. Considering these circumstances, there is a need to develop or discover more compounds that have potential to target SARS-CoV-2. Therefore, we searched for articles on natural products describing anti-SARS-CoV-2 activities by targeting the SARS-CoV-2 life cycle and the cytokine storm in COVID-19 from academic databases. We reviewed anti-SARS-CoV-2 activities of natural products, especially those that target the SARS-CoV-2 life cycle (angiotensin-converting enzyme 2, transmembrane serine protease 2, cathepsin L, 3CL protease, PL protease, RNA-dependent RNA polymerase, and helicase) and cytokine storm in COVID-19. This review may provide a repurposed approach for the discovery of specific medications using natural products to treat COVID-19 through targeting the SARS-CoV-2 life cycle and the cytokine storm in COVID-19.


Subject(s)
Biological Products , COVID-19 , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biological Products/pharmacology , Biological Products/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Drug Discovery , Humans , Life Cycle Stages , SARS-CoV-2
11.
Methods Mol Biol ; 2511: 285-295, 2022.
Article in English | MEDLINE | ID: covidwho-1941383

ABSTRACT

SARS-CoV-2 can stimulate the expression of various inflammatory cytokines and induce the cytokine storm in COVID-19 patients leading to multiple organ failure and death. Curcumin as a polyphenolic compound has been shown to have anti-inflammatory properties and inhibit the release of numerous pro-inflammatory cytokines. We present multiplex analysis using the Evidence Investigator biochip system to determine the effect of curcumin on serum level of cytokines which are typically elevated in cytokine storm events, including tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and IL-10.


Subject(s)
COVID-19 , Curcumin , Cytokine Release Syndrome , COVID-19/drug therapy , Curcumin/pharmacology , Curcumin/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Protein Array Analysis/methods , SARS-CoV-2
12.
Int Immunopharmacol ; 111: 109075, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1936581

ABSTRACT

Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data about effective immunomodulatory agents to prevent cytokine release in COVID-19. Cytokine release syndrome in COVID-19 resembles secondary hemophagocytic lymphohistiocytosis, in which interleukin-1 (IL-1) plays a key role. Anakinra is the first recombinant IL-1 receptor antagonist studied for off-label use in COVID-19 treatment. This study reviews the current clinical evidence on the role of interleukin-1 in COVID-19-related cytokine storm, therapeutic effects, significant clinical concerns, and pros and cons of anakinra administration in the management of COVID-19 patients. In this review, four items are shown to be important for achieving the optimal therapeutic effects of anakinra in COVID-19 patients. These items include duration of treatment ≥ 10 days, doses ≥ 100 mg, intravenous administration, and early initiation of therapy. Also, anakinra might be more beneficial in the early stages of the disease when higher levels of cytokines are yet to be observed, which could prevent progression to severe illness and mechanical ventilation. Further studies are required to address the SARS-CoV-2 induced cytokine release syndrome and the role of anakinra in identifying ideal treatment approaches for COVID-19 patients based on their clinical status.


Subject(s)
COVID-19 , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , SARS-CoV-2
13.
Molecules ; 27(14)2022 Jul 17.
Article in English | MEDLINE | ID: covidwho-1938912

ABSTRACT

Cytokine storm is a condition in which the immune system produces an excessive number of inflammatory signals, which can result in organ failure and death. It is also known as cytokine release syndrome, CRS, or simply cytokine storm, and it has received a lot of attention recently because of the COVID-19 pandemic. It appears to be one of the reasons why some people experience life-threatening symptoms from COVID-19, a medical condition induced by SARS-CoV-2 infection. In situations where natural substances can be exploited as therapeutics to reduce cytokine storm, the drug development process has come to the rescue. In the present study, we tested the potentiality of Andrographolide, labdane diterpenoid targeting several key cytokines that are secreted as a result of cytokine storm. We used molecular docking analyses, molecular dynamics simulations, and pharmacokinetic properties to test the stability of the complexes. The compound's binding energy with some cytokines was over -6.5 Kcal/mol. Furthermore, a post-molecular dynamics (MD) study revealed that Andrographolide was extremely stable with these cytokines. The compound's pharmacokinetic measurements demonstrated excellent properties in terms of adsorption, distribution, metabolism, and excretion. Our research revealed that this compound may be effective in lowering cytokine storm and treating severe symptoms.


Subject(s)
COVID-19 , Diterpenes , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines , Diterpenes/pharmacology , Diterpenes/therapeutic use , Humans , Molecular Docking Simulation , Pandemics , SARS-CoV-2
14.
Int J Mol Sci ; 23(14)2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1938840

ABSTRACT

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3-5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6 , SARS-CoV-2
15.
Front Immunol ; 13: 875546, 2022.
Article in English | MEDLINE | ID: covidwho-1933655

ABSTRACT

Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1ß and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflammation, as in severe COVID-19 disease, is characterized by increased T-cell homing to the lungs. Our investigation revealed that CBD-X extract impaired T-cell migration induced by the chemoattractant SDF1. In addition, the phosphorylation levels of T cell receptor (TCR) signaling proteins Lck and Zap70 were significantly reduced, demonstrating an inhibitory effect on the early events downstream to TCR activation. In a lung inflamed mouse model, we observed a reduction in leukocytes including neutrophil migration to the lungs and decreased levels of IL-1ß, MCP-1, IL-6 and TNFα, in response to the administration of the high-CBD extract. The results presented in this work offer that certain high-CBD extract has a high potential in the management of pathological conditions, in which the secretion of cytokines is dysregulated, as it is in severe COVID-19 disease or other infectious or inflammatory diseases.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Mice , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Tumor Necrosis Factor-alpha
16.
Small Methods ; 5(5): e2001108, 2021 05.
Article in English | MEDLINE | ID: covidwho-1930144

ABSTRACT

During the global outbreak of COVID-19 pandemic, "cytokine storm" conditions are regarded as the fatal step resulting in most mortality. Hemoperfusion is widely used to remove cytokines from the blood of severely ill patients to prevent uncontrolled inflammation induced by a cytokine storm. This article discoveres, for the first time, that 2D Ti3 C2 Tx MXene sheet demonstrates an ultrahigh removal capability for typical cytokine interleukin-6. In particular, MXene shows a 13.4 times higher removal efficiency over traditional activated carbon absorbents. Molecular-level investigations reveal that MXene exhibits a strong chemisorption mechanism for immobilizing cytokine interleukin-6 molecules, which is different from activated carbon absorbents. MXene sheet also demonstrates excellent blood compatibility without any deleterious side influence on the composition of human blood. This work can open a new avenue to use MXene sheets as an ultraefficient hemoperfusion absorbent to eliminate the cytokine storm syndrome in treatment of severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Hemoperfusion/methods , Nanostructures/administration & dosage , SARS-CoV-2/immunology , Titanium/administration & dosage , Adsorption , COVID-19/transmission , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/virology , Humans , Interleukin-6/immunology , Nanostructures/chemistry , SARS-CoV-2/isolation & purification , Titanium/chemistry
17.
EMBO Mol Med ; 14(9): e15997, 2022 09 07.
Article in English | MEDLINE | ID: covidwho-1918175

ABSTRACT

A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO-CD24 was produced and purified from CD24-expressing 293-TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO-CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo. In a phase Ib/IIa study, 35 patients with moderate-high severity COVID-19 were recruited and given escalating doses, 108 -1010 , of EXO-CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443-575 days. EXO-CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO-CD24 may be a treatment strategy to suppress the hyper-inflammatory response in the lungs of COVID-19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm.


Subject(s)
COVID-19 , Exosomes , Animals , CD24 Antigen/metabolism , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Exosomes/metabolism , Humans , Lung , Mice
18.
J Control Release ; 349: 118-132, 2022 09.
Article in English | MEDLINE | ID: covidwho-1914570

ABSTRACT

Cytokine storms are a primary cause of multiple organ damage and death after severe infections, such as SARS-CoV-2. However, current single cytokine-targeted strategies display limited therapeutic efficacy. Here, we report that peritoneal M2 macrophage-derived extracellular vesicles (M2-EVs) are multitarget nanotherapeutics that can be used to resolve cytokine storms. In detail, primary peritoneal M2 macrophages exhibited superior anti-inflammatory potential than immobilized cell lines. Systemically administered M2-EVs entered major organs and were taken up by phagocytes (e.g., macrophages). M2-EV treatment effectively reduced excessive cytokine (e.g., TNF-α and IL-6) release in vitro and in vivo, thereby attenuating oxidative stress and multiple organ (lung, liver, spleen and kidney) damage in endotoxin-induced cytokine storms. Moreover, M2-EVs simultaneously inhibited multiple key proinflammatory pathways (e.g., NF-κB, JAK-STAT and p38 MAPK) by regulating complex miRNA-gene and gene-gene networks, and this effect was collectively mediated by many functional cargos (miRNAs and proteins) in EVs. In addition to the direct anti-inflammatory role, human peritoneal M2-EVs expressed angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2 spike protein, and thus could serve as nanodecoys to prevent SARS-CoV-2 pseudovirus infection in vitro. As cell-derived nanomaterials, the therapeutic index of M2-EVs can be further improved by genetic/chemical modification or loading with specific drugs. This study highlights that peritoneal M2-EVs are promising multifunctional nanotherapeutics to attenuate infectious disease-related cytokine storms.


Subject(s)
Cytokine Release Syndrome , Extracellular Vesicles , Macrophages , MicroRNAs , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Endotoxins , Extracellular Vesicles/metabolism , Humans , Interleukin-6/metabolism , Macrophages/metabolism , MicroRNAs/metabolism , NF-kappa B/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases
19.
South Med J ; 115(7): 435-440, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1903947

ABSTRACT

OBJECTIVES: Patients who develop cytokine storm while they have coronavirus disease 2019 (COVID-19) experience more severe symptoms. This article aims to evaluate the effect of biochemical parameters on the clinical course of the disease in patients treated with tocilizumab (TCZ) due to cytokine storm. METHODS: Medical documents of patients with COVID-19 were searched retrospectively. Patients who entered cytokine storm were classified as group 1 and divided into two subgroups as patients who were followed up in the ward and in the intensive care unit (ICU). Less severe COVID-19 patients who did not enter cytokine storm were included in the control group as group 2. RESULTS: A total of 522 patients with COVID-19 infection were included in the study. The mean age was 62.0 ± 15.6 years, and the majority were male (64.4%). Hypertension and diabetes mellitus were the two most common diseases, seen in 50.8% and 29.9%, respectively. There were 392 patients with TCZ application (group 1) and 130 patients without TCZ (group 2). Significantly higher serum glucose, magnesium, and sodium and lower calcium levels were present in group 1 than in group 2 (<0.001). Hypocalcemia, hypernatremia, hypermagnesemia, and hyperkalemia were more frequently detected in the ICU compared with the patients treated in the wards (P = 0.001, P < 0.001, P = 0.039, and P < 0.001, respectively). CONCLUSIONS: Following up closely electrolyte disturbances may support patient survival and decrease the probability of ICU necessity. This approach should be taken before the development of important disorders to be effective in the treatment process of the main disease.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Aged , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Female , Humans , Male , Middle Aged , Retrospective Studies
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