Calming the cytokine storm of COVID-19 through inhibition of JAK2/STAT3 signaling.
Ontology highlight
ABSTRACT:
SUBMITTER: Gajjela BK
PROVIDER: S-EPMC8553370 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The coronavirus disease 19 (COVID-19) pandemic poses a serious global threat to human health and the economy. Based on accumulating evidence, its continuous progression involves not only pulmonary injury but also damage to the cardiovascular system due to intertwined pathophysiological risks. As a point of convergence in the pathophysiologic process between COVID-19 and heart failure (HF), cytokine storm induces the progression of COVID-19 in patients presenting pre-existing or new onset myocardial damage and even HF. Cytokine storm, as a trigger of the progression of HF in patients with COVID-19, has become a novel focus to explore therapies for target populations. In this review, we briefly introduce the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illuminate the mechanism and links among COVID-19, cytokine storm, and HF. Furthermore, we discuss drugs and therapeutic targets for patients with COVID-19 and HF.
| S-EPMC7786163 | biostudies-literature
Project description:The SARS-CoV-2 pandemic spread worldwide unabated. However, achieving protection from the virus in the whole respiratory tract, avoiding blood dissemination, and calming the subsequent cytokine storm remains a major challenge. Here, we develop an inhaled microfluidic microsphere using dual camouflaged methacrylate hyaluronic acid hydrogel microspheres with a genetically engineered membrane from angiotensin-converting enzyme II (ACE2) receptor-overexpressing cells and macrophages. By timely competing with the virus for ACE2 binding, the inhaled microspheres significantly reduce SARS-CoV-2 infective effectiveness over the whole course of the respiratory system in vitro and in vivo. Moreover, the inhaled microspheres efficiently neutralize proinflammatory cytokines, cause an alternative landscape of lung-infiltrated immune cells, and alleviate hyperinflammation of lymph nodes and spleen. In an acute pneumonia model, the inhaled microspheres show significant therapeutic efficacy by regulation of the multisystem inflammatory syndrome and reduce acute mortality, suggesting a powerful synergic strategy for the treatment of patients with severe COVID-19 via non-invasive administration.
| S-EPMC8524658 | biostudies-literature
Project description:BackgroundProinflammatory cytokines are correlated with the severity of disease in patients with COVID-19. IL6-mediated activation of STAT3 proliferates proinflammatory responses that lead to cytokine storm promotion. Thus, STAT3 inhibitors may play a crucial role in managing the COVID-19 pathogenesis. The present study discusses a method for predicting inhibitors against the STAT3 signaling pathway.MethodThe main dataset comprises 1565 STAT3 inhibitors and 1671 non-inhibitors used for training, testing, and evaluation of models. A number of machine learning classifiers have been implemented to develop the models.ResultsThe outcomes of the data analysis show that rings and aromatic groups are significantly abundant in STAT3 inhibitors compared to non-inhibitors. First, we developed models using 2-D and 3-D chemical descriptors and achieved a maximum AUC of 0.84 and 0.73, respectively. Second, fingerprints are used to build predictive models and achieved 0.86 AUC with an accuracy of 78.70% on the validation dataset. Finally, models were developed using hybrid descriptors, which achieved a maximum of 0.87 AUC with 78.55% accuracy on the validation dataset.ConclusionWe used the best model to identify STAT3 inhibitors in FDA-approved drugs and found few drugs (e.g., Tamoxifen and Perindopril) to manage the cytokine storm in COVID-19 patients. A webserver "STAT3In" (https://webs.iiitd.edu.in/raghava/stat3in/) has been developed to predict and design STAT3 inhibitors.
| S-EPMC8378993 | biostudies-literature
Project description:Severe COVID-19 may progress into acute respiratory distress syndrome (ARDS) with high mortality risk. Its exact pathological mechanism, therapeutic obstacles and the clinical sequelae are critical and unresolved issues. Here, we reported a representative COVID-19 induced ARDS case experienced initially stable, then suddenly deteriorating up to final respiratory failure courses, until his death despite of lung transplantation. His lung pathology showed necrosis of parenchymal tissues, extensive immune cell infiltration and lung fibrosis. Single-cell RNA sequencing revealed various immune cell populations were largely expanded in his lung, and manifested inflammatory/activated functions. We also showed that cell-crosstalk between lung macrophages and fibroblasts promoted pulmonary fibrosis through IL-1B and TGF-Β signaling pathways. Although SARS-CoV-2 RNA remained undetectable in his respiratory tract specimens including BALF at the later stage of his disease, the presence of SARS-CoV-2 was definitely confirmed in his lung tissues. Thus, this case indicates the pathological mechanism of severe COVID-19 includes pulmonary SARS-CoV-2 persistence, deranged inflammation and the extensive lung fibrosis which set the barriers for effective treatments and indicate potential health complications for severe COVID-19 patients.
2020-12-01 | GSE149878 | GEO
Project description:Acute cardiac injuries occur in 20%–25% of hospitalized COVID‐19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID‐19 hyperinflammation. As IL‐1β is an upstream cytokine and a core COVID‐19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID‐19 cytokine storm. The IL‐1β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID‐19 hearts. The comparison of IL‐1β treated hCOs with cardiac tissue from COVID‐19 autopsies illustrated the critical roles of hyper‐inflammation in COVID‐19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL‐1β treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID‐19 cardiac in- juries at baseline and simulated exercise conditions.
2023-12-20 | GSE250520 | GEO
Project description: Not available
| S-EPMC7242961 | biostudies-literature
Project description:The risk of Coronavirus infection continues, and the fear of resurgence indicates the lack of a successful therapeutic strategy. In severe COVID-19 infection, many immune cells and their products are involved, making management difficult. The abundant release of cytokines and chemokines in severe COVID-19 patients leads to profound hyper inflammation and the mobilization of immune cells, triggering the cytokine storm. The complications associated with the cytokine storm include severe respiratory distress, intravascular coagulation, multi-organ failure, and death. The enormous formation of interleukin (IL)-6 and hemopoietic factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the severity of the infection. Moreover, these inflammatory cytokines and factors signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway causing the activation of cytokine-related genes. The neutralization of these proteins could be of therapeutic help in COVID-19 patients and could mitigate the risk of mortality. IL-6 antagonist, IL-6 receptor antagonists, GM-CSF receptor inhibitors, and JAK-STAT inhibitors are being investigated to prevent intense lung injury in COVID-19 patients and increase the chances of survival. The review focuses the role of IL-6, GM-CSF, and JAK-STAT inhibitors in regulating the immune response in severely affected COVID-19 patients.
| S-EPMC8030716 | biostudies-literature
Project description:Corona virus disease 2019 (COVID-19) has caused a global outbreak and severely posed threat to people's health and social stability. Mounting evidence suggests that immunopathological changes, including diminished lymphocytes and elevated cytokines, are important drivers of disease progression and death in coronavirus infections. Cytokine storm not only limits further spread of virus in the body but also induces secondary tissue damage through the secretion of large amounts of active mediators and inflammatory factors. It has been determined that cytokine storm is a major cause of deaths in COVID-19; therefore, in order to reverse the deterioration of severe and critically ill patients from this disease, the cytokine storm has become a key therapeutic target. Although specific mechanisms of the occurrences of cytokine storms in COVID-19 have not been fully illuminated, hyper-activated innate immune responses, and dysregulation of ACE2 (angiotensin converting enzyme 2) expression and its downstream pathways might provide possibilities. Tailored immunoregulatory therapies have been applied to counteract cytokine storms, such as inhibition of cytokines, corticosteroids, blood purification therapy, and mesenchymal stem cell therapy. This review will summarize advances in the research of cytokine storms induced by COVID-19, as well as potential intervention strategies to control cytokine storms.
| S-EPMC7734084 | biostudies-literature
Project description:A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death. The term cytokine storm was first used in 1993 to describe the graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. It was then reused to define the adverse syndromes secondary to the administration of immunostimulating agents, such as anti-CD28 antibodies or bioengineered immune cells, i.e., CAR T-cell therapy. Currently, the concept of cytokine storm has been better elucidated and extended to the pathogenesis of many other conditions, such as sepsis, autoinflammatory disease, primary and secondary hemophagocytic lymphohistiocytosis, and multicentric Castleman disease. Moreover, cytokine storm has recently emerged as a key aspect in the novel Coronavirus disease 2019, as affected patients show high levels of several key pro-inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-α, IFN-γ, IP-10, GM-CSF, MCP-1, and IL-10, some of which also correlate with disease severity. Therefore, since the onset of the pandemic, numerous agents have been tested in the effort to mitigate the cytokine storm in COVID-19 patients, some of which are effective in reducing mortality, especially in critically ill patients, and are now becoming standards of care, such as glucocorticoids or some cytokine inhibitors. However, the challenge is still far from being met, and other therapeutic strategies are being tested in the hope that we can eventually overcome the disease.
| S-EPMC8876409 | biostudies-literature
Project description:BackgroundAngiotensin receptor blockers (ARBs) reducing inflammation and protecting lung and brain function, could be of therapeutic efficacy in COVID-19 patients.MethodsUsing GSEA, we compared our previous transcriptome analysis of neurons injured by glutamate and treated with the ARB Candesartan (GSE67036) with transcriptional signatures from SARS-CoV-2 infected primary human bronchial epithelial cells (NHBE) and lung postmortem (GSE147507), PBMC and BALF samples (CRA002390) from COVID-19 patients.ResultsHundreds of genes upregulated in SARS-CoV-2/COVID-19 transcriptomes were similarly upregulated by glutamate and normalized by Candesartan. Gene Ontology analysis revealed expression profiles with greatest significance and enrichment, including proinflammatory cytokine and chemokine activity, the NF-kappa B complex, alterations in innate and adaptive immunity, with many genes participating in the COVID-19 cytokine storm.ConclusionsThere are similar injury mechanisms in SARS-CoV-2 infection and neuronal injury, equally reduced by ARB treatment. This supports the hypothesis of a therapeutic role for ARBs, ameliorating the COVID-19 cytokine storm.
| S-EPMC7439834 | biostudies-literature