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• For the first time, established a predictive model to anticipate the cytokine storms in the acute phase of SFTS patients. • By visualizing the predictive model through a nomogram, it becomes more convenient and user-friendly. • The predictive capacity of the model was evaluated based on the outcomes of 48 cytokines in the validation cohort. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease known for its high mortality rate and its correlation with Cytokine Storms (CS). Timely detection of CS is crucial for improving the prognosis of the disease. The objective of this investigation was to develop a model for identifying cytokine storms in the acute phase of SFTS. A total of 245 patients diagnosed with SFTS were included in this study between January 2020 and July 2022. Among them, 184 patients were part of the training set, while 61 patients were part of the validation set. Variables identified by LASSO were subsequently included in a multivariate logistic regression analysis to determine independent predictors. Subsequently, a nomogram was then developed to predict the likelihood of CS in SFTS patients. The predictive efficacy and clinical applicability of the nomogram model were further assessed through ROC analysis and the DCA curve. Following LASSO analysis, a total of 11 indicators were included in multivariate logistic regression analysis. The findings indicated that PLT (OR 0.865, P < 0.001), LDH (OR 1.002, P < 0.001), Na+ (OR 1.155, P = 0.005), and ALT (OR 1.019, P < 0.001) serve as independently predictors of CS in the acute phase of SFTS. Furthermore, a nomogram named the PLNA was constructed by integrating these four factors. The PLNA model exhibited favorable predictive accuracy with an AUC of 0.958. Moreover, the PLNA model exhibited excellent clinical applicability in both the training and validation sets, as evidenced by the DCA curve. The PLNA model, constructed using clinical indicators, can predict the probability of cytokine storm in the acute phase of SFTS patients. [ABSTRACT FROM AUTHOR]

• CAR-T therapy offers durable remissions in refractory hematological malignancies. • Meta-analyses show significant efficacy in various hematologic cancers. • CAR T-cell therapy improves quality of life for blood cancer patients. • Encouraging results in CD22-targeting CAR T-cell therapy for B-cell malignancies. • Long-term studies reveal durable remissions but also persistent adverse effects. Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. [ABSTRACT FROM AUTHOR]

• CRS is the most prevalent complication of CAR-T therapy. • Therapeutic plasma exchange can be a valuable and safe treatment for severe CRS caused by CAR-T cell infusion. • The temperature and inflammatory markers exhibited a significant reduction following therapeutic plasma exchange treatment. The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding. [ABSTRACT FROM AUTHOR]

• Sepsis promotes deep vein thrombosis. • Wnt/β-catenin signaling pathway participates in the process of deep vein thrombosis promoted by sepsis. • LGK974 protects against DVT formation in sepsis mice by inhibiting the activation of the Wnt/β-catenin signal and down-regulating the production of proinflammatory cytokines, PAI-1, and adhesion molecules. • LGK974 may be a new candidate for the treatment of sepsis complicated with DVT. Sepsis is a disorder characterized by host inflammation and is caused by systemic infection. The inflammatory cytokine storm results in platelet overactivation, leading to coagulation dysfunction and thrombosis, but the underlying mechanism remains poorly understood. Recent evidence has shown that the Wnt/β-catenin signaling pathway is related to sepsis, but its role and mechanism in sepsis complicated with deep vein thrombosis (DVT) are unclear. In this study, a cecal ligation and puncture (CLP)-induced sepsis model and DVT mouse model were constructed by inferior vena cava ligation. The levels of serum inflammatory factors and adhesion molecules were measured in each group, and the thrombus weight and size, hematoxylin-eosin staining, collagen fiber tissue, and transcriptome of the venous wall were analyzed. The activation of the Wnt/β-catenin signal was evaluated by quantitative real-time polymerase chain reaction, Western blotting, ELISA, and immunohistochemical and immunofluorescence methods. Sepsis significantly promoted the formation of venous wall collagen fibers and DVT. In addition, Porcn significantly upregulated and activated the Wnt/β-catenin signaling pathway in sepsis mouse models with DVT. In contrast, the Wnt signaling inhibitor LGK974 was found to improve the survival rate, decrease thrombosis, and inhibit the expression of inflammation and adhesion molecules in sepsis mice with DVT. Therefore, activation of the Wnt/β-catenin signal may promote the formation of DVT in sepsis mice. LGK974 protects against DVT formation in sepsis mice by inhibiting the activation of the Wnt/β-catenin signal and down-regulating the production of proinflammatory cytokines, PAI-1, and adhesion molecules. LGK974 may be a new candidate for the treatment of sepsis complicated with DVT. [ABSTRACT FROM AUTHOR]

Figure (S5): The diagram of the Mechanism of COVID-19 Infection and the role of Imatinib &Indinavir. [Display omitted] • The SARS-CoV-2 infection caused tissue damage. • Widely dispersed, uncontrolled immune dysregulation, often known as the "cytokine storm. • Anti-TNF therapy may be an option for COVID-19 patients. • COVID-19 patients had higher NF-κB plasma concentrations. A worldwide coronavirus pandemic has affected many healthcare systems in 2019 (COVID-19). Following viral activation, cytokines and chemokines are released, causing inflammation and tissue death, particularly in the lungs, resulting in severe COVID-19 symptoms such as pneumonia and ARDS. COVID-19 induces the release of several chemokines and cytokines in different organs, such as the cardiovascular system and lungs. COVID-19 and its more severe effects, such as an elevated risk of death, are more common in patients with metabolic syndrome and the elderly. Cytokine storm and COVID-19 severity may be mitigated by immunomodulation targeting NF-κB activation in conjunction with TNF- α -inhibition. In severe cases of COVID-19, inhibiting the NF-κB/TNF- α, the pathway may be employed as a therapeutic option. The study will elaborate on the Egyptian pattern for COVID-19 patients in the first part of our study. An Egyptian patient with COVID-19 inflammatory profiling will be discussed in the second part of this article using approved marine drugs selected to inhabit the significant inflammatory signals. A biomarker profiling study is currently being performed on Egyptian patients with SARS‐COV‐2. According to the severity of the infection, participants were divided into four groups. The First Group was non-infected with SARS-CoV-2 (Control, n = 16), the Second Group was non-intensive care patients (non-ICU, n = 16), the Third Group was intensive care patients (ICU, n = 16), and the Fourth Group was ICU with endotracheal intubation (ICU + EI, n = 16). To investigate COVID-19 inflammatory biomarkers for Egyptian patients, several inflammatory, oxidative, antioxidant, and anti-inflammatory biomarkers were measured. The following are examples of blood tests: CRP, Ferritin, D-dimer, TNF-α, IL-8, IL-6., IL-Ib, CD8, NF-κB, MDA, and total antioxidants. The results of the current study revealed many logical findings, such as the elevation of CRP, Ferritin, D-dimer, TNF- α, CD8, IL-6, IL-, NF-κB, and MDA. Where a significant increase showed in ICU group results (23.05 ± 0.30, 2.35 ± 0.86, 433.4 ± 159.3, 26.67 ± 3.51, 7.52 ± 1.48, 7.49 ± 1.04, 5.76 ± 1.31, 7.41 ± 0.73) respectively, and also ICU group results (54.75 ± 3.44, 0.65 ± 0.13, 460.2 ± 121.42, 27.43 ± 2.52, 8.63 ± 2.68, 10.65 ± 2.75, 5.93 ± 1.4, 10.64 ± 0.86) respectively, as well as ICU + EI group results (117.63 ± 11.89, 1.22 ± 0.65, 918.8 ± 159.27, 26.68 ± 2.00, 6.68 ± 1.08, 11.68 ± 6.16, 6.23 ± 0.07, 22.41 ± 1.39),respectively.The elevation in laboratory biomarkers of cytokines storm in three infected groups with remarkable increases in the ICU + EI group was due to the elevation of oxidative stress and inflammatory storm molecules, which lead to highly inflammatory responses, specifically in severe patients of COVID-19. Another approach to be used in the current study is investigating new computational drug compounds for SARS‐COV‐2 protective agents from the marine environment. The results revealed that (Imatinib and Indinavir) had the highest affinity toward Inflammatory molecules and COVID-19 proteins (PDB ID: −7CZ4 and 7KJR), which may be used in the future as possible COVID-19 drug candidates. The investigated inflammatory biomarkers in Egyptian COVID-19 patients showed a strong correlation between IL6, TNF-α, NF-κB, CRB, DHL, and ferritin as COVID-19 biomarkers and determined the severity of the infection. Also, the oxidative /antioxidant showed good biomarkers for infection recovery and progression of the patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • The mesenchymal Stem Cells (MSCs) is one of the leading contender in therapeutic management of cytokine storm implicated in the COVID-19 and other inflammatory conditions. • IFNγ and AA preconditioning of UCMSCs yield distinct growth factors and cytokine profile of the secretome and relatively effective in ameliorating the cytokine storm. • IFNγ and AA preconditioning of MSCs could give better therapeutic outcomes in the cell mediated therapies for COVID-19 and other inflammatory conditions. The mesenchymal Stem Cells (MSCs) is one of the leading contender in therapeutic management of cytokine storm implicated in the COVID-19 and other inflammatory conditions. This study was aimed to investigate the effect of Interferon gamma (IFN-γ) and Ascorbic Acid (AA) preconditioning on the secretome of the human Umbilical Cord Derived MSCs (UCMSCs) and their potential to ameliorate the lipopolysaccharide (LPS) induced cytokine storm in the human peripheral blood mononuclear cells (PBMCs). UCMSCs were preconditioned with IFN-γ, AA and secretome (UCMSCs-S, IFNγ-UCMSCs-S and AA-UCSMCs-S) was analysed for the levels of growth factors and cytokines by flow cytometry. The potential of secretome to ameliorate cytokine storm and augment angiogenesis was assessed in the LPS induced PBMCs and yolk sac membrane (YSM) assay respectively. The mRNA transcript and protein levels of IL-6, IL-1β and TNF-α was analysed by RT-PCR and flow cytometry respectively. IFNγ-UCMSCs-S and AA-UCSMCs-S ameliorated the LPS induced cytokine storm as revealed by the decreased mRNA and protein expression of IL-6, IL-1β and TNF-α as compared to the UCMSCs-S. IFNγ-UCMSCs-S and AA-UCSMCs-S augmented angiogenesis in YSM assay. Furthermore, IFNγ and AA preconditioning of UCMSCs exhibited distinct growth factors and cytokine profile in the secretome. Our results unequivocally show that IFNγ and AA preconditioning of MSCs could give better therapeutic outcomes in the cell mediated therapies for COVID-19 and other inflammatory conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Withaferin-A (WA) administration to mice mitigates aGvHD morbidity and improves survival. • WA also showed superiority over standard regimen in terms of lowering the aGvHD sign and improving the survival of mice. • WA do not interfere with graft versus leukemia effect. • Mechanistically, WA inhibits T-cell proliferation, cytokine storm and regulates immune cell phenotypes of hPBMCs probably via inhibition of JAK2-STAT3 signaling. Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from Withania somnifera (Ashwagandha), is known to have anti-inflammatory, anti-proliferative and immunomodulatory properties. The efficacy of WA for the prevention and treatment of aGvHD was evaluated using a murine model of alloHSCT. Prophylactic administration of WA to mice mitigated the clinical symptoms of aGvHD and improved survival significantly compared to the GvHD control [HR = 0.07 (0.01–0.35); P < 0.001]. Furthermore, WA group had better overall survival compared to standard prophylactic regimen of CSA + MTX [HR = 0.19 (0.03–1.1), P < 0.05]. At the same time, WA did not compromise the beneficial GvL effect. In addition, WA administered to animals after the onset of aGvHD could reverse the clinical severity and improved survival, thus establishing its therapeutic potential. Our findings suggest that WA reduced the systemic levels of Th1, Th2 and Th17 inflammatory cytokine and increased the anti-inflammatory cytokine IL-10 levels significantly (P < 0.05). WA also inhibited lymphocytes migration to gut, liver, skin and lung and protected these organs from damage. Ex-vivo , WA inhibited proliferation of human peripheral blood mononuclear cells (hPBMCs), modulated immune cell phenotype and decreased cytokine release. In addition, WA inhibited pJAK2 and pSTAT3 protein levels in mouse splenocytes and hPBMCs. In conclusion, our study demonstrates the utility of WA for the prevention and treatment of aGvHD, which should be further evaluated in a clinical setting. [ABSTRACT FROM AUTHOR]

• knockdown of Versican 1 could bring dramatically increased expression of inflammatory factors. • LPS-induced inflammation is induced by knockdown of V1 via the SP1-TLR2-NF-κB axis. • Increased expression of V1 might be protective in acute inflammation. Versican participates in various pathological processes like inflammation and fibrosis and is a potential therapeutic target for inflammatory diseases. Versican 1 (V1) has increased expression in inflammatory diseases, but its role is unclear. We explored the effects of V1 on acute lung inflammation to determine whether targeting V1 had therapeutic potential. Human fetal lung fibroblast (HFL1) was transfected with or without V1-inhibiting lentivirus and treated with LPS. The expression levels of inflammatory cytokines, V1, cellular signaling pathway and Toll-like receptors (TLRs) were detected by qPCR, ELISA and western blot. The migration and adhesion of neutrophils and monocytes to HFL1s were performed. The activity of transcriptional factors was determined by dual-luciferase reporter assay. Inflammatory factors increased dramatically and continuously with V1 knockdown and LPS stimulation (P < 0.01), orchestrating migration of inflammatory cells and an enhanced inflammatory reaction. V1-knockdown increased TLR2 (P < 0.01) and activated the NF-κB pathway, which was partially reversed with a TLR2 neutralizing antibody and an NF-κB inhibitor. Explosion of LPS-induced inflammation was induced by knockdown of V1 via the SP1-TLR2-NF-κB axis. Increased expression of V1 might be protective in acute inflammation, and an infection-induced cytokine storm might be a severe complication of V1-targeted interventions. [ABSTRACT FROM AUTHOR]

• The serum level of MCP-1 was high in COVID-19 patients. • AG genotype of the rs1024611 was associated with COVID-19 hospitalization. • The serum levels of MCP-1 could be dependent on COVID-19 and polymorphism. As a result of SARS-CoV-2 infection, the host's immune system is disrupted, and chemokines and cytokines are intensified to eliminate the virus, resulting in cytokine storm syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19 have been observed to have elevated levels of MCP-1, a chemokine associated with the severity of the disease. In some diseases, polymorphisms in the regulatory region of the MCP-1 gene correspond to serum levels and disease severity. An attempt was made in this study to assess the relationship between MCP-1 G-2518A and serum MCP-1 levels in Iranian COVID-19 patients and the severity of the disease. In this study, patients were randomly sampled from outpatients on the first day of diagnosis and from inpatients on the first day of their hospitalization. Patients were classified into the outpatient (without symptoms or with mild symptoms) and inpatient (with moderate, severe, and critical symptoms) groups. The serum level of MCP-1 was measured by ELISA and the frequency of MCP-1 G-2518A gene polymorphism genotypes in COVID-19 patients was checked by the RFLP-PCR method. Participants with COVID-19 infection had a higher rate of underlying diseases, such as diabetes, high blood pressure, kidney disease, and cardiovascular disease than the control group (P-value < 0.001). Also, the frequency of these factors in inpatients was significantly higher compared to outpatients (P-value < 0.001). Additionally, the level of MCP-1 in serum was significantly different with an average of 11.90 in comparison to 2.98 in the control group (P-value, 0.05), which is attributed to elevated serum levels among patients in hospitals with an average of 11.72 in comparison to 2.98 in the control group. Compared with outpatients, inpatients had a higher frequency of the G allele of the MCP-1-2518 polymorphism (P-value < 0.05), while a notable difference was observed in the serum level of MCP-1 in COVID-19 patients with the MCP-1-2518 AA genotype in the whole group in comparison to the control group (P-value: 0.024). Totally, the results showed that a high frequency of the G allele is related to hospitalization and poor outcome in COVID-19 cases. [ABSTRACT FROM AUTHOR]

First infusion reactions along with severe anaphylactic responses can occur as a result of systemic administration of therapeutic antibodies. The underlying mechanisms by which monoclonal antibodies induce cytokine release syndrome (CRS) can involve direct agonistic effects via the drug target, or a combination of target-engagement along with innate receptor interactions. Despite the wide variety of pathways and cells that can play a role in CRS, many currently used assays are devoid of one or more components that must be present for these responses to occur. One assay that has not been assessed for its capacity to predict CRS is the modified Chandler loop model. Herein we evaluate a plethora of commercially available monoclonal antibodies to evaluate the modified Chandler loop model's potential in CRS prediction. We demonstrate that in a 4-hour loop assay, both the superagonistic antibodies, anti-CD3 (OKT3) and anti-CD28 (ANC28.1), display a clear cytokine response with a mixed adaptive/innate cytokine source. OKT3 induce TNFα and IFN-γ release in 20 out of 23 donors tested, whereas ANC28.1 induce TNF-α, IL-2 and IFN-γ release in all donors tested (n = 18–22). On the other hand, non-agonistic antibodies associated with no or low infusion reactions in the clinic, namely cetuximab and natalizumab, neither induce cytokine release nor cause false positive responses. A TGN1412-like antibody also display a clear cytokine release with an adaptive cytokine profile (IFN-γ and IL-2) and all donors (n = 9) induce a distinct IL-2 response. Additionally, the value of an intact complement system in the assay is highlighted by the possibility to dissect out the mechanism-of-action of alemtuzumab and rituximab. The loop assay can either complement lymph node-like assays or stand-alone to investigate drug/blood interactions during preclinical development, or for individual safety screening prior to first-in-man clinical trial. [ABSTRACT FROM AUTHOR]

• The median detection time of safety-related items within 1 month and efficacy-related indicators beyond 1 month and up to 3 months of CAR-T therapy in multiple myeloma should be referred and followed. • For short-term effects of CAR-T therapy in multiple myeloma, median detection time of cytokine release syndrome onset, immune effector cell-associated neurotoxicity syndrome onset, neutrophils recovery and CAR-T expansion peak were 4.5 days, 8 days, 10 days and 12 days, respectively. • For medium-term effects of CAR-T therapy in multiple myeloma, median detection time of minimal residual disease negativity, the reduction of serum light chain to minimum, and the reduction of M protein to minimum were 30 days, 30 days, and 90 days, respectively. Multiple myeloma (MM) is the second most common hematological malignancy without cure, and Chimeric Antigen Receptor T Cell (CAR-T) therapy has been shown great promising in MM. Unlike previous published studies mainly focusing on efficacy and safety, this study aims to summarize time points in the process of CAR-T therapy in MM and establish a standardized time-related CAR-T therapy platform to provide a reference for CAR-T treatment in MM. All the literatures were retrieved from PubMed, Web of Science, Embase, American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). Relevant median detection time of efficacy and safety-related indicators of CAR-T therapy in MM were extracted from included literatures, and median values were applied to represent detection time points of indicators. Notably, the median values were not the certain and optimal detection time points, while the significance is that indicators could be detected more frequently around the median values to obtain the ideal results. This review presented the median detection time points of efficacy and safety-related indicators of CAR-T therapy in MM according to the chronological order. For short-term effects on inflammation status within 1 month after CAR-T initiation, the median time points of cytokine release syndrome onset, immune effector cell-associated neurotoxicity syndrome onset, neutrophils recovery and CAR-T expansion peak were 4.5, 8, 10 and 12 days, respectively. For medium-term effects on clinical response in MM beyond 1 month and up to 3 months following CAR-T infusion, the median time points of minimal residual disease negativity, the reduction of serum light chain to minimum, platelet recovery and the reduction of M protein to minimum were 30, 30, 44 and 90 days, respectively. This systematic review summarized the median detection time points of efficacy and safety-related indicators of CAR-T therapy in MM and constructed the time-related CAR-T therapy platform, providing an evidence-based standard for establishment of CAR-T treatment regimen in MM. [ABSTRACT FROM AUTHOR]

Mentioned in Blinatumomab (Blincyto®) clinical safety report, a 5 year old boy with acute lymphoblastic leukemia (ALL) receiving Blincyto® with the concentration of 30 μg/m 2 /day on the fourth day of therapy developed both Cytokine Release Syndrome (CRS) and Tumor Lysis Syndrome (TLS). Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Bilirubin peaks were 18, 7 and 8 folds more than upper normal limit (UNL) respectively. However, albumin was reduced to approximately half of the lower Normal limit (LNL). Although Blincyto® administration was immediately withdrawn, he expired in the day 10 due to a fatal cardiac failure. Based on evidence, FDA concluded that CRS was the main cause of death in this patient. Evoking evidence now propose that aberrant pro-inflammatory cytokines secretion, the hallmark of CRS, and subsequent elevation in nitric oxide (NO) can result in both inotropic and chronotropic alterations in myocardial excitation-contraction coupling, myocardial contractility suppression, desensitization of β-adrenergic receptors stimulation, development of acute cardiac failure and death. The probably neglecting point here is that TLS itself can also develop life threatening conditions including sudden cardiac failure through induction of hypocalcemia, hyperkalemia and hyperuricemia, making CRS monitoring and proper required supportive interventions more complex. Here, first we enumerate probable mechanisms through which CRS results in development of fatal cardiac failure and then explain the possible neglected role of TLS in development of the fatal cardiac failure. [ABSTRACT FROM AUTHOR]

• Imbalance of RAAS system and hyper-activation of the Ang-II/AT1R axis promote hyper-inflammatory state and cytokine storm leading to end-organ damages. • Activation of inflammasomes, JAK/STAT, IFN , NF-κB and TLR pathways are involved in COVID-19-associated cytokine storm. • SARS-CoV-2 promotes ROS production via activation of the NF-kB pathway and inducing mitochondrial damage leading to cell and tissue degeneration. • Elevated levels of IL-1, TNF-α, IFN-γ and IL-6 results in recruitment of various immune cells and subsequent tissue damage. • Exaggerated inflammation can affect remote organs and cause multi-organ failure. Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called "cytokine storm" is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19. [ABSTRACT FROM AUTHOR]

• Imbalance of RAAS system and hyper-activation of the Ang-II/AT1R axis promote hyper-inflammatory state and cytokine storm leading to end-organ damages. • Activation of inflammasomes, JAK/STAT, IFN , NF-κB and TLR pathways are involved in COVID-19-associated cytokine storm. • SARS-CoV-2 promotes ROS production via activation of the NF-kB pathway and inducing mitochondrial damage leading to cell and tissue degeneration. • Elevated levels of IL-1, TNF-α, IFN-γ and IL-6 results in recruitment of various immune cells and subsequent tissue damage. • Exaggerated inflammation can affect remote organs and cause multi-organ failure. Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called "cytokine storm" is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19. [ABSTRACT FROM AUTHOR]

• Application and design strategy of different CAR cells in solid tumors. • Improving the CAR costimulatory domain architecture might overcome solid tumor immunosuppressive microenvironmental barriers. • CAR cell therapy will become an important part and the future direction of solid tumor immunotherapy. In addition to chimeric antigen receptor (CAR)-αβ T -cell therapy, CAR-NK, CAR-NKT, CAR-M and CAR-γδ T -cell therapy have gradually been applied to the treatment of solid tumors. Compared to hematological tumors, solid tumors have the characteristics of strong tumor heterogeneity, limited target antigen selection, and low T -cell infiltration to build immunosuppressive tumor microenvironment. These features would present great obstacles to CAR cell therapy. This paper comprehensively analyzed the application of different CAR cells to solid tumors and summarized the design principles of different CAR cells to provide the direction for the development of CAR cell therapy in solid tumors. [ABSTRACT FROM AUTHOR]

• CD4+ T cell reduction, a reliable indicator of severity and hospitalization in COVID-19 patients. • Exposure to IL-1β, IL-6, TNF-α and IFN-γ of COVID-19 cytokine storm caused activated T cells substantial death. • IL-6 induced gasderminE-mediated pyroptosis of T cells. Lymphopenia is a common observation in patients with COVID-19. To explore the cause of T cell lymphopenia in the disease, laboratory results of 64 hospitalized COVID-19 patients were retrospectively analyzed and six patients were randomly selected to trace their changes of T lymphocytes and plasma concentration of IL-6 for the course of disease. Results confirmed that the T -cell lymphopenia, especially CD4+ T cell reduction in COVID-19 patients, was a reliable indicator of severity and hospitalization in infected patients. And CD4+ T cell count below 200 cells/μL predicts critical illness in COVID-19 patients. In vitro assay supported that exposure to key contributors (IL-1β, IL-6, TNF-α and IFN-γ) of COVID-19 cytokine storm caused substantial death of activated T cells. Among these contributors, IL-6 level was found to probably reversely correlate with T cell counts in patients. And IL-6 alone was potent to induce T cell reduction by gasderminE-mediated pyroptosis, inferring IL-6 took a part in affecting the function and status of T cells in COVID-19 patients. Intervention of IL-6 mediated T cell pryprotosis may effectively delay disease progression, maintain normal immune status at an early stage of infection. [ABSTRACT FROM AUTHOR]

• IL-6 is a cornerstone in B cell maturation and antibody production. • IL-6 dysregulation underlies inflammatory, autoimmunity, and cancer pathogenesis. • IL-6 inhibitors offer hope to patients with autoimmune and inflammatory conditions. • Tocilizumab and Sarilumab are promising in COVID-19 cytokine storm management. Several studies have shown that interleukin 6 (IL-6) is a multifunctional cytokine with both pro-inflammatory and anti-inflammatory activity, depending on the immune response context. Macrophages are among several cells that secrete IL-6, which they express upon activation by antigens, subsequently inducing fever and production of acute-phase proteins from the liver. Moreover, IL-6 induces the final maturation of B cells into memory B cells and plasma cells as well as an adaptive role for short-term energy allocation. Activation of IL-6 receptors results in the intracellular activation of the JAK/STAT pathway with resultant production of inflammatory cytokines. Several mechanisms-controlled IL-6 expression, but aberrant production was shown to be crucial in the pathogenesis of many diseases, which include autoimmune and chronic inflammatory diseases. IL-6 in combination with transforming growth factor β (TGF-β) induced differentiation of naïve T cells to Th17 cells, which is the cornerstone in autoimmune diseases. Recently, IL-6 secretion was shown to form the backbone of hypercytokinemia seen in the Coronavirus disease 2019 (COVID-19)-associated hyperinflammation and multiorgan failure. There are two classes of approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., tocilizumab) and anti-IL-6 monoclonal antibodies (i.e., siltuximab). These drugs have been evaluated in patients with rheumatoid arthritis, juvenile idiopathic arthritis, cytokine release syndrome, and COVID-19 who have systemic inflammation. JAK/STAT pathway blockers were also successfully used in dampening IL-6 signal transduction. A better understanding of different mechanisms that modulate IL-6 expression will provide the much-needed solution with excellent safety and efficacy profiles for the treatment of autoimmune and inflammatory diseases in which IL-6 derives their pathogenesis. [ABSTRACT FROM AUTHOR]

• IL-1 plays a key role in COVID-19 HLH-like syndrome. • Anakinra is the IL-1 receptor antagonist studied for off-label use in COVID-19. • Anakinra doses ≥ 100 mg for ≥ 10 days were important to be effective in COVID-19. • Anakinra might not be effective in patients with severe respiratory failure. • Anakinra prevented mechanical ventilation when cytokines were not extensively high. 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. [ABSTRACT FROM AUTHOR]

• Uncontrolled immunothrombosis is a life-threatening event in the critical COVID-19. • The vicious cycle of the excessive inflammatory responses and hemostatic reactions underlies the uncontrolled immunothrombosis. • miRNAs are essential for fine-tuning the expression of pro-/anti-inflammatory and pro/anticoagulant genes. • Some genetic agents and uncontrolled immunothrombosis-induced interfering factors disturb the expression/function of miRNAs. • Identification/resolution of the interfering factors may increase the patients' survival. Known as a pivotal immunohemostatic response, immunothrombosis is activated to restrict the diffusion of pathogens. This beneficial intravascular defensive mechanism represents the close interaction between the immune and coagulation systems. However, its uncontrolled form can be life-threatening to patients with the critical coronavirus disease 2019 (COVID-19). Hyperinflammation and ensuing cytokine storm underlie the activation of the coagulation system, something which results in the provocation of more immune-inflammatory responses by the thrombotic mediators. This vicious cycle causes grave clinical complications and higher risks of mortality. Classified as an evolutionarily conserved family of the small non-coding RNAs, microRNAs (miRNAs) serve as the fine-tuners of genes expression and play a key role in balancing the pro/anticoagulant and pro-/anti-inflammatory factors maintaining homeostasis. Therefore, any deviation from their optimal expression levels or efficient functions can lead to severe complications. Despite their extensive effects on the molecules and processes involved in uncontrolled immunothrombosis, some genetic agents and uncontrolled immunothrombosis-induced interfering factors (e.g., miRNA-single nucleotide polymorphysms (miR-SNPs), the complement system components, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and reactive oxygen species (ROS)) have apparently disrupted their expressions/functions. This review study aims to give an overview of the role of miRNAs in the context of uncontrolled immunothrombosis/thromboinflammation accompanied by some presumptive interfering factors affecting their expressions/functions in the critical COVID-19. Detecting, monitoring, and resolving these interfering agents mafy facilitate the design and development of the novel miRNAs-based therapeutic approaches to the reduction of complications incidence and mortality in patients with the critical COVID-19. [ABSTRACT FROM AUTHOR]

• Clinical grade NK cells can be obtained from different sources. • CAR NK cell therapy cause ADCC-dependent cytotoxicity against tumor cells. • CAR-NK cell therapy causes no on-target, off-tumor toxicity. CAR-T (chimeric antigen receptor T cell) technology, which has recently showed successful results in the treatment of hematological tumors, has been the focus of attention as one of the most potent approaches in tumor immunotherapy. However, side effects and limitations of this application, such as the risk of graft versus host disease (GvHD), make it challenging to be as accessible as other treatments. Natural killer cells (NK) could be transplanted without alloreactivity, making them as an off-the-shelf product. CAR-NK (chimeric antigen receptor NK cell) therapy can circumvent some serious limitations of CAR-T cell therapy. Application of CAR-NK cells have some considerable advantages over CAR-T cells. These include lack of cytokine release syndrome (CRS), neurotoxicity, and G v HD when using allogenic CAR-T cell. These features lessen the risk of tumor antigen loss and disease relapse. Moreover, NK cells which were derived from different sources, can make the CAR therapy more feasible. In this narrative review, we outlined the key features of CAR-NK cells as an alternative to CAR-T cell therapy in cancer immunotherapy and highlighted the main advantages. [ABSTRACT FROM AUTHOR]

The possible onset of Cytokine Release Syndrome (CRS) is an important consideration in the development of monoclonal antibody (mAb) therapeutics. In this study, several machine learning approaches are used to analyze CRS data. The analyzed data come from a human blood in vitro assay which was used to assess the potential of mAb-based therapeutics to produce cytokine release similar to that induced by Anti-CD28 superagonistic (Anti-CD28 SA) mAbs. The data contain 7 mAbs and two negative controls, a total of 423 samples coming from 44 donors. Three (3) machine learning approaches were applied in combination to observations obtained from that assay, namely (i) Hierarchical Cluster Analysis (HCA); (ii) Principal Component Analysis (PCA) followed by K-means clustering; and (iii) Decision Tree Classification (DTC). All three approaches were able to identify the treatment that caused the most severe cytokine response. HCA was able to provide information about the expected number of clusters in the data. PCA coupled with K-means clustering allowed classification of treatments sample by sample, and visualizing clusters of treatments. DTC models showed the relative importance of various cytokines such as IFN-γ, TNF-α and IL-10 to CRS. The use of these approaches in tandem provides better selection of parameters for one method based on outcomes from another, and an overall improved analysis of the data through complementary approaches. Moreover, the DTC analysis showed in addition that IL-17 may be correlated with CRS reactions, although this correlation has not yet been corroborated in the literature. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cytokine release syndrome (CRS) is the major underlying mechanism for multi-organ damage and mortality due to COVID-19. • Interleukin-6 (IL-6) signaling pathway is one of the key mediators of hyperinflammatory syndrome and CRS in COVID-19. • Inhibition of the IL-6 signaling by inhibiting IL-6 receptor (IL-6-R) and Janus-kinase (JAK) can improve the outcome by suppressing the hyperinflammation. • Studies support treatment with tocilizumab and baricitinib to improve the outcome in severely ill COVID-19 patients. • Special clinical considerations, including the timely application of the drug, dosage, the risk of secondary infections must be noticed using IL-6 signaling inhibitors. Since 2019, COVID-19 has become the most important health dilemma around the world. The dysregulated immune response which results in ARDS and cytokine storm has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through induction of pro-inflammatory chemokines and cytokines, is the pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, IL-6 pathway blockade is considered an emerging approach with high efficacy to reduce lung damage in COVID-19. This article aims to review the pleiotropic roles of the IL-6 pathway in lung damage and ARDS in severe COVID-19, and the rationale for IL-6 signaling blockade at different levels, including IL-6 soluble and membrane receptor pathways, IL-6 downstream signaling (such as JAK-STAT) inhibition, and non-specific anti-inflammatory therapeutic approaches. Recent clinical data of each method, with specific concentration on tocilizumab, along with other new drugs, such as sarilumab and siltuximab, have been discussed. Challenges of IL-6 signaling inhibition, such as the risk of superinfection and hepatic injury, and possible solutions have also been explained. Moreover, to achieve the highest efficacy, ongoing clinical trials and special clinical considerations of using different IL-6 inhibitors have been discussed in detail. Special considerations, including the appropriate timing and dosage, monotherapy or combination therapy, and proper side effect managment must be noticed regarding the clinical administration of these drugs. Future studies are still necessary to improve the productivity and unknown aspects of IL-6 signaling blockade for personalized treatment of severe COVID-19. [ABSTRACT FROM AUTHOR]

[Display omitted] • The effect of ruxolitinib (RXB) on concanavalin A (Con A)-hepatitis was examined. • RXB alleviated Con A-elicited hepatic injury, necrosis and apoptosis. • RXB countered Con A-enhanced hepatic production of TNF-α, IFN-γ, IL-17A, IL-10 and IL-1β. • RXB attenuated Con A-enhanced infiltrated immune cells, NF-κB and CD98. • RXB reversed Con A-induced abnormalities in oxidative stress and antioxidants. Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1β and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A. [ABSTRACT FROM AUTHOR]

• Tocilizumab is a reasonable treatment option for worsening COVID-19 pneumonia. • Tocilizumab may reduce the need for mechanical ventilator and improves outcome. • Use of tocilizumab may lead to adverse events including secondary infections. • This is a large retrospective study on COVID-19 patients receiving tocilizumab. Tocilizumab decreases inflammatory response in the cytokine storm which is one of the mechanisms behind the development of ARDS in COVID-19 patients. The objective of our study was to determine response of tocilizumab in patients suffering from COVID-19 by analyzing clinical parameters and inflammatory markers. A single-arm observational retrospective study was conducted from March 15, 2020 to March 15, 2021. Clinical outcomes in terms of mortality, weaning from mechanical ventilator, improvement in laboratory parameters including inflammatory cytokines, and length of hospital stay were documented. Reduction in values of inflammatory markers, and patients discharged home in stable condition were defined as an improvement after tocilizumab administration. A total of 514 patients received tocilizumab, majority of whom were critically sick 333 (64.8%). Out of the total sample 363 (70.6%) patients were discharged home in stable condition. Overall mean length of stay was 11.50 ± 8.4 days. There was significant difference in length of stay of patients who required invasive mechanical ventilation as compared to those who were kept only on supplemental oxygen (p < 0.05). Patients who were discharged home showed significant improvement in inflammatory markers and neutrophil to lymphocyte ratio as compared to those who expired (p < 0.05). A total of 21 (4.1%) patients had positive blood culture while 57 (11.1%) had positive culture of tracheal aspirate. Hence, tocilizumab is found to be a reasonable therapeutic option for worsening COVID-19 pneumonia by decreasing the need for mechanical ventilation. However, it is associated with adverse events including bacterial and fungal infections. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2-induced dsRNA-dependent protein kinase triggers IκB release of NF-κB. • IL-6 Amp promotes inflammatory responses by reactivating the NF-κB via STAT3. • Spike protein-induced NF-κB increases the turnover of pro-inflammatory cytokines. • Cross-talk of NF-κB, JAK/STAT and MAPKS orchestrate cytokine storm in COVID-19. • Therapeutic strategies based on NF-κB inhibition are effective in advanced COVID-19. The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein. [ABSTRACT FROM AUTHOR]

• COVID-19 is characterized by a deep inflammatory state, known as "cytokine storm". • Interleukin-8 (IL-8) is upregulated in COVID-19 and is a therapeutic target. • Upregulation of IL-8 was found in Spike-treated human bronchial epithelial cells. • An agomiRNA mimicking miR-93-5p down regulates Spike-induced IL-8 gene expression. • Delivery of miR-93-5p agomiRs might be an anti-COVID-19 therapeutic strategy. One of the major clinical features of COVID-19 is a hyperinflammatory state, which is characterized by high expression of cytokines (such as IL-6 and TNF-α), chemokines (such as IL-8) and growth factors and is associated with severe forms of COVID-19. For this reason, the control of the "cytokine storm" represents a key issue in the management of COVID-19 patients. In this study we report evidence that the release of key proteins of the COVID-19 "cytokine storm" can be inhibited by mimicking the biological activity of microRNAs. The major focus of this report is on IL-8, whose expression can be modified by the employment of a molecule mimicking miR-93-5p, which is able to target the IL-8 RNA transcript and modulate its activity. The results obtained demonstrate that the production of IL-8 protein is enhanced in bronchial epithelial IB3-1 cells by treatment with the SARS-CoV-2 Spike protein and that IL-8 synthesis and extracellular release can be strongly reduced using an agomiR molecule mimicking miR-93-5p. [ABSTRACT FROM AUTHOR]

• The lovastatin administration was decreased inflammatory markers in COVID-19 patients. • The reduction of IL-6 and IL-8 was dose-dependent manner. • The decrease in CRP levels was not dose-dependent. • The receiving of lovastatin in COVID-19 cases was associated with reducing the time of hospitalization. • The COVID-19 cases receiving lovastatin were decreased mortality rate than the control group. The mounting evidence regarding the pathogenesis of COVID-19 indicated that the cytokine storm has an axial role in the severity of this disease, which may lead to thrombotic complications, acute respiratory distress syndrome (ARDS), and myocardial damage, among other consequences. It has recently been demonstrated that statins are known to have anti-viral, anti-inflammatory, anti-thrombotic, and immunomodulatory features; however, their advantage has not been evaluated in COVID-19. This study aimed to investigate the protective effects of lovastatin in intensive care unit (ICU) patients with COVID-19. The case-control study consists of 284 ICU patients, which classified into three groups as follows: 1) the patients who no received lovastatin as a control (92 patients), 2) patients received 20 mg per day lovastatin (99 patients), and 3) patients received 40 mg per day lovastatin (93 patients). Each group's demographic and clinical parameters, along with CRP, interleukin (IL)-6, IL-8 levels, and mortality rate, were studied in three-time points. The results showed that there was no statistically significant difference between our study groups in terms of age and sex. (P > 0.05). Besides, in patients, receiving lovastatin the CRP, IL-6, IL-8 levels were significantly decreased from T1 to T3 than to the control group. Our results also showed that the use of lovastatin in COVID-19 patients significantly reduced the length of hospitalization in the ICU compared with the control group. In addition, our results showed that the mortality rate in patients receiving lovastatin was lower when compared to the control group; however, this difference was not statistically significant. Since the cytokine storm is a significant factor in the pathology of SARS-CoV-2, our findings highlighted the potential use of lovastatin to mitigate the inflammatory response induced by SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

• Cytokine storm is a fatal hyper-inflammatory circumstance in severe/critical COVID-19. • Uncontrolled inflammatory responses and suppressed IFNs-I-related pathways underlie the cytokine storm. • miRNAs are essential for the maintenance of immune system homeostasis. • SARS-CoV-2-induced interfering factors disturb the expression/function of miRNAs. • Identification/resolution of the interfering factors may increase the patients' survival. SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease. [ABSTRACT FROM AUTHOR]

• The majority of hospitalized COVID-19 patients are zinc deficient. • There is a weak correlation between plasma zinc and the length of hospital stay. • cHIS score, described by Webb et al., is externally validated in this study. • Current findings do not support plasma zinc as a robust prognostic factor. Zinc deficiency is associated with impaired antiviral response, cytokine releasing syndrome (CRS), and acute respiratory distress syndrome. Notably, similar complications are being observed during severe SARS-CoV-2 infection. We conducted a prospective, single-center, observational study in a tertiary university hospital (CUB-Hôpital Erasme, Brussels) to address the zinc status, the association between the plasma zinc concentration, development of CRS, and the clinical outcomes in PCR-confirmed and hospitalized COVID-19 patients. One hundred and thirty-nine eligible patients were included between May 2020 and November 2020 (median age of 65 years [IQR = 54, 77]). Our cohort's median plasma zinc concentration was 57 µg/dL (interquartile range [IQR] = 45, 67) compared to 74 µg/dL (IQR = 64, 84) in the retrospective non-COVID-19 control group (N = 1513; p < 0.001). Markedly, the absolute majority of COVID-19 patients (96%) were zinc deficient (<80 µg/dL). The median zinc concentration was lower in patients with CRS compared to those without CRS (-5 µg/dL; 95% CI = -10.5, 0.051; p = 0.048). Among the tested outcomes, zinc concentration is significantly correlated with only the length of hospital stay (rho = -0.19; p = 0.022), but not with mortality or morbidity. As such, our findings do not support the role of zinc as a robust prognostic marker among hospitalized COVID-19 patients who in our cohort presented a high prevalence of zinc deficiency. It might be more beneficial to explore the role of zinc as a biomarker for assessing the risk of developing a tissue-damaging CRS and predicting outcomes in patients diagnosed with COVID-19 at the early stage of the disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Purinergic modulation may act as a dampening of the cytokine storm in COVID-19. • Purinergic modulation may act on the generalized inflammation of COVID-19. • P1 receptors such as A2A and A2B are associated with reduced pulmonary edema. • The pro-inflammatory action of P2X7 exacerbates the pulmonary and systemic inflammatory. • Modulation with P2X7 antagonists and A2A and A2B agonists looks promising. The etiological agent of coronavirus disease (COVID-19) is the new member of the Coronaviridae family, a severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), responsible for the pandemic that is plaguing the world. The single-stranded RNA virus is capable of infecting the respiratory tract, by binding the spike (S) protein on its viral surface to receptors for the angiotensin II-converting enzyme (ACE2), highly expressed in the pulmonary tissue, enabling the interaction of the virus with alveolar epithelial cells promoting endocytosis and replication of viral material. The infection triggers the activation of the immune system, increased purinergic signaling, and the release of cytokines as a defense mechanism, but the response can become exaggerated and prompt the so-called "cytokine storm", developing cases such as severe acute respiratory syndrome (SARS). This is characterized by fever, cough, and difficulty breathing, which can progress to pneumonia, failure of different organs and death. Thus, the present review aims to compile and correlate the mechanisms involved between the immune and purinergic systems with COVID-19, since the modulation of purinergic receptors, such as A2A, A2B, and P2X7 expressed by immune cells, seems to be effective as a promising therapy, to reduce the severity of the disease, as well as aid in the treatment of acute lung diseases and other cases of generalized inflammation. [ABSTRACT FROM AUTHOR]

• Drug repurposing is the principal treatment strategy against COVID-19 right now. • IL-6/1β, CCL2 and complement inhibition are vital in reducing disease exacerbation. • NF-κB signaling inhibitors would be the crucial targets in COVID-19 treatment. Setting up treatment strategies is the highest concern today to reduce the fatality of COVID-19. Due to a very new kind of virus attack, no specific treatment has been discovered to date. The most crucial way to dominate the disease severity is now the repurposing of drugs. In this review, we focused on the current treatment approaches targeting the crucial causative factors for the disease burden through cytokine storm or cytokine release syndrome. Several vaccines have been developed and have been applied already for prevention purposes, and several are on the way to be developed, although the effects and side effects are under observation. Presently, regulation of the immune response through intervention treatment methods has been adjusted on the basis of the COVID-19 severity stage and generally includes vaccines, immunotherapies including convalescent plasma and immunoglobulin treatment, monoclonal antibodies, cytokine therapy, complement inhibition, regenerative medicine, and repurposed anti-inflammatory and immune-regulatory drugs. Combination therapy is not acceptable in all respects because there is no concrete evidence in clinical trials or in vivo data. Target-specific drug therapies, such as inhibition of cytokine-producing signaling pathways, could be an excellent solution and thus reduce the severity of inflammation and disease severity. Therefore, gathering information about the mechanism of disease progression, possible goals, and drug efficacy of immune-based approaches to combat COVID-19 in the context of orderly review analysis is consequential. [ABSTRACT FROM AUTHOR]

• The emerging COVID-19 disease outbreak continues to spread worldwide. • A randomized trial with or without O3-autohemotherapy (O3-AHT) was performed. • No differences in mortality, length of hospital stays, mechanical ventilation, admission to ICU were observed. • A score to assess clinical improvement show a significant improvement in the O3-AHT arm. • O3-AHT, as adjuvant therapy, may provide useful support in mild to moderate SARS-CoV-2 pneumonia. Following positive experience on the use of blood ozonation in SARS-CoV-2, the CORMOR randomized trial was designed to evaluate the adjuvant role of oxygen/ozone therapy in mild to moderate SARS-CoV-2 pneumonia. The trial (ClinicalTrial.gov NCT04388514) was conducted in four different Italian centers (April-October 2020). Patients were treated according to best available standard of care (SoC) therapy, with or without O3-autohemotherapy (O3-AHT). A total of 92 patients were enrolled: SoC + O3-AHT (48 patients) were compared to the SoC treatment (44 patients). The two groups differed in steroids therapy administration (72.7% in SoC arm vs. 50.0% in O3-AHT arm; p = 0.044). Steroid therapy was routinely started when it was subsequently deemed as effective for the treatment of COVID-19 disease. No significant differences in mortality rates, length of hospital stay, mechanical ventilation requirement and ICU admission were observed. Clinical improvement in patients with pneumonia was assessed according to a specifically designed score (decrease in SIMEU class, improvement in radiology imaging, improvement in PaO2/FiO2, reduction in LDH and requirement of oxygen therapy ≤ 5 days). Score assessment was performed on day-3 (T3) and day-7 (TEnd) of O3-AHT treatment. A significant increase in the score was reported at TEnd, in the O3-AHT treatment arm (0 [0–1] in the SoC arm vs. 2 [1–3] the O3-AHT arm; p = 0.018). No adverse events related O3-AHT treatment was observed. In mild-to-moderate pneumonia due to SARS-CoV-2, adjuvant oxygen/ozone therapy did not show any effect on mortality, or mechanical intubation but show a clinical improvement a day 7 from randomization in a composite clinical endpoint. Larger Randomized prospective studies alone or in combination with steroids are needed to confirm our results. [ABSTRACT FROM AUTHOR]

• We found that medications currently in use for COVID-19 can be eliminated via TPE. • The pharmacokinetic profiles of medications should be considered during TPE. • The timing of medication administration is a crucial point to prevent their removal. Since late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, better known as COVID-19) has rapidly spread worldwide. The primary pathophysiology by which COVID-19 leads to severe lung damage is cytokine releasing syndrome (CRS), which can cause death. Therefore, removing cytokines via therapeutic plasma exchange or hemoperfusion could be a therapeutic approach to treat CRS. However, hemoperfusion or therapeutic plasma exchange could alter the effectiveness of concomitant medications. Thus, concomitant medication doses might need to be adjusted to prevent their elimination via therapeutic plasma exchange or hemoperfusion, thus ensuring that these medications remain effective. This narrative review investigates the elimination status of current medications used to manage COVID-19 during hemoperfusion and therapeutic plasma exchange, with a focus on their pharmacokinetic profiles. [ABSTRACT FROM AUTHOR]

• Polarized macrophage phenotypes induce cytokine storms and immune paralysis in sepsis. • Macrophage polarization can induce cytokine storm and immune paralysis in sepsis. • Targeted regulation of macrophage polarization is a new immunotherapy for sepsis. Sepsis is a life-threatening clinical syndrome caused by infection. Its pathogenesis is complex and entails coagulation dysfunction, inflammation, and immune disorders. Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. They can polarize into a multi-dimensional spectrum of phenotypes with different functions relating to immune regulation in response to changes in the microenvironment of specific tissues. We reviewed studies that examined the role of macrophage polarization with a focus on the classical activated (M1-like) and alternative activated (M2-like) macrophages as the two main phenotypes involved in the host immune response to sepsis. A complex regulatory network is involved in the process of macrophage polarization, which is influenced by a variety of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. M1-like macrophages release large quantities of pro-inflammatory mediators, while M2-like macrophages release large quantities of anti-inflammatory mediators. An imbalance between M1-like and M2-like macrophages induces the occurrence and development of sepsis. Therefore, targeted regulation of the process of macrophage polarization could be a useful approach to normalize the immune balance of the host, offering a new treatment modality for different stages of sepsis. [ABSTRACT FROM AUTHOR]

• Drugs to attenuate cytokine storm in COVID-19 are unavailable. • Canagliflozin attenuated inflammatory cytokine storm in LPS-treated mice.. • Atomized administration of Canagliflozin also exhibited anti-inflammatory effects. To date, drugs to attenuate cytokine storm in severe cases of Corona Virus Disease 2019 (COVID-19) are not available. In this study, we investigated the effects of intragastric and atomized administration of canagliflozin (CAN) on cytokine storm in lung tissues of lipopolysaccharides (LPS)-induced mice. Results showed that intragastric administration of CAN significantly and widely inhibited the production of inflammatory cytokines in lung tissues of LPS-induced sepsis mice. Simultaneously, intragastric administration of CAN significantly improved inflammatory pathological changes of lung tissues. Atomized administration of CAN also exhibited similar effects in LPS-induced sepsis mice. Furthermore, CAN significantly inhibited hypoxia inducible factor 1α (HIF-1α) and phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) protein levels in LPS-treated lung tissues. These results indicated that CAN might attenuate cytokine storm and reduce the inflammatory symptoms in critical cases in COVID-19. Its action mechanism might involve the regulation of HIF-1α and glycolysis in vivo. However, further studies about clinical application and mechanism analysis should be validated in the future. [ABSTRACT FROM AUTHOR]

• Lactoferrin (LF), a first line defense protein in mammals, attenuates insult-induced oxidative stress. • LF bridges innate and adaptive immunity. • Exogenous LF may attenuate COVID-19 induced "cytokine storm". • There is growing evidence for potential utility of LF as prophylactic and therapeutic agent. The COVID-19 pandemic is a serious global health threat caused by severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are highly variable with common hyperactivity of immune responses known as a "cytokine storm". In fact, this massive release of inflammatory cytokines into in the pulmonary alveolar structure is a main cause of mortality during COVID-19 infection. Current management of COVID-19 is supportive and there is no common clinical protocol applied to suppress this pathological state. Lactoferrin (LF), an iron binding protein, is a first line defense protein that is present in neutrophils and excretory fluids of all mammals, and is well recognized for its role in maturation and regulation of immune system function. Also, due to its ability to sequester free iron, LF is known to protect against insult-induced oxidative stress and subsequent "cytokine storm" that results in dramatic necrosis within the affected tissue. Review of the literature strongly suggests utility of LF to silence the "cytokine storm", giving credence to both prophylactic and therapeutic approaches towards combating COVID-19 infection. [ABSTRACT FROM AUTHOR]

[Display omitted] • DEX promotes inflammation resolving. • DEX increases the protein levels of TGF-β1. • DEX up-regulates the CD11b+F4/80+Ly6G+ population ratio. • DEX enhances resolution of inflammation via TGF-β1. Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1β and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-β1 (TGF-β1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-β1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-β1, leading to the attenuated cytokine storm and accelerated inflammation resolving. [ABSTRACT FROM AUTHOR]

• Anti-viral therapy significantly. • Reduced CT scan scores and the elevated serum levels of CRP and LDH, serum levels of IL-6, CXCL8 and IFNγ were elevated at baseline in COVID-19. • IL-1β and TNFα levels were also enhanced after treatment. • Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4 M patients and resulted in 1,86 M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, IL-8 and interferon (IFN)γ. To investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients. Blood was obtained from 29 patients (aged 32–79 yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied. Anti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, serum levels of IL-6, IL-8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p = 0.006) and IL-8 (p = 0.011) levels being further elevated after antiviral therapy. IL-1β (p = 0.01) and TNFα (p = 0.069) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit. Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects. [ABSTRACT FROM AUTHOR]

• CLL derived patient blood explored in a unique whole blood loop assay. • The CLL specific blood loop assay recapitulates target-specific CRS. • Donor specific responses are apparent in the system. • Both CDC and ADCC profiling are possible in the CLL specific blood loop model. • ADCC or CDC block skews the immune response and alters B cell depletion. Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood "loop" system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting. [ABSTRACT FROM AUTHOR]

• The artificial liver could reduce the cytokine levels in COVID-19 patients. • The artificial liver could decrease the level of inflammation-related indicators in COVID-19 patients. • The artificial liver could promote the absorption of pulmonary lesions in COVID-19 patients. To explore the application value of artificial liver support system in the clinical treatment of coronavirus disease 2019 (COVID-19) patients with cytokine storm. Six cases of severe or critically severe COVID-19 patients treated in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 22 to February 4, 2020 were recruited, and all of them received artificial liver support treatment. Statistical analysis was carried out on the change of cytokines (TNF-α, IL-10, IL-6, IFN-γ, IL-2, IL-4), inflammation-related indicators (white blood cell, neutrophil, lymphocyte, C-reactive protein and procalcitonin), immune-related indicators (B lymphocyte percentage, natural killer cell percentage, CD3+CD4+CD8 T cell percentage), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 6 patients before and after treatment, and the proportions of patients with abnormal indicators were analyzed as well. In addition, computed tomography (CT) was used to observe the absorption of pulmonary lesions before and after the artificial liver support treatment. The levels of cytokines (IL-6 and IL-10) were effectively reduced in the 6 patients after treatment with the artificial liver support system. Meanwhile, the proportions of patients with abnormal TNF-α, IL-10, IL-6 and IFN-γ were all decreased (p < 0.05). The levels of inflammation-related indicators including white blood cell, C-reactive protein and procalcitonin, and the proportions of patients with these abnormal indicators were both significantly reduced (p < 0.05). The level of neutrophil was not effectively reduced before and after the treatment, but the proportion was significantly reduced (p < 0.05). However, the abnormality of lymphocyte in the patients was not improved. There was no significant difference in immune-related indicators, AST and ALT before and after the treatment (p > 0.05). CT imaging showed that the artificial liver support treatment contributed to absorption of pulmonary lesions. The artificial liver support system had a great clinical effect in the treatment of cytokine storm and inflammation in COVID-19 patients, and it could promote the absorption of infected lesions. [ABSTRACT FROM AUTHOR]

• Sepsis infects more than 48.9 million people world-wide, with 19.7 million deaths. • Cytokine storm plays a significant role in sepsis, along with severe COVID-19. • TLR signaling pathways plays a crucial role in generating the cytokine storm. • Endogenous negative regulators of TLR signaling are crucial to regulate cytokine storm. Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators [cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS)], which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role. [ABSTRACT FROM AUTHOR]

• Lethal forms of the disease are associated with cytokine storm. • The severity of COVID-19 was associated with abdominal adipose tissue distribution. • Exhaustion markers upregulated in T cells and NK cells from COVID-19 patients. • There might be a connection between SARS-CoV-2 related mortality and gut microbiota. Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) is responsible for recent ongoing public health emergency in the world. Sharing structural and behavioral similarities with its ancestors [SARS and Middle East Respiratory Syndrome (MERS)], SARS-CoV-2 has lower fatality but faster transmission. We have gone through a long path to recognize SARS and MERS, therefore our knowledge regarding SARS-CoV-2 is not raw. Various responses of the immune system account for the wide spectrum of clinical manifestations in Coronavirus disease-2019 (COVID-19). Given the innate immune response as the front line of defense, it is immediately activated after the virus entry. Consequently, adaptive immune response is activated to eradicate the virus. However, this does not occur in every case and immune response is the main culprit causing the pathological manifestations of COVID-19. Lethal forms of the disease are correlated with inefficient and/or insufficient immune responses associated with cytokine storm. Current therapeutic approach for COVID-19 is in favor of suppressing extreme inflammatory responses, while maintaining the immune system alert and responsive against the virus. This could be contributing along with administration of antiviral drugs in such patients. Furthermore, supplementation with different compounds, such as vitamin D, has been tested to modulate the immune system responses. A thorough understanding of chronological events in COVID-19 contributing to the development of a highly efficient treatment has not figured out yet. This review focuses on the virus-immune system interaction as well as currently available and potential therapeutic approaches targeting immune system in the treatment of COVID-19 patients. [ABSTRACT FROM AUTHOR]

• Cytokine release syndrome can lead to severe deterioration in COVID-19 patients. • No treatment has yet proven completely beneficial for COVID-19 patients. • Tocilizumab was administered to 40 severely ill COVID-19 patients. • Majority of our study patients showed improvement after Tocilizumab administration. COVID-19 pandemic has become a global concern. Cytokine release syndrome (CRS) complicates acute respiratory distress syndrome (ARDS) and causes multi-organ failure which can subsequently lead to mortality in COVID-19 patients. Tocilizumab, an interleukin-6 antagonist, has shown to salvage patients with cytokine release storm. In this study, we aim to evaluate therapeutic response of Tocilizumab in COVID-19 patients. A single-arm retrospective review of 40 patients with COVID-19, admitted to The Aga Khan University Hospital Karachi, from March 2020 to May 2020 was performed. Selection of patients for use of Tocilizumab was based on severity of disease, rapid clinical deterioration, presence of CRS and absence of any absolute contraindication to Tocilizumab. Improvement after Tocilizumab was defined as improvement in oxygen requirement and inflammatory parameters. Serum levels of inflammatory cytokines like C-reactive protein, ferritin, D-dimer and lactate dehydrogenase levels were monitored before and after administering Tocilizumab. Mean age was 62.4 years and 33 (82.5%) were male. 19 (47.5%) patients were critically sick, 18 (45%) were severely sick and 3 (7.5%) were moderately sick. 29 (77.5%) patients showed significant improvement in oxygen requirement, inflammatory parameters and chest x-rays, out of which 28 patients were discharged home. The mean duration between administration of Tocilizumab and overall improvement was 4.3 ± 3.2 days. Hence, Tocilizumab can be used as a possible treatment option in patients with COVID-19 induced CRS but needs monitoring for its adverse effects. [ABSTRACT FROM AUTHOR]

• Rational strategy to carry out drugs repurposing for management COVID-19 patients. • Anti-inflammation therapy plays a pivotal role in the management COVID-19 patients. • Drugs mitigate the cytokines production induced by SARS-CoV-2's immunological activation. • Reduction in hyperinflammation lead to a decrease in multiple organ failure. Coronavirus disease 2019 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an aggressive disease that attacks the respiratory tract and has a higher fatality rate than seasonal influenza. The COVID‐19 pandemic is a global health crisis, and no specific therapy or drug has been formally recommended for use against SARS-CoV-2 infection. In this context, it is a rational strategy to investigate the repurposing of existing drugs to use in the treatment of COVID-19 patients. In the meantime, the medical community is trialing several therapies that target various antiviral and immunomodulating mechanisms to use against the infection. There is no doubt that antiviral and supportive treatments are important in the treatment of COVID-19 patients, but anti-inflammatory therapy also plays a pivotal role in the management COVID-19 patients due to its ability to prevent further injury and organ damage or failure. In this review, we identified drugs that could modulate cytokines levels and play a part in the management of COVID-19. Several drugs that possess an anti-inflammatory profile in others illnesses have been studied in respect of their potential utility in the treatment of the hyperinflammation induced by SAR-COV-2 infection. We highlight a number of antivirals, anti-rheumatic, anti-inflammatory, antineoplastic and antiparasitic drugs that have been found to mitigate cytokine production and consequently attenuate the "cytokine storm" induced by SARS-CoV-2. Reduced hyperinflammation can attenuate multiple organ failure, and even reduce the mortality associated with severe COVID-19. In this context, despite their current unproven clinical efficacy in relation to the current pandemic, the repurposing of drugs with anti-inflammatory activity to use in the treatment of COVID-19 has become a topic of great interest. [ABSTRACT FROM AUTHOR]

• The pathophysiology of SARS-CoV-2 infection may be attributed to cytokine release syndrome. • In this syndrome, interleukin 6 is released after the activation of the inflammatory cascade. • The mortality rate in the current study was 16%. • Tocilizumab may be a promising agent to decrease the mortality rate in severe or critical SARS-CoV-2 infection. The clinical presentation of SARS-CoV-2 infection ranges from mild symptoms to severe complications, including acute respiratory distress syndrome. In this syndrome, inflammatory cytokines are released after activation of the inflammatory cascade, with the predominant role of interleukin (IL)-6. The aim of this study was to evaluate the effects of tocilizumab, as an IL-6 antagonist, in patients with severe or critical SARS-CoV-2 infection. In this prospective clinical trial, 76 patients with severe or critical SARS-CoV-2 infection were evaluated for eligibility, and ultimately, 42 patients were included. Tocilizumab was administered at a dose of 400 mg as a single dose via intravenous infusion. Primary outcomes included changes in oxygenation support, need for invasive mechanical ventilation, and death. Secondary outcomes included radiological changes in the lungs, IL-6 plasma levels, C-reactive protein levels, and adverse drug reactions. The data were analyzed using SPSS software. Of the 42 included patients, 20 (48%) patients presented the severe infection stage and 22 (52%) were in the critical stage. The median age of patients was 56 years, and the median IL-6 level was 28.55 pg/mL. After tocilizumab administration, only 6 patients (14%) required invasive ventilation. Additionally, 35 patients (83.33%) showed clinical improvement. By day 28, a total of 7 patients died (6 patients in the critical stage and 1 patient in the severe stage). Neurological adverse effects were observed in 3 patients. Based on the current results, tocilizumab may be a promising agent for patients with severe or critical SARS-CoV-2 infection, if promptly initiated during the severe stage. [ABSTRACT FROM AUTHOR]

• Cytokine storm is a key factor in the rapid deterioration of COVID-19. • Baricitinib could interrupt the passage of SARS-CoV-2 into the cells and treat cytokine storm. • The key points of pharmaceutical care have been elaborated in this article. In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1–2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19. [ABSTRACT FROM AUTHOR]

• Withaferin A is a pharmacologically active steroidal lactone from Withania somnifera. • It prevents acute Graft-versus-host disease without affecting graft-vs-tumor activity. • It suppresses T-cell lymphoblast formation and activation of AKT/mTOR pathway. • It does not hamper immune reconstitution allowing stable and complete donor chimerism. Acute Graft versus Host Disease (aGVHD) is a frequent and serious complication in patients receiving allogeneic bone marrow transplantation (allo-BMT) and often requires rigorous prophylaxis. The current treatment regimens for aGVHD are associated with several side effects which necessitates the development of novel interventions that prevent aGVHD without precluding graft-versus-tumor effects. In the present study, we show that treatment of donor graft with plant steroidal lactone Withaferin A (WA) prior to transplantation markedly reduced aGVHD mediated damage in target organs without compromising the graft-versus.-tumor activity of the transplanted lymphocytes. WA abrogated post-transplant cytokine storm associated with allo-activation of donor lymphocytes. This was attributed to the ability of WA to inhibit early signaling events in T-cell activation including lymphoblast formation and activation of AKT/mTOR pathway. Mortality and morbidity related to allo-transplantation was significantly reduced in recipients of WA treated donor splenocytes compared to recipient of vehicle treated donor splenocytes. Further, WA treatment did not have any effect on reconstitution of lymphoid and myeloid lineages in recipients, resulting in stable and complete donor chimerism. In agreement with previous reports showing the effectiveness of WA in a mouse model of partial chimerism, our data further establishes that WA is able to attenuate aGVHD in an MHC-mismatched high dose chemo-conditioned murine model without compromising engraftment. This study provides compelling scientific basis for possible application of WA for prevention and treatment of aGVHD in patients receiving allo-BMT. [ABSTRACT FROM AUTHOR]

• Licorice defect in TCM recipes leads to the hepatotoxicity in administrated mice. • GA inhibits viral hepatitis by suppressing HMGB1 release and cytokine activity. • GA treatment effect on infected mice is similar with HMGB1 neutralizing antibody. • HMGB1-TLR4 axis is involved in murine hepatic injury during MHV infection. Various human disorders are cured by the use of licorice, a key ingredient of herbal remedies. Glycyrrhizic acid (GL), a triterpenoid glycoside, is the aqueous extract from licorice root. Glycyrrhetinic acid (GA) has been reported to be a major bioactive hydrolysis product of GL and has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis. However, the mechanism by which GA inhibits viral hepatic inflammatory injury is not completely understood. In this study, we found that, by consecutively treating mice with a traditional herbal recipe, licorice plays an important role in the detoxification of mice. We also employed a murine hepatitis virus (MHV) infection model to illustrate that GA treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity. Furthermore, decreased HMGB1 levels and downstream signaling triggered by injection of a neutralizing HMGB1 antibody or TLR4 gene deficiency, also significantly protected against MHV-induced severe hepatic injury. Thus, our findings characterize GA as a hepatoprotective therapy agent in hepatic infectious disease not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via an underlying viral-induced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm. The present study provides a new therapy strategy for the treatment of acute viral hepatitis in the clinical setting. [ABSTRACT FROM AUTHOR]