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The coronavirus disease (COVID)-19 pandemic led to a new challenge in the field of effective treatment methods for this disease. Antiviral and immunomodulatory agents were suggested as potential therapeutic methods in this field. Since the most severe clinical symptoms associated with COVID-19 disease appear to be acute respiratory syndrome, azithromycin has been proposed as a potentially effective drug in this context. We have updated the evidence and selected all relevant items to understand the mechanism of role of azithromycin, clinical efficacy, and their side effects in coronavirus disease-19 treatment on July 20th and updated on March 20th, 2020. A literature search of electronic databases including the Web of Science, PubMed, and Google Scholar was conducted by searching keywords such as "Azithromycin", "COVID-19", and "Combination therapy". The ultimate goal of this review was identifying eligible studies about the pharmacological activities, safety, and effectiveness of azithromycin in treating COVID-19 patients. Immunomodulatory properties of azithromycin include the ability to reduce cytokine production, maintain epithelial cell integrity, or prevent lung fibrosis. The use of azithromycin in some studies was associated with a decrease in mortality and need for ventilation in patients. These properties can be useful during the period of COVID-19 infection, especially in patients with underlying diseases. However, the evidence for the use of azithromycin is still scarce and the quality of the studies is low. In some retrospective studies, azithromycin was mainly evaluated in combination with hydroxychloroquine, which showed no particular advantage. The results of this review showed that azithromycin has appropriate and well-known safety characteristics in the treatment of patients with COVID-19. However, the most appropriate dosage in different stages of the disease and the effect of its combination with other drugs are important questions that should be considered in future clinical trials. [ABSTRACT FROM AUTHOR]

Hyperinflammation characterized by elevated proinflammatory cytokines known as 'cytokine storms' is the major cause of high severity and mortality seen in COVID‐19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID‐19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS‐CoV‐2 infection might release a large amount of HMGB1 and RNA of SARS‐CoV‐2 into extracellular space. HMGB1 is a well‐known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS‐CoV‐2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1‐SARS‐CoV‐2 RNA complexes mediate proinflammatory responses in COVID‐19. The contribution of these pathways to impair host immune responses against SARS‐CoV‐2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1‐SARS‐CoV‐2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1‐ SARS‐CoV‐2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID‐19 therapy. [ABSTRACT FROM AUTHOR]

Introduction. COVID-19, an epidemic of coronavirus infection, has become a major global threat. The coronavirus mainly targets the human respiratory system, followed by cytokine storm, and altered immune responses associated with disease progression and adverse outcomes. Sumac and pomegranate juice are rich in bioactive compounds, which potentially have antiviral activities. This study is aimed at investigating the effect of a diet based on the use of sumac and pomegranate juice on the treatment of outpatients with COVID-19. Methods. In this study, 182 outpatients with COVID-19 were randomly divided into two groups receiving a diet containing pomegranate juice and sumac along with standard treatment and the control group (group 2) receiving standard treatment. Results. Consumption of a diet containing pomegranate juice and sumac in outpatients with COVID-19, who were receiving standard-of-care treatment, led to a significant decrease in fever, chills, cough, weakness, smell and taste disorders, shortness of breath, diarrhea, nausea and vomiting, and abdominal pain compared with outpatients with COVID-19 who received only standard treatment. Conclusion. Clinical trials of outpatients have limitations such as patients' resilience to post-COVID-19 follow-up. However, the use of pomegranate juice and sumac can be efficacious in reducing COVID-19 symptoms. This trial is registered with IRCT20190406043175N3. [ABSTRACT FROM AUTHOR]

Introduction: The preferred treatment for COVID-19 cases is Convalescent Plasma. In COVID-19 patients, cytokine storms are caused by high levels of cytokines including: Inflammatory cytokines such as (IL-10, IL-12, IL-27, IL-21, TNF-α and IFN-γ, IL-2, and IL-6), are triggered by T cell responses. The goal of this research is to determine Does administration of convalescent plasma affect the TNF-α and IFN-γ cases of COVID-19 sufferers. Materials and methods: The experimental research method uses (a post-test only control group design). The study material in the form of serum from the blood of COVID-19 patients as many as 38 samples selected randomly with details of COVID-19 patients as many as 19 samples were not given convalescent plasma treatment and 19 samples of COVID-19 patients receiving convalescent plasma therapy. Results: This study showed that there was no effect on TNF-α levels before and after convalescent plasma administration (P> 0.05), while IFN-γ levels showed an effect between before and after convalescent plasma administration (P< 0.05). Conclusion: Although in this study there were differences in the results of statistical analysis of TNF-α and IFN-γ levels in convalescent plasma treatment of COVID-19 patients, this study proved to be able to improve the clinical condition of COVID-19 cases. [ABSTRACT FROM AUTHOR]

For COVID-19 survivors, defeating the virus is just the beginning of a long road to recovery. The inducibility and catastrophic effects of the virus are distributed across multiple organs. The induction of cytokine storms in COVID-19 patients is due to the interaction of the SARS-CoV-2 virus and the host receptor, leading to various immunopathological consequences that may eventually lead to death. So far, COVID-19 has affected tons of people across the world, but there is still no effective treatment. Patients facing complications of COVID-19 after recovery have shown extensive clinical symptoms similar to that of patients recovering from previously circulating coronaviruses. Previous knowledge and literature have opened up ways to treat this disease and manage post-COVID-19 complications, which pose a severe challenge to the health system globally and may exacerbate the fragmentation of diseases. The use of steroids as a treatment has resulted in various health problems and side-effects in COVID-19 patients. This review discusses various post-COVID-19 complications observed and adjunctive therapies used along with common COVID-19 treatment and spotlights their side effects and consequences. This review provides the latest literature on COVID-19, which emphasizes the subsequent complications in various organs, side effects of drugs, and alternative regimens used to treat COVID-19. [ABSTRACT FROM AUTHOR]

Since the beginning of the COVID-19 pandemic in 2019–2020, Cytokine & Growth Factor Reviews has published several Special Issues focused on the biology, pathogenesis and therapeutic options in the treatment of COVID-19 infection, including articles on the involvement of the chemokine system in the cytokine storm in COVID-19, intervention in the early stages of COVID-19 pneumonia, the therapeutic value of corticosteroid treatment, early clinical intervention with type 1 interferons, progress in vaccine development, and organ specific complications of COVID-19. By 2022, multiple highly efficacious vaccines are available and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become the most thoroughly studied virus in history. But, with progress has also come unanticipated problems – misinformation, anti-vaxxers, opposition to protective masks, and politically motivated interference disguised as knowledge. With this issue of CGFR, we continue to document the global coronavirus pandemic and provide an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment. [ABSTRACT FROM AUTHOR]

Objective: Treatment for COVID-19 is still urgent need for the critically ill and severe cases. UC-MSC administration has a therapeutic benefit for severe COVID-19 patients even in the recovery period. In this paper, we aimed to present our clinical experience with UC-MSC treatment in severe and critical severe COVID-19 patients. Methods: In this study we evaluated the clinical outcome of severe/critically severe 210 COVID-19 patients treated with UC-MSCs, 1–2 × 106 per kilogram to 210 patients from 15/10/2020 until 25/04/2021. Results: Out of 99 critically severe intubated patients we have observed good clinical progress/discharged from ICU in 52 (52.5%) patients. Where as 86 (77.5%) of 111 severe unintubated patients discharged from ICU. Intubated 47 (47.5%) patients and unintubated 25 (22.5%) patients pass away. Significantly higher survival was observed in patients who underwent UC-MSCs before intubation (OR = 1.475, 95% CI = 1.193–1.824 p < 0.001). It was observed that the SaO2 parameter tended to improve after UC-MSC therapy compared to all groups. But SaO2 parameter between intubated and unintubated groups was not statistically significant (p > 0.05), while in discharged cases SaO2 parameter was statistically significant (p = 0.01). Besides, there was a statistically significant relation with intubation status, age (OR = 3.868, 95% CI = 0.574–7.152 p = 0.02) and weigh (OR = 6.768, 95% CI = 3.423–10.112 p < 0.001) thus presented an elevated risk for COVID-19. The linear regression analysis confirmed that the high weight was associated with the risk of intubation in COVID-19 (p = 0.001). Conclusions: According to our results and from recent studies, UC-MSC treatment is safe with high potential to be used as an added therapeutic treatment for severe COVID-19 patients. Our experience showed that UC-MSC therapy may restore oxygenation and downregulate cytokine storm in patients hospitalized with severe COVID-19. We advice wider randomised studies to discover the detailed therapeutic pathophysiology of the MSCs on COVID-19 patients. MSCs transplantation improves the damaging effects of the cytokine storm through immunomodulation and improving tissue and organ repair. Severe patients who were unintubated were in the Phase I, while critical patients who were intubated were in the Phase II. The figure is created via biorender application, (BioRender.com). [ABSTRACT FROM AUTHOR]

Blockade of IL-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T-cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T-cell therapy and COVID-19 is then discussed. [ABSTRACT FROM AUTHOR]

An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. Patients with COVID‐19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID‐19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically. [ABSTRACT FROM AUTHOR]

The harmful COVID-19 pandemic caused by the SARS-CoV-2 coronavirus imposes the scientific community to develop or find conventional curative drugs, protective vaccines, or passive immune strategies rapidly and efficiently. Passive immunity is based on recovering hyper-immune plasma from convalescent patients, or monoclonal antibodies with elevated titer of neutralizing antibodies with high antiviral activity, that have potential for both treatment and prevention. In this review, we focused on researching the potentiality of monoclonal antibodies for the prevention and treatment of COVID-19 infection. Our research review includes antibody-based immunotherapy, using human monoclonal antibodies targeting SARS-CoV-2 viral protein regions, specifically the spike protein regions, and using hyper-immune plasma from convalescent COVID-19 patients, in which monoclonal antibodies act as immunotherapy for the cytokine storm syndrome associated with the COVID-19 infection. In addition, we will demonstrate the role of the monoclonal antibodies in the development of candidate vaccines for SARS-CoV-2. Moreover, the recent progress of the diagnostic mouse monoclonal antibodies' role will be highlighted, as an accurate and rapid diagnostic assay, in the antigen detection of SARS-CoV-2. In brief, the monoclonal antibodies are the potential counter measures that may control SARS-CoV-2, which causes COVID-19 disease, through immunotherapy and vaccine development, as well as viral detection. [ABSTRACT FROM AUTHOR]

Background: COVID-19 a pandemic, affecting worldwide causing significant morbidity and to some extent mortality needs to be evaluated and urgently identify reliable predictors of disease severity and outcome. The fatal outcomes by COVID-19 are accompanied by cytokine storm syndrome. The cytokine storm is determined by serum ferritin. Aims and Objective: To determine the role of Serum ferritin in assessing the severity and outcome of COVID-19. Materials and Methods: A single-center, cross-sectional, observational study was conducted among SARS-CoV-2 infected patients from March 2020 to May 2020. The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR). Serum ferritin levels were compared with the treatment outcomes of COVID-19 positive patients. Results: A total of 1977 COVID-19 patients were studied. The mean age was 43.89±15.58 years and had male preponderance of 61.56% of the total subjects. The mean serum ferritin levels among recovered and expired patients were 1225.6 ± 2502.91 ng/ml and 285.71 ± 391.99 ng/ml, respectively. Conclusion: Serum ferritin was markedly increased in COVID-19 patients who could not survive as compared to the patients who finally recovered from the infection, proving it as a useful marker for assessing the severity of COVID-19. [ABSTRACT FROM AUTHOR]

During the global outbreak of COVID‐19 pandemic, "cytokine storm" conditions are regarded as the fatal step resulting in most mortality. Hemoperfusion is widely used to remove cytokines from the blood of severely ill patients to prevent uncontrolled inflammation induced by a cytokine storm. This article discoveres, for the first time, that 2D Ti3C2Tx MXene sheet demonstrates an ultrahigh removal capability for typical cytokine interleukin‐6. In particular, MXene shows a 13.4 times higher removal efficiency over traditional activated carbon absorbents. Molecular‐level investigations reveal that MXene exhibits a strong chemisorption mechanism for immobilizing cytokine interleukin‐6 molecules, which is different from activated carbon absorbents. MXene sheet also demonstrates excellent blood compatibility without any deleterious side influence on the composition of human blood. This work can open a new avenue to use MXene sheets as an ultraefficient hemoperfusion absorbent to eliminate the cytokine storm syndrome in treatment of severe COVID‐19 patients. [ABSTRACT FROM AUTHOR]

• Anakinra is an adjuvant treatment in severe COVID-19 by blocking IL-1. • We aimed to summarize the studies that evaluated its the safety and efficacy. • 23 studies and 3179 patients were incorporated in the study. • Anakinra had some promising results in COVID-19 by reducing mortality and need of invasive mechanical ventilation. • Anakinra may be effective in immunocompromised cases. The most important presentation of COVID-19 is hyper inflammatory condition and cytokine storm that occurs due to excessive increase of the inflammatory mediators specially, pro-inflammatory interleukins such as IL-1β, IL-6 and tumor necrosis factor-α which have an important role in the cytokine storm pathway. Up till now there is not a definitive treatment for COVID-19 disease, but according to the pathophysiology of the disease, Anakinra (Interleukin- 1 inhibitor) is an adjuvant treatment option in patients with severe COVID-19 by blocking the effect of IL-1. So, we aimed to summarize the studies that evaluated the safety and efficacy of Anakinra in patients diagnosed with COVID-19. We performed a search in PubMed, Cochrane Library, Scopus, and Web of Science (WOS) databases from inception till 7 Jan 2022. Additionally, we searched randomized and non-randomized clinical trials, cohort, case series, case control, case report more than 3 patients which contain confirmed cases of COVID-19 who received Anakinra (Interleukin- 1 inhibitor) for the management of hyper-inflammatory condition associated with COVID-19 disease. A meta-analysis was conducted using review manager 5.4. We included 44 articles in the systematic review. Ultimately, 23 studies were incorporated in the meta-analysis with a total number of 3179 patients. Our analysis showed statistically significant difference in the following outcomes: duration of ICU stays [MD = −0.65, 95% CI (−1.09, −0.03), p = 0.04], the number of patients who needed invasive mechanical ventilation [RR = 0.57, 95% CI (0.39, 0.84), p = 0.004], and number of deaths [RR = 0.80, 95% CI (0.66, 0.99), p = 0.04]. Our analysis showed no statistically significant difference in the following outcomes: length of hospital stays [MD = −0.16, 95% CI (−0.42, 0.11), p = 0.26], oxygen-free days [MD = −0.81, 95% CI (−3.81, 2.20), p = 0.60], and the number of patients who needed non-invasive mechanical ventilation [RR = 1.09, 95% CI (0.47, 2.52), p = 0.84]. Anakinra showed some promising results in important outcomes related to COVID-19 as it significantly reduced the rate of mortality and the need of invasive mechanical ventilation. It should be used in severe cases more than mild and moderate cases to avoid possible immunosuppression complications. Anakinra use is safe in cases of COVID-19 at dose less than 100 mg. Another important outcome was significant reduction is the D-dimer level. Anakinra may be effective in the treatment of specific immunocompromised cases, but it should be used cautiously. [ABSTRACT FROM AUTHOR]

Is it possible to develop a reliable, safe treatment for the widespread COVID-19 pandemic shortly? COVID-19 is characterized by a disruptive cytokine storm, quickly and often irreversibly damaging the patient's lungs, as its main target organ, leading to lung failure and death. Actual experimental therapies are trying to reduce the activation of some specific cytokines, such as IL-6, somewhat reducing the burden for the patient. However, they are often unable to block the whole storm occurring at the cytokine level. In presence of the cytokine storm, especially in severe patients, antagomiRs, already demonstrated to be efficient and secure in cardiovascular disease, could represent a useful alternative to such treatment, customizable upon the disease specificities and applicable to other coronaviruses possibly associated with such clinical manifestations, while a reliable, efficient vaccine is being distributed. [ABSTRACT FROM AUTHOR]

The fear of SARS-CoV-2 infection is due to its high mortality related to seasonal flu. To date, few medicines have been developed to significantly reduce the mortality of the severe COVID-19 patients, especially those requiring tracheal intubation. The severity and mortality of SARS-CoV-2 infection not only depend on the viral virulence, but are primarily determined by the cytokine storm and the destructive inflammation driven by the host immune reaction. Thus, to target the host immune response might be a better strategy to combat this pandemic. Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication. These render it a potentially excellent candidate for treatment of the severe COVID-19 cases. Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality. If successful, it would make the SARS-CoV-2 pandemic less fearful and help to return life back to normalcy. [ABSTRACT FROM AUTHOR]

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed. BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg. These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19. • BromAc is a strong mucolytic for COVID-19 sputum ex vivo. • Select chemokines and cytokines were downregulated following BromAc exposure. • Mucolytic and anti-inflammatory effects of BromAc were dose-dependent. • Further assessment of BromAc in COVID-19 clinical trials is warranted. [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]

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19. [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]

Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment. • STAT-3 can be activated by numerous cytokines during COVID-19. • STAT-3 is hyper-activated and can play a central role in COVID-19 pathogenesis. • Activated STAT-3 can promote hyper-inflammation, lung fibrosis and thrombosis. • Activated STAT-3 promotes lymphopenia and impairs anti-virus immune responses. • STAT3 may be a potential therapeutic target for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]