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COVID-19 may cause the release of systemic inflammatory cytokines resulting in severe inflammation. PARP-1 has been identified as a nuclear enzyme that is activated by DNA strand breaks. It has been suggested that PARP-1 has a role in the cytokine storm shown as a cause of mortality in COVID-19, and its inhibition may adversely affect the replication of SARS -CoV-2. We aimed to investigate the relationship between PARP-1 gene polymorphisms and the clinical severity of COVID-19. rs8679 TT genotype was found to increase with the COVID-19 disease severity. The 3′UTR polymorphism rs8679 may cause PARP-1 activity as a result of viral replication increase by changing the binding site of antiviral or anti-inflammatory miRNAs. PARP-1 may affect the severity of COVID-19 by cytokine release and maybe a possible treatment target. • COVID-19 disease causes the release of systemic inflammatory cytokines resulting in severe inflammation in the lung. • Although PARP-1 has been associated with the COVID-19's complications, this relationship has not been investigated before. • miRNA binding site polymorphism rs8679 may be altering the binding site of antiviral or antiinflammatory miRNAs. The effect of these miRNAs on viral replication may result in PARP-1 activity. • The effect of these miRNAs on viral replication may result in PARP-1 activity. • NFK-B/NLRP3 inflammasome pathways activated by PARP-1 may increase the severity of COVID-19 by triggering cytokine release. • rs8679 polymorphism is a possible prognostic marker for clinical severity of COVID-19. • PARP-1/NLRP3 inflammasome pathway may be a possible treatment target. [ABSTRACT FROM AUTHOR]

Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage. [Display omitted] • COVID-19 leads to hyperinflammation and endothelial dysfunction, resulting in pulmonary and vascular complications. • NOand H 2 S are endogenous gasotransmitters with antiviral, anti-inflammatory, and anti-thrombotic activity. • Modulation of NO and H 2 S levels may be protective against pulmonary and vascular complications in viral infections. • Further investigation into efficacy, dosage, delivery methods, and timing of therapy is necessary. [ABSTRACT FROM AUTHOR]

• Cytokine storm/excessive pro-inflammatory is the major causes of pathology in COVID-19, malaria and other infectious diseases. • Relationship of inflammation, viral infection and the coagulation system is covered. • Targeting an excessive pro-inflammatory response and coagulation could be crucial in COVID-19 and P. falciparum -caused malaria. Infectious diseases are affecting the people worldwide. Mostly, infectious agents activate excessive production of cytokines so called cytokine storm. Among the infectious diseases COVID-19 is one of the deadliest diseases affecting individuals all over the world, moreover, Plasmodium falciparum malaria and HIV are major killers. An excessive pro-inflammatory response is one of the major causes of pathological conditions in these diseases. It is important to investigate the pathophysiology in the infectious diseases such as COVID-19, malaria and HIV as there is no concrete therapy against them so far. Exploration of excessive pro-inflammation could be important for therapeutic intervention. In this article, an attempt has been made to analyze the pathological conditions arise due to excessive inflammatory response in COVID-19, malaria and other infectious diseases. Targeting excessive pro-inflammatory response/cytokine storm in infectious diseases could be a useful strategy. [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]

The emergence of Coronavirus disease 2019 (Covid-19) is a global problem nowadays, causing health difficulty with increasing mortality rates, which doesn't have a verified treatment. SARS-CoV-2 infection has various pathological and epidemiological characteristics, one of them is increased amounts of cytokine production, which in order activate an abnormal unrestricted response called "cytokine storm". This event contributes to severe acute respiratory distress syndrome (ARDS), which results in respiratory failure and pneumonia and is the great cause of death associated with Covid-19. Endotoxemia and the release of bacterial lipopolysaccharides (endotoxins) from the lumen into the bloodstream enhance proinflammatory cytokines. SARS-CoV-2 can straightly interplay with endotoxins via its S protein, leading to the extremely elevating release of cytokines and consequently increase the harshness of Covid-19. In this review, we will discuss the possible role of viral-bacterial interaction that occurs through the transfer of bacterial products such as lipopolysaccharide (LPS) from the intestine into the bloodstream, exacerbating the severity of Covid-19 and cytokine storms. • SARS-CoV-2 infection can increased amounts of cytokine production. • Interaction between viral and bacterial can be transfer bacterial products into the bloodstream. • SARS-CoV-2 infection can be activated an abnormal unrestricted response called "cytokine storm. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) infection evokes severe proinflammatory storm and pulmonary infection with the number of confirmed cases (more than 200 million) and mortality (5 million) continue to surge globally. A number of vaccines (e.g., Moderna, Pfizer, Johnson/Janssen and AstraZeneca vaccines) have been developed over the past two years to restrain the rapid spread of COVID-19. However, without much of effective drug therapies, COVID-19 continues to cause multiple irreversible organ injuries and is drawing intensive attention for cell therapy in the management of organ damage in this devastating COVID-19 pandemic. For example, mesenchymal stem cells (MSCs) have exhibited promising results in COVID-19 patients. Preclinical and clinical findings have favored the utility of stem cells in the management of COVID-19-induced adverse outcomes via inhibition of cytokine storm and hyperinflammatory syndrome with coinstantaneous tissue regeneration capacity. In this review, we will discuss the existing data with regards to application of stem cells for COVID-19. Proposed mechanisms for MSCs function in severe COVID-19 patients. [Display omitted] [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]

The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1β, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS , the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19. • SARS-CoV-2 infection is associated with an exacerbated inflammatory responses. • IL-6, IL-1β, TNF-α, IL-17, IL-8 are involved in COVID19 cytokine release syndrome. • Cytokines exacerbation participates in thrombo-embolism associated with poor outcome. • CRS may be due to pyroptosis, microbiota alteration or delayed IFN response. [ABSTRACT FROM AUTHOR]

• Inhibition of IL-6 trans-signaling is crucial to rescue from cytokine storm. • sgp130Fc selectively inhibit IL-6 trans-signaling. • ADAM17/TACE prodomain inhibitor (TPD) effectively stop ADAM17 shedding activity. • Combination of sgp130Fc and TPD have potentiality to reduce cytokine storm in COVID-19. • Future trial may consider combination of sgp130Fc, TPD, anti-coagulant and antivirals for severe cases. The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 receptor blockers improve COVID-19 inpatient outcomes? A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg b.i.d. and famotidine 20 mg b.i.d. plus standard-of-care. Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine receptor blockade for at least 48 h, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 h of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited beneficial reductions in inpatient mortality and symptom progression when compared to published reports of COVID-19 inpatients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine receptor blockers. [ABSTRACT FROM AUTHOR]