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Chimeric antigen receptor (CAR) T therapy has shown remarkable success in discovering novel CAR-T cell products for treating malignancies. Despite of successful results from clinical trials, CAR-T cell therapy is ineffective for long-term disease progression. Numerous challenges of CAR-T cell immunotherapy such as cell dysfunction, cytokine-related toxicities, TGF-β resistance, GvHD risks, antigen escape, restricted trafficking, and tumor cell infiltration still exist that hamper the safety and efficacy of CAR-T cells for malignancies. The accumulated data revealed that these challenges could be overcome with the advanced CRISPR genome editing technology, which is the most promising tool to knockout TRAC and HLA genes, inhibiting the effects of dominant negative receptors (PD-1, TGF-β, and B2M), lowering the risks of cytokine release syndrome (CRS), and regulating CAR-T cell function in the tumor microenvironment (TME). CRISPR technology employs DSB-free genome editing methods that robustly allow efficient and controllable genetic modification. The present review explored the innovative aspects of CRISPR/Cas9 technology for developing next-generation/universal allogeneic CAR-T cells. The present manuscript addressed the ongoing status of clinical trials of CRISPR/Cas9-engineered CAR-T cells against cancer and pointed out the off-target effects associated with CRISPR/Cas9 genome editing. It is concluded that CAR-T cells modified by CRISPR/Cas9 significantly improved antitumor efficacy in a cost-effective manner that provides opportunities for novel cancer immunotherapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Pirfenidone (PFD) is a non-peptide synthetic chemical that inhibits the production of transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), Interleukin 1 beta (IL-1β), and collagen 1 (COL1A1), all of which have been linked to the prevention or removal of excessive scar tissue deposition in many organs. PFD has been demonstrated to decrease apoptosis, downregulate angiotensin-converting enzyme (ACE) receptor expression, reduce inflammation through many routes, and alleviate oxidative stress in pneumocytes and other cells while protecting them from COVID-19 invasion and cytokine storm. Based on the mechanism of action of PFD and the known pathophysiology of COVID-19, it was recommended to treat COVID-19 patients. The use of PFD as a treatment for a range of disorders is currently being studied, with an emphasis on outcomes related to reduced inflammation and fibrogenesis. As a result, rather than exploring the molecule's chemical characteristics, this review focuses on innovative PFD efficacy data. Briefly, herein we tried to investigate, discuss, and illustrate the possible mechanisms of actions for PFD to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2 candidate. [Display omitted] [ABSTRACT FROM AUTHOR]

Covid-19 mortality is largely associated with a severe increase in inflammatory cytokines and polyunsaturated fatty acids (PUFAs) play an important role in modulating immune pathways and inflammatory responses; so this study was done to evaluate the effect of polyunsaturated fatty acids on the prognosis of Covid-19 disease. A comprehensive search was conducted in PubMed, Scopus and Web of Science. For systematic identification, the search was performed based on the following keywords COVID-19, SARS-CoV-2, COVID, Coronavirus Disease 19, SARS COV- 2 Infection, SARS-CoV-2, COVID19, Coronavirus Disease, Fatty Acids, Omega-3, Omega-3 Fatty Acid, Omega-6, n 3 Fatty and Omega-9 in the mentioned databases, using OR, and AND. All searched articles were included in the study and retrieved, and End-Note X7 software was used to manage the studies. Findings on the relationship between omega-3 and omega-6 fatty acids and the risk of Covid-19 are various, but omega-3 supplements have been found to be 12 to 21% effective in reducing the risk of Covid-19. Most studies emphasized the increasing severity of the disease and the need for mechanical ventilation and hospitalization due to polyunsaturated fatty acid deficiency. It is also demonstrated that omega-3 fatty acid deficiency increased mortality in patients with Covid-19. However, there is also a warning that in critical cases, elevated levels of fatty acids in patients' lungs and a cytokine storm are the main reasons for mortality in Covid-19 patients. Polyunsaturated fatty acids can reduce the risk of covid-19 which could be considered as a preventative, inexpensive and safe method. However, the risk of taking high-dose omega-3 supplements before or during SARS-COV-2 infection needs to be investigated. [Display omitted] [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]

Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. The literature search resulted in numerous in vitro , in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm. [Display omitted] [ABSTRACT FROM AUTHOR]

Early diagnosis and appropriate treatment are essential in reducing the morbidity and mortality of COVID-19-infected patients. The current study aimed to measure the levels of serum IP-10 and SAA in positive COVID-19 Egyptian patients to explore their clinical values and significance in discrimination between moderate and severe COVID-19 infection and predicting the severity and prognosis of COVID-19 disease. A total of 150 COVID-19 patients and 50 controls were enrolled into our study. Beside the routine lab work of positive COVID-19 patients; IP-10 and SAA were measured using ELISA kit. Our results revealed that the levels of D-dimer (2.64 ± 3.34), ferritin (494.11 ± 260.96), SAA (171.89 ± 51.96), IP-10 (405.0 ± 85.27), WBCs count (14.38 ± 6.06) and neutrophils count (79.26 ± 5.57) were highly significantly increased in severe to critically severe patients when compared with mild to moderate patients; while lymphocytes count (14.21 ± 5.13) was highly significantly decreased when compared to moderate patients. ROC curve analysis results showed that AUC from high to low was IP-10 ˃ SAA ˃ Ferritin ˃ D-dimer ˃ CRP. From these results we can conclude that both IP-10 and SAA could be excellent biomarkers in discrimination between moderate and severe COVID-19 infection and predicting the severity and prognosis of COVID-19 disease. [ABSTRACT FROM AUTHOR]

Such testing and trying time probably never seen before in the human history. The novel coronavirus disease abbreviated as COVID-19 is the ongoing health crisis which entered into human life in late December 2019. The ease of transmission between humans and the undetectability in early stage makes COVID-19 frightening and unprecedented. The disease is characterised by pneumonia progressing to breathing difficulty, acute respiratory distress syndrome (ARDS) and multi-organ failure. Clinical studies suggest excessive release of inflammatory mediators leads to cytokine storm, a phenomenon which appears to be potentially life-threatening in COVID-19. Across the globe, when the world authorities are grappling to contain the virus, our review provides a glimpse on structure, pathophysiology of the virus and further sheds light on various clinical complications associated with the disease in order to open up/raise new horizons to explore various possible theoretical targets for COVID-19. The review also portrays a question and debates: Can targeting cytokine storm can be a feasible approach to combat COVID-19? Unlabelled Image [ABSTRACT FROM AUTHOR]

The outbreak of COVID-19 in December 2019, has become an urgent and serious public health emergency. At present, there is no effective treatment or vaccine for COVID-19. Therefore, there is a crucial unmet need to develop a safe and effective treatment for COVID-19 patients. Mesenchymal stem cells (MSCs) are widely used in basic science and in a variety of clinical trials. MSCs are able to engraft to the damaged tissues after transplantation and promote tissue regeneration, besides MSCs able to secrete immunomodulatory factors that suppress the cytokine storms. Moreover, the contribution of MSCs to prevent cell death and inhibit tissue fibrosis is well established. In the current review article, the potential mechanisms by which MSCs contribute to the treatment of COVID-19 patients are highlighted. Also, current trials that evaluated the potential of MSC-based treatments for COVID-19 are briefly reviewed. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the most common co-morbidity associated with COVID-19 and the fatality rate in COVID-19 patients with CVD is higher compared to other comorbidities, such as hypertension and diabetes. Preliminary data suggest that COVID-19 may also cause or worsen cardiac injury in infected patients through multiple mechanisms such as 'cytokine storm', endotheliosis, thrombosis, lymphocytopenia etc. Autopsies of COVID-19 patients reveal an infiltration of inflammatory mononuclear cells in the myocardium, confirming the role of the immune system in mediating cardiovascular damage in response to COVID-19 infection and also suggesting potential causal mechanisms for the development of new cardiac pathologies and/or exacerbation of underlying CVDs in infected patients. In this review, we discuss the potential underlying molecular mechanisms that drive COVID-19-mediated cardiac damage, as well as the short term and expected long-term cardiovascular ramifications of COVID-19 infection in patients. Unlabelled Image [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a prominent pandemic disease that emerged in China and hurriedly stretched worldwide. There are many reports on COVID-19 associated with the amplified incidence of thrombotic events. In this review, we focused on COVID-19 coupled with the coagulopathy contributes to severe outcome inclusive of comorbidities such as venous thromboembolism, stroke, diabetes, lung, heart attack, AKI, and liver injury. Initially, the COVID-19 patient associated coagulation disorders show an elevated level of the D-dimer, fibrinogen, and less lymphocyte count such as lymphopenia. COVID-19 associated with the Kawasaki disease has acute vasculitis in childhood which further affects the vessels found all over the body. COVID-19 linked with the thrombotic microangiopathy triggers the multiple vasculitis along with the arterioles thrombosis, medium, large venous and arterial vessels mediates the disseminated intravascular coagulation (DIC). SARS-Co-V-2 patients have reduced primary platelet production, increased destruction of the platelet, decreased circulating platelet leads to the condition of increased thrombocytopenia which contributes to the coagulation disorder. Endothelial dysfunction plays an important role in the coagulation disorders via increased generation of the thrombin and stops fibrinolysis further leads to hypercoagulopathy. Along with that endothelial dysfunction activates the complement system pathways and contributes to the acute and chronic inflammation via cytokine storm with the production of the cytokines and chemokines, coagulation in different organs such as lung, brain, liver, heart, kidney and further leads to multi-organ failure. Unlabelled Image [ABSTRACT FROM AUTHOR]

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed. Unlabelled Image [ABSTRACT FROM AUTHOR]

The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital. Unlabelled Image • IL-6 and NLRP3 inflammasome play a pivotal role in SARS-CoV-2-induced cytokine storm. • Anti-inflammatory agents diminish inflammatory responses mediated by COVID-19 by targeting IL-6 and NLRP3 inflammasome. • Large number of lncRNAs is implicated in inflammatory responses mediated by IL-6 and NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

The COVID-19-, SARS- and MERS-related coronaviruses share many genomic and structural similarities. However, the SARS-CoV-2 is less pathogenic than SARS-CoV and MERS-CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID-19-, SARS- and MERS. Monocytes and macrophages may be infected by SARS-CoV-2 through ACE2-dependent and ACE2-independent pathways. SARS-CoV-2 can effectively suppress the anti-viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs) act as antigen presenting cells (APCs), the infection of these cells by SARS-CoV-2 impairs the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development of COVID-19-related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID-19 patients. Here, we describe the monocytes and macrophage responses during severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage-related inflammatory reactions in possible approaches for COVID-19 treatment. Unlabelled Image • A subset of monocytes and macrophages may be infected by SARS-CoV-2. • Coronavirus-infected monocyte can migrate to tissue and become infected macrophage. • Coronavirus-infected monocyte/macrophage produces high level of inflammatory factors. • Monocyte/macrophage-related cytokines promote organ inflammation and cytokine storm. • Local tissue inflammation and cytokine storm cause multi-organ failure in COVID-19. [ABSTRACT FROM AUTHOR]

The outbreak of Coronavirus disease 2019 (COVID-19) is the current world health concern, presenting a public health dilemma with ascending morbidity and mortality rates exceeding any previous viral spread, without a standard effective treatment yet. SARS-CoV-2 infection is distinguished with multiple epidemiological and pathological features, one of them being the elevated levels of cytokine release, which in turn trigger an aberrant uncontrolled response known as "cytokine storm". This phenomenon contributes to severe acute respiratory distress syndrome (ARDS), leading to pneumonia and respiratory failure, which is considered a major contributor to COVID-19-associated fatality rates. Taking into account that the vast majority of the COVID-19 cases are aggravated by the respiratory and multiorgan failure triggered by the sustained release of cytokines, implementing therapeutics that alleviate or diminish the upregulated inflammatory response would provide a therapeutic advantage to COVID-19 patients. Indeed, dexamethasone, a widely available and inexpensive corticosteroid with anti-inflammatory effects, has shown a great promise in reducing mortality rates in COVID-19 patients. In this review, we have critically compared the clinical impact of several potential therapeutic agents that could block or interfere with the cytokine storm, such as IL-1 inhibitors, IL-6 inhibitors, mast cell targeting agents, and corticosteroids. This work focused on highlighting and contrasting the current success and limitations towards the involvement of these agents in future treatment protocols. Unlabelled Image • Sustained cytokine release is the major hallmark in COVID-19 patients. • Cytokine storm contributes to COVID-19 associated pulmonary damage. • Attenuating cytokine storm offers a promising therapeutic window to COVID-19. • Targeting interleukins, JAK, and mast cell can counteract cytokine storm. • Dexamethasone showed promise as an effective treatment in Covid-19 severe cases. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a novel highly contagious infection caused by SARS-CoV-2, which has been became a global public health challenge. The pathogenesis of this virus is not yet clearly understood, but there is evidence of a hyper-inflammatory immune response in critically ill patients, which leads to acute respiratory distress syndrome (ARDS) and multi-organ failure. A literature review was performed to identify relevant articles on COVID-19 published up to April 30, 2020. The search resulted in 361 total articles. After reviewing the titles and abstracts for inclusion, some irrelevant papers were excluded. Additional relevant articles were identified from a review of citations referenced. SARS-CoV-2, directly and indirectly, affects the immune system and avoids being eliminated in early stages. On the other hand, the secretion of inflammatory cytokines creates critical conditions that lead to multi-organ failure. The immune system which is affected by the virus tries to respond via a cytokine storm and hyperinflammation, which itself leads to further multi-organ damage and even death. Unlabelled Image [ABSTRACT FROM AUTHOR]

In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication. ACE2 Downregulation in severe COVID-19 patient and appearance of MAS. Unlabelled Image • Protective role of ACE2 in the organs and system • Downregulation of ACE2 expression by SARS-CoV-2 leads to Ang II-induced organ damage. • The appearance of MAS in COVID-19 patient • Suggested treatment to diminish the deleterious effect of Ang II or appearance of MAS [ABSTRACT FROM AUTHOR]

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation. Melatonin as a potential adjuvant treatment for COVID-19. Unlabelled Image [ABSTRACT FROM AUTHOR]