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Autonomic dysfunction is a clinical hallmark of infection caused by SARS‐CoV‐2, but the underlying mechanisms are unknown. The vagus nerve inflammatory reflex is an important, well‐characterized mechanism for the reflexive suppression of cytokine storm, and its experimental or clinical impairment facilitates the onset and progression of hyperinflammation. Recent pathological evidence from COVID‐19 victims reveals viral infection and inflammation in the vagus nerve and associated nuclei in the medulla oblongata. Although it has been suggested that vagus nerve inflammation in these patients mediates dysregulated respiration, whether it also contributes to dysfunction of the vagus nerve inflammatory reflex has not been addressed. Because lethality and tissue injury in acute COVID‐19 are characterized by cytokine storm, it is plausible to consider evidence that impairment of the inflammatory reflex may contribute to overproduction of cytokines and resultant hyperinflammatory pathogenesis. Accordingly, here the authors discuss the inflammatory reflex, the consequences of its dysfunction in COVID‐19, and whether there are opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

COVID-19, caused by the SARS-CoV-2 virus, has emerged as a global health threat. Due to coronovirus mutations and genetic variations, effective treatments remain elusive. Currently, the primary strategy for disease management revolves around coronovirus vaccines, representing the sole avenue for disease control. A prominent factor in the pathogenesis of COVID-19 is the severe inflammation triggered by a phenomenon known as cytokine storm. This review delves into the pivotal role of interleukin-6 (IL-6) in orchestrating the cytokine storm and explores the intricate network of signaling pathways and inhibitors, including phytochemicals. Numerous clinical trials have explored the potential of anti-cytokine agents and medicinal plants with cytokine-modulating attributes in COVID-19 patients. According to various studies investigating the effects of medicinal plants on COVID-19, four specific plants—Silybum marianum L., Tanacetum parthenium L., Curcuma longa L., and Zingiber officinale Rosc.—have exhibited significant anti-IL-6 signaling properties. However, further rigorous clinical data are needed to establish their prophylactic or therapeutic efficacy. Overall, both in-vivo and clinical studies suggest that the aforementioned medicinal plants, endowed with proven anti-inflammatory and immune-modulatory properties, particularly through IL-6 reduction, could make valuable contributions to the management of COVID-19. [ABSTRACT FROM AUTHOR]

Paraguay is currently facing a new outbreak of Chikungunya virus. This report summarizes two severe cases of Chikungunya (CHIKV) infection, confirmed by real-time reverse transcription polymerase chain reaction. We present the cases of patients with acute CHIKV infection and multisystem involvement, with fever, rash, abdominal pain, vomiting, myocarditis, and coronary artery anomalies, very similar to the cases described in MIS-C related to SARS-CoV-2 during the COVID-19 Pandemic. Both patients received IVIG and methylprednisolone, with good clinical response. In this setting of cytokine storm in Chikungunya, can we call it "Multisystem inflammatory syndrome associated with Chikungunya"?. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Since ancient times, spices such as black pepper, cinnamon, ginger, turmeric, garlic, black cumin, clove, ocimum, saffron, and nutmeg constitute an important part of foods and beverages in India. Besides, adding aroma and flavour to the food, they are also known for multiple medicinal benefits. During the COVID-19 pandemic, an interesting pattern of disease prevalence and severity was observed especially in the countries where spices are consumed regularly. It has attracted researchers worldwide to explore the therapeutic potential of spices in COVID-19 management. Various in silico studies have reported good binding affinities of spices and derived components towards structural druggable targets of SARS-CoV2. There are several compelling pieces of evidence for the role of spices in the attenuation of inflammatory cytokine storm which is the crux in the pathogenesis of COVID-19. Therefore, this review is written to provide deep insights into the role of food spices and their underlying mechanism in targeting SARS-CoV2. Based on experimentally verified data from different in-vitro, in-vivo, in-silico, and clinical studies, the information presented will certainly help in the development of promising drug therapeutics or preventive strategies to deal with SARS-CoV2. Further studies geared towards the development of drugs based on spices and derived compounds are suggested. [ABSTRACT FROM AUTHOR]

Severe respiratory involvement that follows a process of immune dysregulation and intense cytokine production remains to be the most dreaded complication of Coronavirus Disease-2019 (COVID-19) infection. The aim of this study was to analyze T lymphocyte subsets and natural killer (NK) lymphocytes in moderate and severe cases of COVID-19 infection and assess their significance in disease severity and prognosis. Twenty moderate cases and 20 severe cases of COVID-19 were studied and compared regarding blood picture, biochemical markers, T lymphocyte population subsets, and NK lymphocytes, which were determined by flow cytometric analysis. On analyzing the flow cytometric data of T lymphocyte cells and their subsets and NK cells in two groups of COVID-19 infection (one group moderate and the other severe cases), some immature NK lymphocyte relative and absolute counts were higher in the severe patients with worse outcome and death, while some mature NK lymphocyte relative and absolute counts were depressed in both groups. Also, interleukin (IL)-6 was significantly higher in severe cases when compared to moderate cases, and there was a positive significant correlation between immature NK lymphocyte relative and absolute counts and IL-6. There was no statistically significant difference between T lymphocyte subsets (T helper and T cytotoxic) with disease severity or outcome. Some immature NK lymphocyte subsets contribute to the widespread inflammatory response that complicates severe cases of COVID-19; therapeutic approaches directed to enhancing NK maturation or drugs that block NK cell inhibitory receptors have a potential role in controlling COVID-19 induced cytokine storm. [ABSTRACT FROM AUTHOR]

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of “SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. [ABSTRACT FROM AUTHOR]

In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1–7)/MasR pathway activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be beneficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension. In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS) function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the biochemical and immunological effects of VitD on immune function in the underlying diseases and its role in the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The world has been rocked by the 2019 coronavirus disease (COVID-19), which has significantly changed our way of life. Despite the unusual measures taken, COVID-19 still exists and affects people all over the world. A remarkable amount of study has been done to find ways to combat the infection's unsurpassed level. No ground-breaking antiviral agent has yet been introduced to remove COVID-19 and bring about a return to normalcy, even though numerous pharmaceuticals and therapeutic technologies have been reused and discovered. The cytokine storm phenomenon is of utmost importance since fatality is strongly connected with the severity of the disease. This severe inflammatory phenomenon marked by increased amounts of inflammatory mediators can be targeted for saving patients’ life. Our analysis demonstrates that SARS-CoV-2 specifically generates a lot of interleukin-6 (IL-6) and results in lymphocyte exhaustion. Tocilizumab is an IL-6 inhibitor that is currently thought to be both generally safe and effective. Additionally, corticosteroids, tumor necrosis factor (TNF)-blockers and Janus kinase (JAK) inhibitors could be effective and dependable methods to reduce cytokine-mediated storm in SARS-CoV-2 patients. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 has been a shocking disaster for healthcare systems worldwide since December 2019. This virus can affect all systems of the body and its symptoms vary from a simple upper respiratory infection to fatal complications including end-organ damage. On the other hand, the normal immune system plays a pivotal role in the recovery of infectious diseases such as COVID-19. However, occasionally, exaggerated immune system inflammation and an excessive synthesis of cytokines, known as a "cytokine storm," can deteriorate the patient's clinical condition. Secondary bacterial co-infection is another problem in COVID-19 which affects the prognosis of patients. Although there are a few studies about this complication, they suggest not using antibiotics commonly, especially broad-spectrum ones. During this pandemic, various approaches and therapeutics were introduced for treating COVID-19 patients. However, available treatments are not helpful enough, especially for complicated cases. Hence, in this era, cell therapy and regenerative medicine will create new opportunities. Therefore, the therapeutic benefits of mesenchymal stem cells, especially their antimicrobial activity, will help us understand how to treat COVID-19. Herein, mesenchymal stem cells may stop the immune system from becoming overactive in COVID-19 patients. On the other side, the stem cells' capacity for repair could encourage natural healing processes. [ABSTRACT FROM AUTHOR]

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis‐associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The coronavirus disease 2019 (COVID‐19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS‐CoV‐2‐induced ARDS at the infective and post‐infective stages. In this minireview, we examine drugs targeting IL‐1β, IL‐4/IL‐13, IL‐6 and TNF‐α tested in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Considering the high impact that severe Coronavirus disease 2019 (COVID-19) cases still pose on public health and their complex pharmacological management, the search for new therapeutic alternatives is essential. Mesenchymal stromal cells (MSCs) could be promising candidates as they present important immunomodulatory and anti-inflammatory properties that can combat the acute severe respiratory distress syndrome (ARDS) and the cytokine storm occurring in COVID-19, two processes that are mainly driven by an immunological misbalance. In this review, we provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation that occurs in COVID-19, discussing the potential that the cytokines and growth factors that constitute the MSC-derived secretome present to treat the disease. Moreover, we revise the latest clinical progress made in the field, discussing the most important findings of the clinical trials conducted to date, which follow 2 different approaches: MSC-based cell therapy or the administration of the secretome by itself, as a cell-free therapy. • Provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation in COVID-19. • Discuss the potential of the cytokines and growth factors that constitute MSC-derived secretome to treat the disease. • Revise the latest clinical progress made in the field, discussing the most important findings conducted to date. [ABSTRACT FROM AUTHOR]

• Treatment of adults with severe COVID-19 and cytokine storm were compared. • In all, 102/463 patients received tocilizumab, and 361 of 463 received baricitinib. • At 28 days, there was no difference in all-cause mortality between subgroups. • No differences regarding side effects were observed between groups. Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib. A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications. Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P -value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P <0.01), rate of major infectious complications was similar (32/102, 31.4% vs 96/361, 26.6%; P -value = 0.34). In logistic regression, the immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan–Meier analysis revealed statistically similar survival distributions. All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is responsible for coronavirus disease 2019 (COVID-19), progressively extended worldwide countries on an epidemic scale. Along with all the drug treatments suggested to date, currently, there are no approved management protocols and treatment regimens for SARS-CoV-2. The unavailability of optimal medication and effective vaccines against SARS-CoV-2 indicates the requirement for alternative therapies. Probiotics are living organisms that deliberate beneficial effects on the host when used sufficiently and in adequate amounts, and fermented food is their rich source. Probiotics affect viruses by antiviral mechanisms and reduce diarrhea and respiratory tract infection. At this point, we comprehensively evaluated the antiviral effects of probiotics and their mechanism with a particular focus on SARS-CoV-2. In this review, we suggested the conceptual and potential mechanisms of probiotics by which they could exhibit antiviral properties against SARS-CoV-2, according to the previous evidence concerning the mechanism of antiviral effects of probiotics. This study reviewed recent studies that speculate about the role of probiotics in the prevention of the SARS-CoV-2-induced cytokine storm through the mechanisms such as induction of anti-inflammatory cytokines (IL-10), downregulation of pro-inflammatory cytokines (TNF-α, IL-2, IL-6), inhibition of JAK signaling pathway, and act as HDAC inhibitor. Also, the recent clinical trials and their outcome have been reviewed. [ABSTRACT FROM AUTHOR]

Objective: In coronavirus disease -- 19 (COVID-19) patients, cytokine storm develops due to the increase of pro-inflammatory cytokines. Tocilizumab (TCZ), has been used in the treatment of COVID-19 patients and successful results have been obtained. The aim of this study was to determine the efficacy of TCZ and also investigate the prognostic factors affecting the success of treatment and mortality in COVID-19 patients treated with TCZ. Patients and Methods: Between March 2020 and August 2021, a total of 326 confirmed severe COVID-19 pneumonia patients, treated in the intensive care unit, were included in the study. Results: The mean age of the patients was 63.02±11.58 years, and 203 (62.3%) of the patients were male. Patients treated with TCZ had a longer survival time compared with the standard therapy (p=0.012). It was found that type of respiratory support (HR:2.19, CI:1.10- 4.36, p=0.025) and hyperlactatemia on the day of TCZ therapy admission (HR:2.93 CI:1.53-5.64, p=0.001) were the significant and independent prognostic factors of survival in severe COVID-19 pneumonia patients treated with TCZ. Conclusion: Tocilizumab therapy improved 30-days survival in critically ill COVID-19 pneumonia patients. Also, among the patients with TCZ, types of respiratory support and hyperlactatemia on the day of TCZ admission were the independent prognostic factors. [ABSTRACT FROM AUTHOR]

The number of hospitalizations and fatalities brought on by COVID-19 has considerably grown since the World Health Organization proclaimed the disease as a global pandemic. New combination therapy is required to lessen the risk of COVID-19 progression during this time when the danger of transmission rises as new Omicron sub-variants arise. In this situation, it is critical to boost the immune system to combat highly inflammatory conditions like the cytokine storm brought on by COVID-19. Furthermore, if administered early in COVID-19 illness, monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 can minimize the chance of hospitalization. LY-CoV1404 (bebtelovimab) is one of these mAbs that has recently gained prominence due to its ability to effectively neutralize the SARS-CoV-2 virus and protect binding to spike proteins of several variants including B.1.1.529 (Omicron) and its sub-variants (BA.1, BA.1.1, and BA.2) with various essential receptor binding domain (RBD) mutations. This brief review emphasizes the advantages of combining melatonin with bebtelovimab, which has been demonstrated to be the most effective SARS-CoV-2 neutralizing monoclonal antibody against the Omicron variant in the management of COVID-19. This study suggests that the combination therapy for Omicron sub-variants is beneficial and could be regarded as adjuvant therapy for COVID-19 disease. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation has been linked to morbidity and mortality in COVID-19 patients. Understanding the immunology of COVID-19 is critical for developing effective therapies, diagnostics, and prophylactic strategies to control the disease. Aim: The aim of this study was to correlate cytokine and chemokine serum levels with COVID-19 disease severity and mortality. Subjects and Methods: A total of 60 hospitalized patients from the Tabuk region of Saudi Arabia with confirmed COVID-19 were included in the study. At hospital admission, the IL-1 β, IL-2, IL-8, IL-10, LT-B4, and CCL-2 serum levels were measured. The cytokine levels in COVID-19 patients were compared to the levels in 30 healthy matched control subjects. Results: The IL-1 β, IL-2, LTB-4, CCL-2, and IL-8 levels (but not IL-10) were significantly higher in all COVID-19 patients (47 survivors and 13 non-survivors) compared with the levels in the healthy control group. In the non-survivor COVID-19 patients, patients' age, D-dimer, and creatinine kinase were significantly higher, and IL-1 β, IL-2, and IL-8 were significantly lower compared with the levels in the survivors. Conclusion: Mortality rates in COVID-19 patients are associated with increased age and a failure to mount an effective immune response rather than developing a cytokine storm. These results warrant the personalized treatment of COVID-19 patients based on cytokine profiling. [ABSTRACT FROM AUTHOR]

Cytokine release syndromes represent a severe turn in certain disease states, which may be caused by several infections, including those with the virus SARS‐CoV‐2. This inefficient, even harmful, immune response has been associated with a broad release of chemokines. Although a cellular (type I) immune reaction is efficacious against viral infections, we noted a type I deficit in the cytokine patterns produced by cytokine storms of all reported etiologies. Agents including lipopolysaccharide (LPS, bacterial), anti‐CD3 (antibody) and a version of the prominent SARS‐CoV‐2 viral surface molecule, Spike Glycoprotein, were individually sufficient to induce IL‐6 and multiple chemokines in mice. They failed to upregulate the TH1 inducer cytokine Osteopontin, and the pathophysiologic triggers actually suppressed the PMA‐induced Osteopontin secretion from monocytic cells. Osteopontin administration partially reversed the chemokine elevation, more effectively so in a mouse strain with TH1 bias. Corroboration was obtained from the inverse correlation in the levels of IL‐6 and Osteopontin in plasma samples from acute COVID‐19 patients. We hypothesize that the inhibition of Osteopontin by SARS‐CoV‐2 Spike Glycoprotein or LPS represents an immune evasion mechanism employed by the pathogens of origin. The ensuing dysfunctional inflammatory response promotes a vicious cycle of amplification, resulting in a cytokine storm. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 disease, is a highly infectious and transmissible viral pathogen that continues to impact human health globally. Nearly ~600 million people have been infected with SARS-CoV-2, and about half exhibit some degree of continuing health complication, generically referred to as long COVID. Lingering and often serious neurological problems for patients in the post-COVID-19 recovery period include brain fog, behavioral changes, confusion, delirium, deficits in intellect, cognition and memory issues, loss of balance and coordination, problems with vision, visual processing and hallucinations, encephalopathy, encephalitis, neurovascular or cerebrovascular insufficiency, and/or impaired consciousness. Depending upon the patient's age at the onset of COVID-19 and other factors, up to ~35% of all elderly COVID-19 patients develop a mild-to-severe encephalopathy due to complications arising from a SARS-CoV-2-induced cytokine storm and a surge in cytokine-mediated pro-inflammatory and immune signaling. In fact, this cytokine storm syndrome: (i) appears to predispose aged COVID-19 patients to the development of other neurological complications, especially those who have experienced a more serious grade of COVID-19 infection; (ii) lies along highly interactive and pathological pathways involving SARS-CoV-2 infection that promotes the parallel development and/or intensification of progressive and often lethal neurological conditions, and (iii) is strongly associated with the symptomology, onset, and development of human prion disease (PrD) and other insidious and incurable neurological syndromes. This commentary paper will evaluate some recent peer-reviewed studies in this intriguing area of human SARS-CoV-2-associated neuropathology and will assess how chronic, viral-mediated changes to the brain and CNS contribute to cognitive decline in PrD and other progressive, age-related neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The pandemic of coronavirus disease 2019 (COVID-19), for which there does not appear to be an approved cure, the primary treatment options consist of non-pharmacological preventive measures and supportive treatment that are aimed at halting the progression of the disease. Nuclear factor kappa B (NFκB) presents a promising therapeutic opportunity to mitigate COVID-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the disease. However, the effective clinical application of NFκB modulators in COVID-19 is hampered by a number of factors that must be taken into consideration. This paper therefore explored the modulation of the NFB pathway as a potential strategy to mitigate the severe morbidity and mortality caused by COVID-19. The paper also discusses the factors that form the barrier, and it offers potential solutions to the various limitations that may impede the clinical use of NFκB modulators against COVID-19. This paper revealed and identified three key potential solutions for the future clinical use of NFκB modulators against COVID-19. These solutions are pulmonary tissue-specific NFκB blockade, agents that target common regulatory proteins of both canonical and non-canonical NFκB pathways, and monitoring clinical indicators of hyper inflammation and cytokine storm in COVID-19 prior to using NFκB modulators. [ABSTRACT FROM AUTHOR]

During the coronavirus disease 2019 (COVID-19) pandemic, cognitive impairment of varying degrees of severity began to be observed in a significant percentage of patients. The present study discussed the impact of immunological processes on structural and functional changes in the central nervous system and the related cognitive disorders. The purpose of the present review was to analyse and discuss available information from the scientific literature considering the possible relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection and cognitive impairment, including NeuroCOVID, frontal syndrome and cytokine storm. A systematic literature review was conducted using: Google Scholar, Elsevier and the PubMed database. When searching for materials, the following keywords were used: 'cognitive dysfunctions', 'SARS-CoV-2', 'COVID-19', 'Neuro-SARS2', 'NeuroCOVID', 'frontal syndrome', 'cytokine storm', 'Long COVID-19'. A total of 96 articles were included in the study. The analysis focused on the characteristics of each study's materials, methods, results and conclusions. SARS-CoV-2 infection may induce or influence existing cognitive disorders of various nature and severity. The influence of immunological factors related to the response against SARS-CoV-2 on the disturbance of cerebral perfusion, the functioning of nerve cells and the neuroprotective effect has been demonstrated. Particular importance is attached to the cytokine storm and the related difference between pro- and anti-inflammatory effects, oxidative stress, disturbances in the regulation of the hypothalamic-pituitary-adrenal axis and the stress response of the body. [ABSTRACT FROM AUTHOR]

NETosis is a type of neutrophil extinction that outcome in the liberation of extracellular chromatin and protein accumulation, which contains antiviral proteins, produced by an external pathogen. Neutrophils can show bipolar action in special circumstances. This event, along with other circumstances, involves COVID-19. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of COVID-19 by creating a pro-inflammatory and pre-coagulation state that leads to numerous organ losses. This form of host defense, which is promoted by neutrophils, is closely related to the known cytokine storm in severe COVID-19 patients. Hence, these two elements reveal possibly the treatment of the target for SARS-CoV-2 infections intense. [ABSTRACT FROM AUTHOR]

Therefore, dual inhibitors of PGD2 and TXA2 may reduce the risk of immunothrombosis and the development of cytokine and thrombotic storms in Covid-19. Taken together, ramatroban through inhibition of TXA2/PGD2-induced release of pro-inflammatory cytokine and development of immunothrombosis might be effective in damping the development of a cytokine storm in Covid-19 (Fig. Keywords: Ramatroban; Cytokine storm; Covid-19 EN Ramatroban Cytokine storm Covid-19 543 545 3 02/28/23 20230201 NES 230201 Dear editor, In severe Covid-19 with exaggeration of immune response and release of pro-inflammatory cytokines like interleukin (IL)-6, tumor necrosis factor- (TNF- ), IL-1 and chemokines, cytokine storm is developed leading to acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and multi-organ failure (MOF) (Sinha et al. [11]; Batiha et al. [2]). [Extracted from the article]

Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a dysregulated immunological response known as cytokine storm. Many scientists have demonstrated that SARS-CoV-2 impacts oxidative homeostasis and stimulates the production of reactive oxygen species (ROS). In addition, the virus inhibits glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (NRF2)—a major antioxidant which induces expression of protective proteins and prevents ROS damage. Furthermore, the virus stimulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes which play a significant role in inducing a cytokine storm. A variety of agents with antioxidant properties have shown beneficial effects in experimental and clinical studies of COVID-19. This review aims to present mechanisms of oxidative stress induced by SARS-CoV-2 and to discuss whether antioxidative drugs can counteract detrimental outcomes of a cytokine storm. [ABSTRACT FROM AUTHOR]

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than − 6. Then, (−)-gallocatechin gallate, (+)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 μM, 13.14 ± 2.081 μM and 5.158 ± 0.928 μM respectively by FRET assay. Molecular docking results also showed that (−)-gallocatechin gallate, (+)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of (−)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. (−)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, (−)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: The high mortality rate in severe cases of COVID-19 is mainly due to the strong upregulation of cytokines, called a cytokine storm. Hyperinflammation and multiple organ failure comprise the main clinical features of a cytokine storm. Nrf2 is a transcription factor which regulates the expression of genes involved in immune and inflammatory processes. Furthermore, Nrf2, as a master regulator, controls the activity of NF-κB which binds to the promoter of many pro-inflammatory genes inducible of various inflammatory factors. Inhibition of Nrf2 response was recently demonstrated in biopsies from patients with COVID-19, and Nrf2 agonists inhibited SARS-CoV-2 replication across cell lines in vitro. Glucosinolates and their hydrolysis products have excellent anti-inflammatory and antioxidant effects via the Nrf2 activation pathway, reduction in the NF-κB activation, and subsequent reduced cytokines levels. Conclusion: Accordingly, these compounds can be helpful in combating the cytokine storm associated with COVID-19. [ABSTRACT FROM AUTHOR]

In the beginning of the third year of the fight against COVID-19, the virus remains at least still one step ahead in the pandemic "war". The key reasons are evolving lineages and mutations, resulting in an increase of transmissibility and ability to evade immune system. However, from the immunologic point of view, the cytokine storm (CS) remains a poorly understood and difficult to combat culprit of the extended number of in-hospital admissions and deaths. It is not fully clear whether the cytokine release is a harmful result of suppression of the immune system or a positive reaction necessary to clear the virus. To develop methods of appropriate treatment and therefore decrease the mortality of the so-called COVID-19-CS, we need to look deeply inside its pathogenesis, which is the purpose of this review. [ABSTRACT FROM AUTHOR]

COVID-19 is a viral disease that commonly presents with mild symptoms with predominant respiratory system involvement. However, it can cause serious complications such as acute respiratory disease, multi-organ dysfunction, especially in patients with comorbidities. As it is a new disease, the full picture of the disease and its complications are not yet fully understood. Moreover, the patients at risk of complications are not well identified, and the data about the biphasic pattern of cytokine storm syndrome are limited. Here, we report the case of a 64-year-old male having diabetes mellitus, hypertension, ischemic heart disease with triple-vessel coronary artery disease tested positive for severe acute respiratory syndrome coronavirus 2, then complicated with acute respiratory distress syndrome and two waves of cytokine storm in 28 days. [ABSTRACT FROM AUTHOR]

COVID-19-infected patients require an intact immune system to suppress viral replication and prevent complications. However, the complications of SARS-CoV-2 infection that led to death were linked to the overproduction of proinflammatory cytokines known as cytokine storm syndrome. This article reported the various checkpoints targeted to manage the SARS-CoV-2-induced cytokine storm. The literature search was carried out using PubMed, Embase, MEDLINE, and China National Knowledge Infrastructure (CNKI) databases. Journal articles that discussed SARS-CoV-2 infection and cytokine storm were retrieved and appraised. Specific checkpoints identified in managing SARS-CoV-2 induced cytokine storm include a decrease in the level of Nod-Like Receptor 3 (NLRP3) inflammasome where drugs such as quercetin and anakinra were effective. Janus kinase-2 and signal transducer and activator of transcription-1 (JAK2/STAT1) signaling pathways were blocked by medicines such as tocilizumab, baricitinib, and quercetin. In addition, inhibition of interleukin (IL)-6 with dexamethasone, tocilizumab, and sarilumab effectively treats cytokine storm and significantly reduces mortality caused by COVID-19. Blockade of IL-1 with drugs such as canakinumab and anakinra, and inhibition of Bruton tyrosine kinase (BTK) with zanubrutinib and ibrutinib was also beneficial. These agents' overall mechanisms of action involve a decrease in circulating proinflammatory chemokines and cytokines and or blockade of their receptors. Consequently, the actions of these drugs significantly improve respiration and raise lymphocyte count and PaO2/FiO2 ratio. Targeting cytokine storms' pathogenesis genetic and molecular apparatus will substantially enhance lung function and reduce mortality due to the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease-2019 (COVID-19) imposed public health emergency and affected millions of people around the globe. As of January 2021, 100 million confirmed cases of COVID-19 along with more than 2 million deaths were reported worldwide. SARS-CoV-2 infection causes excessive production of pro-inflammatory cytokines thereby leading to the development of "Cytokine Storm Syndrome." This condition results in uncontrollable inflammation that further imposes multiple-organ-failure eventually leading to death. SARS-CoV-2 induces unrestrained innate immune response and impairs adaptive immune responses thereby causing tissue damage. Thus, understanding the foremost features and evolution of innate and adaptive immunity to SARS-CoV-2 is crucial in anticipating COVID-19 outcomes and in developing effective strategies to control the viral spread. In the present review, we exhaustively discuss the sequential key immunological events that occur during SARS-CoV-2 infection and are involved in the immunopathogenesis of COVID-19. In addition to this, we also highlight various therapeutic options already in use such as immunosuppressive drugs, plasma therapy and intravenous immunoglobulins along with various novel potent therapeutic options that should be considered in managing COVID-19 infection such as traditional medicines and probiotics. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has shaken the world and triggered drastic changes in our lifestyle to control it. Despite the non-typical efforts, COVID-19 still thrives and plagues humanity worldwide. The unparalleled degree of infection has been met with an exceptional degree of research to counteract it. Many drugs and therapeutic technologies have been repurposed and discovered, but no groundbreaking antiviral agent has been introduced yet to eradicate COVID-19 and restore normalcy. As lethality is directly correlated with the severity of disease, hospitalized severe cases are of the greatest importance to reduce, especially the cytokine storm phenomenon. This severe inflammatory phenomenon characterized by elevated levels of inflammatory mediators can be targeted to relieve symptoms and save the infected patients. One of the promising therapeutic strategies to combat COVID-19 is nucleic acid-based therapeutic approaches, including microRNAs (miRNAs). This work is an up-to-date review aimed to comprehensively discuss the current nucleic acid-based therapeutics against COVID-19 and their mechanisms of action, taking into consideration the emerging SARS-CoV-2 variants of concern, as well as providing potential future directions. miRNAs can be used to run interference with the expression of viral proteins, while endogenous miRNAs can be targeted as well, offering a versatile platform to control SARS-CoV-2 infection. By targeting these miRNAs, the COVID-19-induced cytokine storm can be suppressed. Therefore, nucleic acid-based therapeutics (miRNAs included) have a latent ability to break the COVID-19 infection in general and quell the cytokine storm in particular. [ABSTRACT FROM AUTHOR]

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the ongoing COVID-19 pandemic, and causes many health complications, including major lung diseases. Besides investigations into the virology of SARS-CoV-2, understanding the immunological routes underlying the clinical manifestations of COVID-19 is important for developing effective therapeutic interventions. The clearance of SARS-CoV-2-infected apoptotic cells by professional efferocytes, through a process termed as 'efferocytosis', is essential for maintaining tissue homeostasis, and reducing the chances of health complications caused by SARS-CoV-2 infection. In this review, we focus on the cellular events leading to engagement of the SARS-CoV-2 with type 2 alveolar cells, and how SARS-COV-2 infection impairs the macrophage anti-inflammatory programming. We also discuss accounts of impaired efferocytosis, and the "cytokine storm" which occur concomitantly with the SARS-CoV-2 infection. Finally, we propose how targeting impaired efferocytosis, due to the SARS-CoV-2 infection, may be a beneficial therapeutic strategy to combat COVID-19, and its complications. [Display omitted] • Efferocytosis, a physiological process essential for maintaining tissue homeostasis, is hampered by SARS-CoV-2 infection. • Engagement with SARS-CoV-2 impairs the efficiency of macrophages, which mediate the phagocytic process. • An imbalance in immune signalling also triggers a 'cytokine storm', which causes tissue inflammation and damage. • Major lung diseases and autoimmune disorders have emerged as common complications in COVID-19 patients. • Boosting efferocytosis, post SARS-CoV-2 infection, could be an effective strategy against COVID-19 and its complications. [ABSTRACT FROM AUTHOR]

In 2020, a deadly pandemic caused by the SARS-COV-2 virus spread worldwide and killed many people. In some viral infections, in addition to the pathogenic role of the virus, impaired immune function leads to inflammation and further damage in internal tissues. For example, coronavirus in some patients prevents the stimulation of the acquired immune system. Therefore, innate immunity is over-stimulated to compensate, followed by the overproduction of inflammatory cytokines and cytokine storm. Various underlying factors such as age, gender, blood pressure, diabetes, and obesity affect cytokine storm. It seems that cytokine storm is one of the leading causes of death among COVID-19 patients, and providing that this storm is detected and controlled in time, it can reduce the mortality of COVID-19 patients. This article aims to investigate the immune system response to COVID-19, various factors associated with cytokine storm, and its treatment. In the current situation, in parallel with the progress made in the field of vaccination, it is necessary to carefully examine the various dimensions of the immune system in response to the COVID-19 virus to seek a suitable treatment strategy to save the lives of patients in intensive care units. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 subtly disrupts the equations of immune responses in COVID-19 patients. • The virus activates infected macrophages and CD4+ T cells to induce cytokine storm. • Cytokine storm and direct interaction of viruses inhibit NK cell cytolytic effect. • Exhausted NK cell fails to lyse infected cells to avoid their unleashed cytokine release. • Adoptive transfer of cytolytic NK cell may reduce cytokine storm while decreasing viral load. The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research. [ABSTRACT FROM AUTHOR]

In the Wuhan province of China, almost two years ago, in December 2019, the novel Coronavirus 2019 has caused a severe involvement of the lower respiratory tract leading to an acute life-threatening respiratory syndrome, coronavirus disease-19 (COVID-19). Subsequently, coronavirus 2 (SARS-CoV-2) rapidly spread to the entire world causing a pandemic and affected every single person on earth either directly or indirectly with destroying all facets of social life and economy. Since the announcement of COVID-19 as a global pandemic, we have witnessed tremendous scientific work on all aspects of COVID-19 across the globe, which has never been witnessed before. The most remarkable achievement would be the introduction of vaccines, which provide protection from the severe infection and is the only premise for the control of disease. However, despite the tremendous work, the number of treatments either antiviral or immunomodulatory for infected patients are considerably limited, yet disease is causing substantial morbidity and mortality. COVID-19 follows heterogenous disease course among infected individuals, and dysregulated immune system is primarily responsible for the worse outcomes. Immune deficiency, being on corticosteroids for inflammatory diseases, delayed interferon response and advanced age adversely influence prognosis with impairing viral clearance. On the other hand, exuberant immune response with features of cytokine storm is the leading cause of death, which can be alleviated by use of either general immunosuppression with corticosteroids or selective neutralization of potent pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6. Herein, we summarized the potential effective immunomodulatory treatments emphasizing in which patient population it is the most suitable, which dose should be administered, and which is the most appropriate timepoint to administer the drug during the course of the disease. [ABSTRACT FROM AUTHOR]

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 represents usually a variety range of symptoms related to influenza-like syndrome and respiratory tract infections. Likewise, kidney involvement and acute kidney injury (AKI) were reported in many previous studies. Although a hypovolemic circulation would be the most common reason in patients with AKI, some strong proofs are suggesting a cytokine storm due to immune system exaggeration and inflammation-mediated tubular injury in COVID-19 infections. The inflammatory response in cytokine storm leads to the high release of cytokines mostly including TNFα, IL-1β, IL-6, INFγ, IL-2, IL-7, and endothelial mediators. The main culprits in the AKI and consequent organ failure are resident leukocytes in specific tissues, activated following the cytokine release, and systemic inflammatory response. AKI management and cytokine profile evaluation should be highly emphasized in patients with COVID-19 to prevent the progression of chronic kidney disease or permanent renal failure. Treatment options in COVID-19 regarding no specific drugs should be supportive and based on stabilizing the patients; however, combination therapy with different antiviral have shown promising outcomes. As a result, utilizing the anti-TNFα and anti-IL-1 agents should be noticed if indicated. Additionally, the hematopoietic stem cell transplantation is a curative approach. [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]

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) disease (COVID-19) is a novel threat that hampers life expectancy especially in obese individuals. Though this association is clinically relevant, the underlying mechanisms are not fully elucidated. SARS CoV2 enters host cells via the Angiotensin Converting Enzyme 2 receptor, that is also expressed in adipose tissue. Moreover, adipose tissue is also a source of many proinflammatory mediators and adipokines that might enhance the characteristic COVID-19 cytokine storm due to a chronic low-grade inflammatory preconditioning. Further obesity-dependent thoracic mechanical constraints may also incise negatively into the prognosis of obese subjects with COVID-19. This review summarizes the current body of knowledge on the obesity-dependent circumstances triggering an increased risk for COVID-19 severity, and their clinical relevance. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a novel coronavirus, is a member of the Coronoviridae family that has spread worldwide. Developing efficacious therapeutics for the treatment of SARS-CoV-2 is of high priority. Therefore, in this study, the chemical constituents obtained from Tinospora cordifolia are investigated for their in-silico interaction with protein targets crucial for SARSCoV-2 infection and cytokine storm. The five important targets chosen for SARSCoV-2 were the main protease (Mpro), Spike receptor binding domain (Spike-RBD), RNA-dependent RNA polymerase (RdRp or Nsp12), nonstructural protein 15 (Nsp15) of SARS-CoV-2 and the host angiotensin converting enzyme-2 (ACE-2) spike-RBD binding domain and cytokine receptors TNF- α (Tumor Necrosis Factor- α) and IL-6 (Interleukine-6). This was accomplished using Maestro 12.4 (Schrodinger Suite) to obtain docking scores. Also, the absorption, distribution, metabolism, elimination, and toxicity parameters (ADMET) were determined using Maestro QikProp modules. The results of computational study revealed that four constituents Cordifolioside-A, Palmatoside-E, Tinocordioside and Tinosporaside significantly antagonize the five targets of SARS-CoV-2 by binding in the binding pocket with docking score ranging from −9.664 to −6.488 kcal/mol and shows drug-like property and also effectively inhibit cytokine storm by antagonizing the TNF- α and IL-6 receptors. Promising drug-like properties, excellent docking scores, and binding pose against each target makes the screened compounds as possible lead candidate which can be further evaluated in future studies to assess their in vitro and in vivo efficacy against SARS-CoV-2. The structure of these compounds can be used further for optimization and design of drugs against COVID-19. In the present work, four terpenoids Cordifolioside-A, Palmatoside-E, Tinocordioside, and Tinosporaside obtained from Tinospora cordifolia were identified as potential inhibitors of five therapeutic targets of SAR-CoV-2: Mpro enzyme, SGp-RBD, ACE2, RdRp, NSP15, and two cytokine receptors TNF-α and IL-6 based on in silico docking and drug-like property analysis. Further in vitro and in vivo studies are needed to determine the efficacy of these compounds against the treatment of COVID-19 caused by SARS-CoV-2 and post COVID syndrome mediated through cytokine storm. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), a pandemic infection with profound effects on human society, has been emerged recently and rigorously challenged our ability to control viral infections. Although at the beginning of the COVID-19 outbreak, the epidemic seems controllable in Southern Iran, the disease presents a critical pattern as of May 2020. After a few months of COVID-19 emergence, in a twisted turn of events, the severity and mortality of COVID-19 increased dramatically. It has been proposed that the antibodies obtained from previous exposure to local circulating human coronaviruses or possibly SARS-CoV-2 might contribute to the development of more severe and lethal presentations of COVID-19 possibly by triggering antibody-dependent enhancement. The binding of virions complexed with antibodies to Fcγ receptors on the target cells initiates receptor-mediated signaling events leading to enhanced expression of inflammatory cytokines and suppression of intracellular antiviral responses at the transcriptomic level, followed by endocytosis of the virus and subsequent activation of immune cells. The activated immune cells might accumulate in the lung and promote cytokine storm and lymphopenia. Furthermore, the formation of immune complexes can promote complement activation and subsequent tissue damage. Although there are currently no clinical data to support this hypothesis, a better understanding of these immunopathologic phenomena and their relation to disease course and severity might give insight into the development of the most efficient prophylactic and therapeutic approaches. This review demonstrates the critical pattern of COVID-19 in Southern Iran and highlights the possible interplaying factors leading to this condition. [ABSTRACT FROM AUTHOR]

Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies. [ABSTRACT FROM AUTHOR]

A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). This global pandemic galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis, transmission, and clinical symptoms. Remarkably, the most common complication associated with this disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine storm with new medications is needed to hamper COVID-19 complications where the most prominent strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially those required for testing drug safety and thus may help in reducing the dissemination of this pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their plausible mechanism of action for possible management of severe COVID-19 cases. [ABSTRACT FROM AUTHOR]

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease 2019 (COVID-19) has reached its pandemic scale within a short period of its first case reported in Wuhan, China in December 2019, leading to a great economic crisis all over the world. As of today, there is no clinically approved antiviral drug available for the treatment of COVID-19. Tocilizumab, a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, clinically approved for the treatment of rheumatoid arthritis, is one such drug used to manage the COVID-19 symptoms. The current study reviews the effectiveness of Tocilizumab as a treatment option for COVID-19. Research findings on Tocilizumab are effective in COVID-19 patients with the risk of cytokine storm and further complications. Nevertheless, this review also recommends further investigation on the effectiveness of this drug with a large group of patients for more accuracy in results with COVID 19 patients. [ABSTRACT FROM AUTHOR]

The primary cause of mortality in patients of coronavirus disease 2019 (COVID-19) is the cytokine storm and not directly due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Therefore, it is being stressed by transfusion medicine specialists to use COVID-19 convalescent plasma (CCP) therapy early in the course of the disease, preferably within 72 h of diagnosis. The authors herein, propose a scoring system for the rapid assessment of the patients who have tested positive for SARS-CoV-2. Therefore, a systematic approach may be followed where the patients are categorised into two groups, namely, the low-risk group [LRG; score < 5] and the high-risk group [HRG; score ≥ 5] based on this scoring system. Those classified as an HRG should be administered CCP therapy within 72 h of a confirmed diagnosis of COVID-19 to neutralise the SARS-CoV-2 virus and prevent the occurrence of the cytokine storm. This in turn could help reduce the overall mortality in the recipients. [ABSTRACT FROM AUTHOR]

[Display omitted] The latest global pandemic corona virus disease − 2019 (COVID-19) caused by the virus SARS-CoV-2 is still a matter of worrying concern both for the scientific communities and health care organizations. COVID-19 disease is proved to be a highly contagious disease transmitted through respiratory droplets and even close contact with affected individuals. COVID-19 disease is also understood to exhibit diverse symptoms of ranging severities i.e., from mild fatigue to death. Affected individuals' susceptibility to induce immunologic dysregulation phenomena termed 'cytokine storm' seems to be playing the damaging role of escalating the disease manifestation from mild to severe. Cytokine storm in patients with severe symptoms is understood to be characterized by enhanced serum levels of many cytokines including interleukin-1β, interleukin-6, IP-10/CXCL10, TNF, interferon-γ, MIP-1α, MIP-1β and VEGF. Since cytokine production in general is the most important antiviral defense response, understanding the COVID-19 associated cytokine storm in particular and differentiating it from the regular cytokine production response becomes crucial in developing an effective therapeutic strategy. This review focuses on the potential targeting of COVID-19 associated cytokine storm and its challenges. [ABSTRACT FROM AUTHOR]

Coronavirus disease is caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) known as COVID-19. COVID-19 has caused the deaths of 6,541,936 people worldwide as of September 27th, 2022. SARS-CoV-2 severity is determined by a cytokine storm condition, in which the innate immune system creates an unregulated and excessive production of pro-inflammatory such IL-1, IL-6, NF Kappa B, and TNF alpha signaling molecules known as cytokines. The patient died due to respiratory organ failure and an acute complication because of the hyper-inflammation phenomenon. Green tea, soybean, and guava bioactive substances are well-known to act as anti-inflammation, and antioxidants become prospective COVID-19 illness candidates to overcome the cytokine storm. Our research aims to discover the bioactivity, bioavailability, and protein targets of green tea, soybean, and guava bioactive compounds as anti-inflammatory agents via the TNF inhibition pathway. The experiment uses in silico methods and harnesses the accessible datasets. Samples of 3D structure and SMILE identity of bioactive compounds were retrieved from the KNApSAck and Dr Duke databases. The QSAR analysis was done by WAY2DRUG web server, while the ADME prediction was performed using SWISSADME web server, following the Lipinsky rules of drugs. The target protein and protein-protein interaction were analyzed using STRING DB and Cytoscape software. Lastly, molecular docking was performed using Autodock 4.2 and visualization with BioVia Discovery Studio 2019. The identified study showed the potential of green tea, soybean, and guava's bioactive compounds have played an important role as anti-inflammation agents through TNF inhibitor pathway. [Display omitted] • Green tea and soybean's active compounds fulfill the requirement as drugs. • Guava's active compounds have slightly over requirements rotatable bonds. • Green tea, Soybean, and Guava have a high potential as anti-inflammation agent. [ABSTRACT FROM AUTHOR]

[Display omitted] Fatal "cytokine storms (CS)" observed in critically ill COVID-19 patients are consequences of dysregulated host immune system and over-exuberant inflammatory response. Acute respiratory distress syndrome (ARDS), multi-system organ failure, and eventual death are distinctive symptoms, attributed to higher morbidity and mortality rates among these patients. Consequent efforts to save critical COVID-19 patients via the usage of several novel therapeutic options are put in force. Strategically, drugs being used in such patients are dexamethasone, remdesivir, hydroxychloroquine, etc. along with the approved vaccines. Moreover, it is certain that activation of the resolution process is important for the prevention of chronic diseases. Until recently Inflammation resolution was considered a passive process, rather it's an active biochemical process that can be achieved by the use of specialized pro-resolving mediators (SPMs). These endogenous mediators are an array of atypical lipid metabolites that include Resolvins, lipoxins, maresins, protectins, considered as immunoresolvents, but their role in COVID-19 is ambiguous. Recent evidence from studies such as the randomized clinical trial, in which omega 3 fatty acid was used as supplement to resolve inflammation in COVID-19, suggests that direct supplementation of SPMs or the use of synthetic SPM mimetics (which are still being explored) could enhance the process of resolution by regulating the aberrant inflammatory process and can be useful in pain relief and tissue remodeling. Here we discussed the biosynthesis of SPMs, & their mechanistic pathways contributing to inflammation resolution along with sequence of events leading to CS in COVID-19, with a focus on therapeutic potential of SPMs. [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]