Search

The Influenza A virus (IAV) is a zoonotic pathogen that infects humans and various animal species. Infection with IAV can cause fever, anorexia, and dyspnea and is often accompanied by pneumonia characterized by an excessive release of cytokines (i.e., cytokine storm). Nanodrug delivery systems and nanoparticles are a novel approach to address IAV infections. Herein, UiO-66 nanoparticles (NPs) are synthesized using a high-temperature melting reaction. The in vitro and in vivo optimal concentrations of UiO-66 NPs for antiviral activity are 200 μg mL−1 and 60 mg kg−1, respectively. Transcriptome analysis revealed that UiO-66 NPs can activate the RIG-I-like receptor signaling pathway, thereby enhancing the downstream type I interferon antiviral effect. These NPs suppress inflammation-related pathways, including the FOXO, HIF, and AMPK signaling pathways. The inhibitory effect of UiO-66 NPs on the adsorption and entry of IAV into A549 cells is significant. This study presents novel findings that demonstrate the effective inhibition of IAV adsorption and entry into cells via UiO-66 NPs and highlights their ability to activate the cellular RIG-I-like receptor signaling pathway, thereby exerting an anti-IAV effect in vitro or in mice. These results provide valuable insights into the mechanism of action of UiO-66 NPs against IAV and substantial data for advancing innovative antiviral nanomedicine. [ABSTRACT FROM AUTHOR]

A wearable sensor capable of directly detecting cytokines in external secretions external to the human body is pivotal for gauging the intensity of the immune response and circumventing inflammatory storms, a significant clinical concern. The detection of low‐concentration cytokines is often hampered due to interference from impurities in secretions. Addressing this challenge, a wearable detection system is developed by integrating a Janus membrane with water auto‐collection/filtering capabilities, and aptamer‐modified graphene field‐effect transistor sensors, enabling the detection of low‐concentration cytokines in undiluted sweat samples. The Janus membrane can automatically filter external secretions and transport them to the sensor surface, effectively eliminating impurity interference and enhancing the sensor's detection capabilities. The device can sensitively detect cytokines (such as TNF‐α, a marker for inflammation and cancer) in undiluted sweat, with a detection range spanning 0.5 to 500 pM, and a detection limit reaching 0.31 pM. The ultra‐flexibility of the sensor is also verified, maintaining stable electrical properties even after enduring up to 50 extreme deformations. These findings indicate that the wearable detection system has the potential to realize low‐concentration cytokines monitoring in the sweat of inflammatory patients, to assist the healthcare system in controlling the body's immune status. [ABSTRACT FROM AUTHOR]

Background: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30–40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. Methods: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. Results: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA–approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. Conclusion: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm. [ABSTRACT FROM AUTHOR]

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]

Phytochemicals are compounds found in plants that possess a variety of bioactive properties, including antioxidant and immunomodulatory properties. Recent studies have highlighted the potential of phytochemicals in targeting specific signalling pathways involved in cytokine storm, a life-threatening clinical condition resulting from excessive immune cell activation and oversupply of proinflammatory cytokines. Several studies have documented the immunomodulatory effects of phytochemicals on immune function, including their ability to regulate essential cellular and molecular interactions of immune system cells. This makes them a promising alternative for cytokine storm management, especially when combined with existing chemotherapies. Furthermore, phytochemicals have been found to target multiple signalling pathways, including the TNF-α/NF-κB, IL-1/NF-κB, IFN-γ/JAK/STAT, and IL-6/JAK-STAT. These pathways play critical roles in the development and progression of cytokine storm, and targeting them with phytochemicals represents a promising strategy for controlling cytokine release and the subsequent inflammation. Studies have also investigated certain families of plant-related constituents and their potential immunomodulatory actions. In vivo and in vitro studies have reported the immunomodulatory effects of phytochemicals, which provide viable alternatives in the management of cytokine storm syndrome. The collective data from previous studies suggest that phytochemicals represent a potentially functional source of cytokine storm treatment and promote further exploration of these compounds as immunomodulatory agents for suppressing specific signalling cascade responses. Overall, the previous research findings support the use of phytochemicals as a complementary approach in managing cytokine storm and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Human coronaviruses can be divided based on their pathogenicity. The types with high pathogenicity including SARS-CoV, MERS-CoV, and the current novel SARS-CoV2. SARS COV2 has led to possibly the worst pandemic of this century in the form of Coronavirus disease 2019 (COVID-19). Initially recognized as a respiratory system disease, COVID-19 has been found to interact with functions of other organ systems like cardiovascular, GIT, CNS Peripheral nervous system, during the course of the disease and postcovid syndromic manifestations including Endocrinal and psychological. The acute manifestations primarily lung will be involved that leads to ARDS, in severe disease all the organs will be effected that may lead to multiorgan dysfunction (MODS), and death. AIM: Evaluation of various endocrinal manifestations secondary to endocrinal gland dysfunction, in COVID 19 peak of the pandemic causing morbidity and mortality. In this COVID 19 pandemic everywhere the mortality was very high, the researchers and all over the globe thought that this is not only viral invasion or host's immune mediated of it's not due to viral virulence and postulated the actual pathogenesis of the disease and its manifestations causing morbidity and mortality. Some patients with coronavirus disease 2019 (COVID-19) develop a life-threatening hyper-inflammatory state that is commonly referred to as cytokine storm. This is the prime cause of all the syndromes presenting in this SARS COV2. The mortality has been increasing and new biochemical parameters are increasing in moderate to severe disease. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

Severe course of COVID-19 is largely determined by hyperactivation of the immune system, or cytokine storm, in which immune cells (lymphocytes, monocytes, etc.) play a major role. Using low-voltage scanning electron microscopy, we studied the morphology of lymphocytes and monocytes during cytokine storm. Monocytes and lymphocytes were isolated by fluorescence sorting from the blood of healthy volunteers (n=6) and patients with COVID-19 (n=5) during cytokine storm (IL-6>23 ng/ml, smear positive for SARS-CoV-2). For each patient, 11-32 individual cells were analyzed at magnification of 18-32,000 times. Measurements showed that monocyte size was increased during cytokine storm (p=0.0001). [ABSTRACT FROM AUTHOR]

The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse. [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]

Introduction: COVID-19 induced cytokine storm is a well-documented phenomena that contributes significantly in the disease's evolution and prognosis. Therefore, therapies such as therapeutic plasma exchange, constitute a mainstay of therapeutic management especially for critically-ill patients. Methods: We conducted a monocentric retrospective cohort study in the Resuscitation Department of the Mohammed VI University Hospital of Oujda-Morocco, to evaluate the efficiency of therapeutic plasma exchange on critically-ill COVID-19 patients over a 6 months period. We divided our patients into two groups: patients who received TPE (Therapeutic Plasma Exchange) sessions (TPE group) and patients who only benefited from the standard protocol treatment (non TPE group). Results: Our study included a total of 165 patients, 34.5% of which benefited from TPE sessions. We observed an improvement of oxygenation parameters (SpO2 and PaO2/FiO2 ratio) and a progressive respiratory weaning, as well as a significant decrease of biomarkers indicative of inflammation (lymphocyte count, CRP (C Reactive Protein), IL-6, Ferritin) and coagulopathy (d-dimers, fibrinogen) in the TPE group after 5 consecutive TPE sessions. In comparison with the non-TPE group, The TPE-group patients had a shorter ICU (Intensive Care Unit) length of stay, required less frequently mechanical ventilation, and we more likely to be extubated. Furthermore, the TPE group had a lower mortality rate. Discussion: Multiple studies have reported the safety and efficiency of therapeutic plasma exchange in the COVID-19 induced cytokine storm. Given the urgent character of the pandemic at the time, each center followed its own protocol in implementing plasma exchange. Conclusion: Similar to the results reported in the literature, our study reports positive results after using TPE specifically in terms of respiratory weaning and an improvement of the cytokine storm biomarkers, and more importantly a lower mortality rate. [ABSTRACT FROM AUTHOR]

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction. [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]

The first cases of COVID-19 were identified in China in 2019, and the disease subsequently spread rapidly around the world, leading it to be declared a pandemic. The disease affects the lungs through the upper and lower respiratory tracts, and with the development of pneumonia, a clinical picture leading to respiratory failure referred to as cytokine storm occurs as a result of excessive cytokine production associated with an excessive inflammatory immune response. The increase in inflammatory markers is related to acute respiratory distress syndrome, disseminated intravascular coagulation and hypercoagulation. We present here an explanation of cytokine storm and the associated immune damage mechanisms. [ABSTRACT FROM AUTHOR]

Background: There is increasing recognition of extensive crosstalk between programmed cell death pathways (PCDPs), such as apoptosis, pyroptosis, and necroptosis, resulting in a highly redundant system responsive to a breadth of potential pathogens. However, because pyroptosis and necroptosis propagate inflammation, these redundancies also present challenges for therapeutic control of dysregulated hyperinflammation seen in cytokine storm (CS) generated organ dysfunction. Hypothesis: We hypothesize that the conversion of existing knowledge regarding apoptosis, pyroptosis, and necroptosis into a computational model can enhance our understanding of the crosstalk between PCDPs via simulation experiments of microbe interactions and experimental interventions. Materials and Methods: Literature regarding apoptosis, pyroptosis, and necroptosis was reviewed and transposed into an agent-based model, the programmed cell death agent-based model (PCDABM). Computational experiments were performed to simulate the activation of various PCDPs as seen by differing microbes, specifically: influenza A virus (IAV), enteropathic Escherichia coli (EPEC), and Salmonella enterica (SE). The potential protective value of PCDP crosstalk was evaluated by silencing either pyroptosis, necroptosis, or both. Computational experiments were also performed simulating the effect of potential therapies blocking tumor necrosis factor (TNF) and interleukin (IL)-1. Results: The PCDABM was implemented in the agent-based modeling toolkit NetLogo. Computational experiments of infection with IAV, EPEC, and SE reproduced cross-activation of PCDPs with effective microbial clearance. Simulations of anti-TNF and anti-IL-1 did not reduce the aggregated amount of inflammation-generated system damage, the surrogate for CS-generated tissue damage. Conclusions: Redundancies have evolved in host PCDPs to maintain protection against a wide range of pathogens. However, these redundancies also challenge attempts at dampening the pathogenic hyperinflammatory state of CS using therapeutic immunomodulation. Integrative simulation models such as the PCDABM can aid in identifying potentially targetable inflection points to mitigate CS while maintaining effective host defense. [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]

COVID-19 patients suffer from the detrimental effects of cytokine storm and not much success has been achieved to overcome this issue. We sought to test the ability of selenium to reduce the impact of two important cytokine storm players: IL-6 and TNF-α. The effects of four selenium compounds on the secretion of these cytokines from THP-1 macrophages were evaluated in vitro following an LPS challenge. Also, the potential impact of methylseleninic acid (MSeA) on Nrf2 and IκBα was determined after a short treatment of THP-1 macrophages. MSeA was found to be the most potent selenium form among the four selenium compounds tested that reduced the levels of IL-6 and TNF-α secreted by THP-1 macrophages. In addition, an increase in Nrf2 and decrease in pIκBα in human macrophages was observed following MSeA treatment. Our data indicate that COVID-19 patients might benefit from the addition of MSeA to the standard therapy due to its ability to suppress the key players in the cytokine storm. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 (coronavirus disease 2019) was first identified in China in December 2019 and is rapidly spreading worldwide as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this context have focused on pathogenesis primarily in the respiratory system. However, evidence shows that the central nervous system (CNS) may also be affected by COVID-19. Since COVID-19 is spreading, it is necessary to study its possible cognitive effects on COVID-19 patients and their recovery. Methods: The articles used in this study were searched by keywords, such as cytokine storm and COVID-19, COVID-19 and executive dysfunction, cognitive disorder, and COVID-19, central nervous system (CNS) and COVID-19, coronavirus, neuroinvasion in Science Direct, Scopus, PubMed, Embase, and Web of Science databases based on preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The study evaluates all observational studies published between December 2019 and April 2021 in peer-reviewed journals, including cross-sectional, cohort, case-control studies, case reports, and case series. The search result was 106 articles, of which 73 articles related to COVID-19, the stages of infection by this virus, its effect on the nervous system and neurological symptoms, the cytokine storm caused by this infection, and the possible cognitive consequences caused by this virus in patients, has been reviewed. Other articles were not checked due to their limited relevance to the topic under discussion. Results: Studies showed that neurons may be directly affected by severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and SARS-CoV-2. Furthermore, various studies indicated that systemic inflammation (so-called “cytokine storm”) is also responsible for brain damage induced by infection with SARS-CoV-1 and SARS-CoV-2. In such a way that these patients showed elevated levels of interleukin (IL-), 6, 8, and 10 and of tumor necrosis factor- alpha (TNF-α) in their blood. Conclusion: Various cognitive defects have been observed following an increased level of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, 8. Therefore, due to the increased level of these pro-inflammatory factors in the brains of these patients, cognitive deficits can be expected, which need further investigation. [ABSTRACT FROM AUTHOR]

A novel coronavirus, severe acute respiratory syndrome coronavirus-2, was isolated from patients' lower respiratory tracts in December 2019. As of May 19, 2021, there were over 33 million reported infections and almost 600,000 deaths in the United States. The infection, coronavirus disease-19 (COVID-19), can lead to cytokine storm, with elevations in interleukin-6 (IL-6), IL-10, tumor necrosis factor-α, nuclear factor-kappaB (NF-kappaB), and glutathione reductase. NF-kappaB activation is necessary for further transcription of other pro-inflammatory markers. Glutathione may play a role in modulation of NF-kappaB activation and elevated glutathione reductase may indicate glutathione depletion. Administration of N-acetylcysteine (NAC) may replenish spent glutathione and attenuate over-activation of NF-kappaB. This retrospective case series included 10 patients who were COVID-19 positive and received intravenous NAC in an attempt to attenuate the cytokine storm. Patients' outcomes were graded based on the World Health Organization symptom severity scale from 0, no evidence of infection, to 8, death. Overall, the median WHO Scale prior to NAC was 6.5, and increased by day seven, which indicated clinical worsening. This retrospective case series showed no benefit of NAC; however, further studies are needed to elucidate if differences in drug regimens would lead to positive results. [ABSTRACT FROM AUTHOR]

Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague–Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS. In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups. LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen. Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1β. [ABSTRACT FROM AUTHOR]

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF- α , IL-6, and IL-1 β in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF- α , MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK α / β , and I κ B α and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF- κ B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections. [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]

Cytokine storm, which is an overreaction of the immune system to external stimulation, is characterized by a rapid increase in cytokine levels and leucocyte counts due to a positive feedback loop, and results in tissue damage and organ dysfunction with a highly inflammatory state. By analyzing the pathogeny, histopathology, disease progression, and clinical manifestation of diseases related to cytokine storm, this article summarizes key information from traditional Chinese medicine for syndrome differentiation. The etiologies of cytokine storm include external causes and causes that are neither internal nor external, and pathologies such as toxin, phlegm, blood stasis, and deficiency are also observed during cytokine storm. The spectrum of diseases covers warm-heat and damp-heat diseases, which could be differentiated using Weifen-Qifen-Yingfen-Xuefen theory; in addition, the fight between vital qi and pathogenic qi can be divided into syndromes with good prognosis and syndromes with unfavorable prognosis. The most commonly injured organs are the lung, heart, spleen, and stomach. However, during the treatment of diseases related to cytokine storm, attention should be paid to the above information to estimate the risk of a cytokine storm occurring, and to adopt appropriate treatment method to prevent its occurrence and improve prognosis. [ABSTRACT FROM AUTHOR]

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

In the current mpox outbreak, infections are usually self-limited. We describe 3 patients with uncontrolled HIV and mpox infections lasting months, causing debilitating lesions, complications, and death, despite initiating anti-mpox and antiretroviral therapy. Delayed treatment of mpox with antiviral agents may contribute to poor outcomes in severely immunocompromised patients. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease (COVID-19) has spread worldwide, and the pathogenic mechanism is still under investigation. Preliminary reports suggest a link between ABO blood groups and susceptibility to severe COVID-19. Aim: The aim of this study was to confirm the link between ABO blood type, the risk of coronavirus infection, and the severity of COVID-19 disease. Setting and Design: This was a retrospective cohort study. Materials and Methods: The study was carried out at tertiary care rural hospital in Central India. The patients admitted to the COVID unit over 6 months were enrolled in the study. The data further statistically analyzed the outcome of COVID-19 disease and its relation with the patient's blood group and serum ferritin levels. Results: The data analysis observed no significant impact of blood group on the outcome of COVID-19 in terms of death and cured cases. The mortality rate was 27.2% in the AB blood group, with the highest reported serum ferritin levels (1007.78 ± 1301.25). Compared to other blood groups, A (8.1%), followed by O (13.5%), with the lowest mortality rate (P = 0.31). Alanine transferase and aspartate transferase were maximally seen in patients having blood group AB +, and lower values were observed in blood group A. Conclusions: Blood groups A and O were considered COVID-19 protective in mortality following the cytokine storm. AB blood group had high serum ferritin levels, so it can be a potential tool to predict mortality and may be considered the culprit for the triggering "cytokine storm.". [ABSTRACT FROM AUTHOR]

Background: Interleukin‐1 alpha (IL‐1α) is a pro‐inflammatory cytokine that can activate immune effector cells and trigger anti‐tumor immune responses. However, dose‐limiting toxicities including cytokine storm and hypotension has limited its use in the clinic as a cancer therapy. We propose that polymeric microparticle (MP)‐based delivery of IL‐1α will suppress the acute pro‐inflammatory side effects by allowing for slow and controlled release of IL‐1α systemically, while simultaneously triggering an anti‐tumor immune response. Methods: Polyanhydride copolymers composed of 1,6‐bis‐(p‐carboxyphenoxy)‐hexane:sebacic 20:80 (CPH:SA 20:80) was utilized to fabricate MPs. Recombinant IL‐1α (rIL‐1α) was encapsulated into CPH:SA 20:80 MPs (IL‐1α‐MPs) and the MPs were characterized by size, charge, loading efficiency, and in‐vitro release and activity of IL‐1α. IL‐1α‐MPs were injected intraperitonially into head and neck squamous cell carcinoma (HNSCC)‐bearing C57Bl/6 mice and monitored for changes in weight, tumor growth, circulating cytokines/chemokines, hepatic and kidney enzymes, blood pressure, heart rate, and tumor‐infiltrating immune cells. Results: CPH:SA IL‐1α‐MPs demonstrated sustained release kinetics of IL‐1α (100% protein released over 8–10 days) accompanied by minimal weight loss and systemic inflammation compared to rIL‐1α‐treated mice. Blood pressure measured by radiotelemetry in conscious mice demonstrates that rIL‐1α‐induced hypotension was prevented in IL‐1α‐MP‐treated mice. Liver and kidney enzymes were within normal range for all control and cytokine‐treated mice. Both rIL‐1α and IL‐1α‐MP‐treated mice showed similar delays in tumor growth and similar increases in tumor‐infiltrating CD3+ T cells, macrophages, and dendritic cells. Conclusions: CPH:SA‐based IL‐1α‐MPs generated a slow and sustained systemic release of IL‐1α resulting in reduced weight loss, systemic inflammation, and hypotension accompanied by an adequate anti‐tumor immune response in HNSCC‐tumor bearing mice. Therefore, MPs based on CPH:SA formulations may be promising as delivery vehicles for IL‐1α to achieve safe, effective, and durable antitumor responses for HNSCC patients. [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]

Idiopathic multicentric Castleman disease (iMCD) is an infrequent and life-threatening disorder characterized by systemic inflammatory symptoms, generalized lymphadenopathy, polyclonal lymphocyte proliferation and organ dysfunction caused by a hyperinflammatory state. It accounts for one-third to one-half of all multicentric Castleman disease (MCD) cases. iMCD is often associated with autoimmune manifestations that may precede the iMCD diagnosis, be identified at the same time or follow it. In addition, iMCD may also coincide with a number of autoimmune diseases (such as psoriasis or myasthenia gravis) or autoinflammatory diseases (such as familial Mediterranean fever). Moreover, diverse inflammatory disorders, such as rheumatoid arthritis, systemic lupus erythematosus, adult-onset Still disease, systemic juvenile idiopathic arthritis, immunoglobulin (IgG4) related disease, or the recently described VEXAS syndrome, can present clinical features or lymphadenopathy with histopathological 'Castleman-like' findings compatible with those of iMCD. Given the iMCD clinical heterogeneity and the overlap with other autoimmune or autoinflammatory disorders, iMCD diagnosis can be challenging. In this review, we explore the overlap between iMCD and inflammatory diseases and provide practical guidance on iMCD diagnosis in order to avoid misdiagnosis and confusion with other autoimmune or autoinflammatory conditions. [ABSTRACT FROM AUTHOR]

Background: Tocilizumab is an interleukin-6 receptor antagonist hypothesized to blunt the uncontrolled immune response, cytokine release syndrome, in severe COVID-19 and prevent attributable morbidity and mortality. Objective: The objective of this study was to assess the impact of tocilizumab on clinical outcomes in COVID-19-associated cytokine release syndrome. Methods: Single-center, retrospective cohort study assessing sixty-nine adult patients receiving tocilizumab for suspected COVID-19 cytokine release syndrome. The primary outcome was change in WHO clinical status scale on day seven post-dose analyzed using the Wilcoxon signed rank test. Secondary outcomes assessed impact of timing of administration on clinical outcome. Safety analyses included development of neutropenia, thrombocytopenia, transaminitis, and sepsis within 7 days post-dose. Statistical analyses were conducted using Microsoft Excel. Results: No aggregate clinical change was found between day 0 and day 7. Eleven patients improved, twenty-seven worsened, and thirty-one showed no change. Clinical outcomes were weakly correlated with time from symptom onset (rs = 0.21; p = 0.08) or hospital admission (rs = -0.08; p = 0.49) to dose. In-hospital mortality was 63%. Sepsis was diagnosed in 21 patients, five of which were post-dose. Transaminitis, neutropenia, and thrombocytopenia occurred in seven, one, and six patients, respectively. Conclusion: Tocilizumab did not appear to influence clinical outcomes in our study population, irrespective of timing of administration. Adverse events were not considered drug-related. [ABSTRACT FROM AUTHOR]

Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach. [ABSTRACT FROM AUTHOR]

Background: In COVID-19, severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm. In this study, we aimed to evaluate the high-dose intravenous anakinra treatment response and outcome in patients with severe and critically ill COVID-19 compared to standard of care. Methods: This retrospective observational study was carried out at a tertiary referral center. The study population consisted of two groups as follows: the patients receiving high-dose intravenous anakinra (anakinra group) between 01.09.2021 and 01.02.2022 and the patients treated with standard of care (SoC, control group) as historical control group who were hospitalized between 01.07.2021 and 01.09.2021. Results: After the propensity score 1:1 matching, 79 patients in anakinra and 79 patients in SoC matched and were included into the analysis. Mean ± SD patient age was 67.4 ± 16.7 and 67.1 ± 16.3 years in anakinra and SoC groups, respectively (p = 0.9). Male gender was 38 (48.7%) in anakinra and 36 (46.2%) in SoC (p = 0.8). Overall, ICU admission was in 14.1% (n = 11) and 30.8% (n = 24) (p = 0.013; OR 6.2), intubation in 12.8% (n = 10) and 16.7% (n = 13) patients (p = 0.5), and 14.1% (n = 11) and 32.1% (n = 25) patients died in anakinra and control groups, respectively (p = 0.008; OR 7.1). Conclusion: In our study, mortality was lower in patients receiving anakinra compared to SoC. Intravenous high-dose anakinra is safe and effective treatment in patients with severe and critical COVID-19. [ABSTRACT FROM AUTHOR]

Liver injury occurs frequently as a consequence of SARS-CoV-2 infection. Direct infection of the liver leads to hepatic impairment with elevated transaminases. In addition, severe COVID-19 is characterized by cytokine release syndrome, which may initiate or exacerbate liver injury. In patients with cirrhosis, SARS-CoV-2 infection is associated with acute-on-chronic liver failure. The Middle East and North Africa (MENA) region is one of the world's regions characterized by a high prevalence of chronic liver diseases. Both parenchymal and vascular types of injury contribute to liver failure in COVID-19, with a myriad of pro-inflammatory cytokines playing a major role in perpetuating liver injury. Additionally, hypoxia and coagulopathy complicate such a condition. This review discusses the risk factors, and the underlying causes of impaired liver functions in COVID-19, with a focus on key players in the pathogenesis of liver injury. It also highlights the histopathological changes encountered in postmortem liver tissues as well as potential predictors and prognostic factors of such injury, in addition to the management strategies to ameliorate liver damage. [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]

A cytokine storm (CS) is an out-of-control inflammatory response closely associated with the progression of diseases, such as multiple organ failure (MOF), severe sepsis, and severe or critical COVID-19. However, there is currently a lack of reliable diagnostic markers to distinguish CS from normal inflammatory responses. Tumor necrosis factor-α (TNF-α) includes transmembrane TNF-α (tmTNF-α) and secreted TNF-α (sTNF-α). The MOF mouse model in this study showed that the tmTNF-α expression changes in the neutrophils differed from the serum TNF-α and serum IL-18, INF-γ, IL-4, and IL-6. Furthermore, tmTNF-α, instead of serum TNF-α, IL-18, INF-γ, IL-4, and IL-6, reflected liver and kidney tissue damage and increased with the aggravation of these injuries. Analysis of the ROC results showed that tmTNF-α effectively distinguished between inflammatory responses and CS and efficiently differentiated between surviving and dead mice. It also significantly improved the diagnostic value of the traditional CRP marker for CS. These results indicated that the tmTNF-α expressed in the neutrophils could be used to diagnose CS in MOF mice, providing an experimental basis to further develop tmTNF-α for diagnosing CS 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]

Objective: Cytokine storm syndrome is a fatal condition related to infectious and autoimmune diseases. Here, we aim to investigate the regulatory mechanisms of Blimp-1 on multiple cytokine production. Methods: The Blimp1 shRNA was transfected into RAW264.7 macrophages, followed by Toll-like receptor (TLR) ligand stimulation. The mRNA and protein levels of cytokines were detected by real-time PCR and flow cytometric bead array. The nuclear translocation of AP-1 and NF-κB p65 was measured by immunofluorescence staining. The transcriptional activity was detected by luciferase reporter assay with 5 × NF-κB reporter or with IL6 promoter reporter. Results: Blimp-1 significantly inhibited the expression and secretion of IL-1β, IL-6, and IL-18 in macrophages during stimulation with a variety of TLR ligands. The immunofluorescence staining results showed that Blimp-1 strictly controlled the nuclear translocation of NF-κB p65 in LPS-challenged macrophages. Furthermore, Blimp-1 directly inhibited the transcriptional activity of NF-κB and the transcription of IL6 gene. Conclusion: Blimp-1 represses the production of multiple pro-inflammatory cytokines by directly binding the genomic region and restricting the nuclear translocation and transcriptional activity of NF-κB. This finding may provide potential therapeutic strategies for the cytokine storm-related diseases. [ABSTRACT FROM AUTHOR]

Hyper-inflammation, cytokine storm, and recruitment of immune cells lead to uncontrollable endothelial cell damage in patients with coronavirus disease 2019 (COVID-19). Sphingosine 1-phosphate (S1P) signaling is needed for endothelial integrity and its de-creased serum level is a predictor of clinical severity in COVID-19. In this clinical trial, the effect of Fingolimod, an agonist of S1P, was evaluated on patients with COVID-19. Forty patients with moderate to severe COVID-19 were enrolled and divided into two groups including (1) the control group (n =21) receiving the national standard regimen for COVID-19 patients and (2) the intervention group (n =19) that prescribed daily Fingolimod (0.5 mg) for 3days besides receiving the standard national regimen for COVID-19. The hospitalization period, re-admission rate, intensive care unit (ICU) administration, need for mechanical ventilation, and mortality rate were assessed as primary outcomes in both groups. The results showed that re-admission was significantly decreased in COVID-19 patients who received Fingolimod compared to the controls (p = .04). In addition, the hemoglobin levels of the COVID-19 patients in the intervention group were increased compared to the controls (p = .018). However, no significant differences were found regarding the intubation or mortality rate between the groups (p > .05). Fingolimod could significantly reduce the re-admission rate after hospitalization with COVID-19. Fingolimod may not enhance patients' outcomes with moderate COVID-19. It is necessary to examine these findings in a larger cohort of patients with severe to critical COVID-19. [ABSTRACT FROM AUTHOR]

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3–4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions. [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]

The massive release of pro-inflammatory cytokines is a crucial step in triggering the inflammatory cascade in sepsis. Exploring the key molecules regulating the expression and release of multiple cytokines has important value for revealing the mechanism of the cytokine storm in sepsis. This study aimed to investigate the role of multifunctional nuclear protein non-POU domain containing octamer-binding protein (NONO) in the sepsis cytokine storm and to elucidate the underlying mechanism. We found that NONO expression in tissues and cells of sepsis mice was significantly upregulated. Downregulation of NONO expression inhibited the mRNA expression of multiple cytokines, including IL-6, IL-1β, MCP-1, MIP-1α, and MIP-1β in inflammatory cells from mice and human leukemic monocyte-THP1 cells challenged with lipopolysaccharide (LPS), and significantly decreased the level of these cytokines and TNF-α in the supernatant of THP1 cells challenged by LPS. Nono knockout also reduced the levels of TNF-α, IL-6, MIP-1α, and MIP-1β in serum, alleviated hepatocyte edema, and improved the survival rate of sepsis mice. Reduced NONO expression decreased the phospho-ERK1/2 level in inflammatory cells from sepsis mice or THP1 cells challenged by LPS. Phospho-ERK1/2 inhibitor decreased the mRNA expression and concentration of cytokines in the culture supernatant of LPS-induced THP1 cells, similar to the effect of NONO knockdown. After LPS challenge, the levels of phospho-ERK1/2 and NONO were increased, with obvious colocalization in the nucleus and vesicular-like organelles in macrophages. NONO knockdown decreased nuclear translocation of phospho-ERK1/2 in LPS-challenged THP1 cells. These results suggest that NONO is a potentially critical molecule involved in multiple cytokine production in sepsis. Upregulated NONO in sepsis may promote the expression and release of multiple cytokines to participate in a sepsis cytokine storm by promoting ERK1/2 phosphorylation. • NONO expression was upregulated in sepsis mice. • Nono knockout inhibited the expression and release of proinflammatory cytokines, and reduced the mortality of sepsis mice. • NONO knockdown inhibited the expression and release of proinflammatory cytokines in lipopolysaccharide-induced THP1 cells. • Reduced NONO expression inhibited the phosphorylation of ERK1/2 in mice and THP1 cells challenged by lipopolysaccharide. • NONO and phospho-ERK1/2 colocalized in macrophages challenged by lipopolysaccharide. [ABSTRACT FROM AUTHOR]

Cytokine storm is a phenomenon whereby the overreaction of the human immune system leads to the release of inflammatory cytokines, which can lead to multiple organ dysfunction syndrome. At present, the existing drugs for the treatment of cytokine storm have limited efficacy and severe adverse effects. Here, we report a lymphatic targeting self-microemulsifying drug delivery system containing baicalein to effectively inhibit cytokine storm. Baicalein self-microemulsion with phospholipid complex as an intermediate carrier (BAPC-SME) prepared in this study could be spontaneously emulsified to form 12-nm oil-in-water nanoemulsion after administration. And then BAPC-SME underwent uptake by enterocyte through endocytosis mediated by lipid valve and clathrin, and had obvious characteristics of mesenteric lymph node targeting distribution. Oral administration of BAPC-SME could significantly inhibit the increase in plasma levels of 14 cytokines: TNF-α, IL-6, IFN-α, MCP-1, IL-17A, IL-27, IL-1α, GM-CSF, MIG, IFN-β, IL-12, MIP-3α, IL-23, and RANTES in mice experiencing systemic cytokine storm. BAPC-SME could also significantly improve the pathological injury and inflammatory cell infiltration of lung tissue in mice experiencing local cytokine storm. This study does not only provide a new lymphatic targeted drug delivery strategy for the treatment of cytokine storm but also has great practical significance for the clinical development of baicalein self-microemulsion therapies for cytokine storm. [ABSTRACT FROM AUTHOR]

Dominant missense mutations in RanBP2/Nup358 cause Acute Necrotizing Encephalopathy (ANE), a pediatric disease where seemingly healthy individuals develop a cytokine storm that is restricted to the central nervous system in response to viral infection. Untreated, this condition leads to seizures, coma, long-term neurological damage and a high rate of mortality. The exact mechanism by which RanBP2 mutations contribute to the development of ANE remains elusive. In November 2021, a number of clinicians and basic scientists presented their work on this disease and on the interactions between RanBP2/Nup358, viral infections, the innate immune response and other cellular processes. [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]

Coronavirus SARS-CoV-2 has represented, and still represents, a real challenge from a clinical, diagnostic and therapeutic point of view. During acute infection, the increased levels of pro-inflammatory cytokines, which are involved in the pathology of disease and the development of SARS-CoV-2-induced acute respiratory disease syndrome, the life-threatening form of this infection, are correlated with patient survival and disease severity. IL-33, a key cytokine involved in both innate and adaptive immune responses in mucosal organs, can increase airway inflammation, mucus secretion and Th2 cytokine synthesis in the lungs, following respiratory infections. Similar to cases of exposure to known respiratory virus infections, exposure to SARS-CoV-2 induces the expression of IL-33, correlating with T-cell activation and lung disease severity. In this work, we analyse current evidence regarding the immunological role of IL-33 in patients affected by COVID-19, to evaluate not only the clinical impact correlated to its production but also to identify possible future immunological therapies that can block the most expressed inflammatory molecules, preventing worsening of the disease and saving patient lives. [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]