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As the limits of fetal viability have increased over the past 30 years, there has been a growing body of evidence supporting the idea that chronic disease should be taken into greater consideration in addition to survival after preterm birth. Accumulating evidence also suggests there is early onset of biologic aging after preterm birth. Similarly, chronic kidney disease (CKD) is also associated with a phenotype of advanced biologic age which exceeds chronologic age. Yet, significant knowledge gaps remain regarding the link between premature biologic age after preterm birth and kidney disease. This review summarizes the four broad pillars of aging, the evidence of premature aging following preterm birth, and in the setting of CKD. The aim is to provide additional plausible biologic mechanisms to explore the link between preterm birth and CKD. There is a need for more research to further elucidate the biologic mechanisms of the premature aging paradigm and kidney disease after preterm birth. Given the emerging research on therapies for premature aging, this paradigm could create pathways for prevention of advanced CKD. [ABSTRACT FROM AUTHOR]

Background We examined effects of single-nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. Results Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P =.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P =.052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P =.030). Conclusions The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) infection can lead to severe outcomes through a virus-induced cytokine storm, resulting in vascular leakage and inflammation. An effective treatment strategy should target both virus replication and cytokine storm. This study identified Kaempferia galanga L. (KG) extract as exhibiting anti-DENV activity. The major bioactive compound, ethyl-p-methoxycinnamate (EPMC), significantly reduced DENV-2 infection, virion production, and viral protein synthesis in HepG2 and A549 cells, with half-maximal effective concentration (EC50) values of 22.58 µM and 6.17 µM, and impressive selectivity indexes (SIs) of 32.40 and 173.44, respectively. EPMC demonstrated efficacy against all four DENV serotypes, targeting the replication phase of the virus life cycle. Importantly, EPMC reduced DENV-2-induced cytokines (IL-6 and TNF-α) and chemokines (RANTES and IP-10), as confirmed by immunofluorescence and immunoblot analyses, indicating inhibition of NF-κB activation. EPMC's role in preventing excessive inflammatory responses suggests it as a potential candidate for dengue treatment. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness for EPMC were predicted using SwissADME and ProTox II servers, showing good drug-like properties without toxicity. These findings highlight KG extract and EPMC as promising candidates for future anti-dengue therapeutics, offering a dual-action approach by inhibiting virus replication and mitigating inflammatory reactions. [ABSTRACT FROM AUTHOR]

COVID-19 is a significant worldwide health concern. The exaggerated immune response known as the "cytokine storm" is a key factor in this illness, and there are potential ways to address it. Janus kinase (JAK) inhibitors are a type of medication that might reduce inflammation and improve the body's production of antibodies. Pharmacokinetic profiles, toxicity characteristics, biological activities prediction, and molecular docking simulation will be conducted to discover, assess, and investigate the molecular interactions of Christinin compounds, including Christinin-A, Christinin-B, Christinin-C, and Christinin-D derived from Ziziphus spina-christi leaves as Janus kinase (JAK) inhibitors using bioinformatics approaches. Based on the molecular docking simulation, it can be concluded that the Christinin compound has a molecular interaction with Janus Kinase (JAK). However, Christinin-A and Christinin-C compounds have better affinity than Christinin-B and Christinin-D compounds, with binding free energy values of -7.59 kcal/mol and -5.37 kcal/mol, respectively. Therefore, these two compounds can be used as candidates for Janus Kinase (JAK) inhibitors in preventing hyperinflammation in the COVID-19 infectious disease. [ABSTRACT FROM AUTHOR]

In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1β and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through β-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, to some extent, a process of exclusion. AOSD has life-threating complications ranging from asymptomatic to severe, such as macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with cytokine storm production and monocyte/macrophage overactivation and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. For the treatment of MAS-HLH, the Histiocyte Society currently suggests high-dose corticosteroids, with the possible addition of cyclosporine A, anti-interleukin (IL)-1, or IL-6 biological drugs; the inclusion of etoposide is recommended for the most severe conditions. In all cases, a multidisciplinary collaboration involving the resources and expertise of several specialists (e.g., rheumatologist, infectiologist, critical care medicine specialist) is advised. Herein, we provide a detailed description of the clinical case of a previously healthy young woman in which MAS developed as a dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge; the condition was finally resolved by applying the HLH-94 protocol (i.e., etoposide in combination with dexamethasone). [ABSTRACT FROM AUTHOR]

COVID-19 emerged in December 2019 in Wuhan, China, spread worldwide rapidly, and caused millions of deaths in a short time. Many preclinical and clinical studies were performed to discover the most efficient therapy to reduce the mortality of COVID-19 patients. Among various approaches for preventing and treating COVID-19, mesenchymal stem cell (MSC) therapy can be regarded as a novel and efficient treatment for managing COVID-19 patients. In this review, we explain the pathogenesis of COVID-19 infection in humans and discuss the role of MSCs in suppressing the inflammation and cytokine storm produced by COVID-19. Then, we reviewed the clinical trial and systematic review studies that investigated the safety and efficacy of MSC therapy in the treatment of COVID-19 infection. [ABSTRACT FROM AUTHOR]

• Infection is very common in alcoholic hepatitis. • Both infection and alcoholic hepatitis are causes of SIRS. • IL-6 may be able to differentiate when infection is present. Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p <0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon‐gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000–1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections. [ABSTRACT FROM AUTHOR]

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and greater risks of other complications, including malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol(SH)-linked alkylation for the metabolic (SLAM) sequencing and Cleavage Under Target & Release Using Nuclease analysis (CUT&RUN), we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNA polymerase II with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitors, OTX015 and MZ1, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals. Author summary: Combined and continuous cytokine stimulation triggers transcription reprogramming and is often used for specific tissue development. Continuous vIL-6 exposure occurs in KSHV-infected patients and leads to inflammatory cytokine storm with high mortality. However, possible epigenetic reprogramming by the vIL-6 and its association with pathogenesis remain unclear. Here, we demonstrate the establishment of a new chromatin landscape mediated by BRD4 through prolonged vIL-6 exposure, contributing to more robust and rapid transcription and increased cytokine production. Inhibition of BRD4 suppressed this inflammatory response. Our results indicate that targeting the epigenetic effect of viral cytokines may lead to novel therapies for KSHV-induced inflammatory cytokine storms. [ABSTRACT FROM AUTHOR]

Depression is among the psychiatric sequelae of COVID-19, affecting more than 20% of the convalescents. Its underlying pathophysiology remains unclear. Interleukin 6 (IL-6), a pro-inflammatory cytokine, plays a critical role in the COVID-19-associated cytokine storm, has been implicated in depressive disorders, and may thus be involved in post-COVID-19 depression. PubMed, Scopus, Embase, and Web of Science were systematically searched for relevant studies assessing peripheral IL-6 levels in convalescents who developed depression after COVID-19 vs. convalescents who did not. Five studies were included in our systematic review, and four entered the meta-analysis. The meta-analysis revealed that post-COVID people with de novo depression did not have statistically significant differences in IL-6 levels compared to those without depression (standardised mean difference (SMD) = 0.09, 95% confidence interval (CI) = −0.35, 0.54, p-value = 0.68). Although convalescents with depression did not have significantly higher IL-6 levels than convalescents without depression, the results should be interpreted considering the limited sample size and the low power of the included studies. [ABSTRACT FROM AUTHOR]

Background: COVID-19 pandemic has caused more than 6 million deaths worldwide. Co-morbid conditions such as Type 2 Diabetes (T2D) have increased mortality in COVID-19. With limited translatability of in vitro and small animal models to human disease, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. Methods: T2D or non-diabetic patient-derived macrophages and human liver sinusoidal endothelial cells were seeded, along with normal hepatocytes and stellate cells in the liver-on-a-chip (LAMPS – liver acinus micro physiological system), perfused with media mimicking non-diabetic fasting or T2D (high levels of glucose, fatty acids, insulin, glucagon) states. The macrophages and endothelial cells were transduced to overexpress the SARS-CoV2-S (spike) protein with appropriate controls before their incorporation into LAMPS. Cytokine concentrations in the efflux served as a read-out of the effects of S-protein expression in the different experimental conditions (non-diabetic-LAMPS, T2D-LAMPS), including incubation with tocilizumab, an FDA-approved drug for severe COVID-19. Findings: S-protein expression in the non-diabetic LAMPS led to increased cytokines, but in the T2D-LAMPS, this was significantly amplified both in the number and magnitude of key pro-inflammatory cytokines (IL6, CCL3, IL1β, IL2, TNFα, etc.) involved in cytokine storm syndrome (CSS), mimicking severe COVID-19 infection in T2D patients. Compared to vehicle control, tocilizumab (IL6-receptor antagonist) decreased the pro-inflammatory cytokine secretion in T2D-COVID-19-LAMPS but not in non-diabetic-COVID-19-LAMPS. Interpretation: macrophages and endothelial cells play a synergistic role in the pathophysiology of the hyper-inflammatory response seen with COVID-19 and T2D. The effect of Tocilizumab was consistent with large clinical trials that demonstrated Tocilizumab's efficacy only in critically ill patients with severe disease, providing confirmatory evidence that the T2D-COVID-19-LAMPS is a robust platform to model human in vivo pathophysiology of COVID-19 in T2D and for screening potential therapeutics. [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]

First reports of the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the disease caused by the virus--coronavirus disease 2019 (COVID-19), were announced in late December 2019. Ever since, the disease has taken more than 6 million lives worldwide. COVID-19 is considered as dominantly respiratory and vascular disease which pathogenesis could be explained by hyperactivation of the immune response. Innate immunity receptors are responsible for the first contact with the virus and subsequent activation of transcription factors leading to the production of the high amounts of interferons (IFNs) and proinflammatory cytokines (IL-1ß, IL-6, TNF, etc.). Such an inflammatory response limits viral replications. However, SARS-CoV-2 have developed several ways to avoid immune protection by the host. Dysregulated secretion of these cytokines may lead to cytokine storm and PANoptosis, a life-threatening condition. This review article aims to describe the main characteristics of the innate immune response during the SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Inflammation is an important immune response to pathogen invasion, but excessive inflammation leads to tissue injury and even cytokine storm. Therefore, proper response is needed depending on the intensity of the infection. Ras guanine nucleotide releasing protein 3 (RasGRP3) is a regulator of the TLR-mediated response. In low-intensity inflammation, it negatively regulates production of pro-inflammatory cytokines, especially IL-6. Citri Reticulatae Pericarpium, the peel of Citrus reticulata Blanco, is a major medicinal herb in Korean medicine. The present study aims to investigate whether the Citri Reticulatae Pericarpium extract (CRE) has immunomodulatory activity using the Raw264.7 macrophage. Also, we investigated the effect of CRE on RasGRP3 expression. In the present study, CRE reduced IL-6 production in the low-LPS environment (1 ng/mL) and did not in the high-LPS environment (100 ng/mL). The suppression of IL-6 production in the low-LPS environment (1 ng/mL) was abolished after the pretreatment of RasGRP3 siRNA. The reduced RasGRP3 protein content by 100 ng/mL LPS treatment was increased by CRE treatment. Additionally, nobiletin, a major component of CRE showed a suppressive effect on IL-6 production in the low-LPS environment (1 ng/mL). The present results suggest that CRE alleviates inflammatory response via activating RasGRP3 expression in low-intensity inflammation. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has been responsible for the recent pandemic all over the world, which has caused many complications. One of the hallmarks of SARS-CoV-2 infection is an induced immune dysregulation, in some cases resulting in cytokine storm syndrome, acute respiratory distress syndrome and many organs such as lungs, brain, and heart that are affected during the SARS-CoV-2 infection. Several physiological parameters are altered as a result of infection and cytokine storm. Among them, microRNAs (miRNAs) might reflect this poor condition since they play a significant role in immune cellular performance including inflammatory responses. Both host and viral-encoded miRNAs are crucial for the successful infection of SARS-CoV-2. For instance, dysregulation of miRNAs that modulate multiple genes expressed in COVID-19 patients with comorbidities (e.g., type 2 diabetes, and cerebrovascular disorders) could affect the severity of the disease. Therefore, altered expression levels of circulating miRNAs might be helpful to diagnose this illness and forecast whether a COVID-19 patient could develop a severe state of the disease. Moreover, a number of miRNAs could inhibit the expression of proteins, such as ACE2, TMPRSS2, spike, and Nsp12, involved in the life cycle of SARS-CoV-2. Accordingly, miRNAs represent potential biomarkers and therapeutic targets for this devastating viral disease. In the current study, we investigated modifications in miRNA expression and their influence on COVID-19 disease recovery, which may be employed as a therapy strategy to minimize COVID-19-related disorders. [ABSTRACT FROM AUTHOR]

The ongoing pandemic of COVID‐19 is intrinsically a systemic inflammatory disorder; hence, those patients suffering an underlying chronic inflammatory disease such as diabetes mellitus are at high risk of severe complications. Preventing or suppressing the inflammatory responses are of importance in diabetic patients. Sodium‐glucose cotransporters‐2 inhibitors (SGLT2i) are a newly introduced anti‐diabetic drugs that have hypoglycemic effects through the urinary excretion of glucose. They also have an anti‐inflammatory potential in diabetes patients, in addition to improving glycemic control, and while there is no direct data available in diabetic patients with COVID‐19 disease, there is evidence that suggests that SGLT2i can reduce systemic inflammation and diminish the cytokine storm effect via several cellular mechanisms. In the current review, our aim was to classify and describe the molecular and cellular pathways by which SGLT2i have anti‐inflammatory effects in diabetic patients with COVID‐19 disease. [ABSTRACT FROM AUTHOR]

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFβ families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation. [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]

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]

Background: Inflammasomes are intracellular multiprotein complexes that sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which results in the proteolytic cleavage of pro-IL-1β and IL-18 into bioactive forms. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and secretion of the proinflammatory cytokines IL-1β/IL-18 in response to disturbances in cellular homeostasis caused by microbial infections and cellular damage. The NLRP3 inflammasome is associated with various inflammatory disorders, including Alzheimer's disease, diabetes, and atherosclerosis. In recent years, NLRP3 inflammasome has also been implicated in inflammation in cystic fibrosis. The differentiation of pro-IL-1β–IL-1β, an active cytokine, is mediated by neutrophil expression of the NLRP3 inflammasome. Furthermore, it maintains a cytokine storm in the lungs during the pathogenesis of CF. Short conclusion: This review highlights neutrophil metabolic reprogramming characterized by the Warburg effect, NLRP3-mediated inflammation in cystic fibrosis, and its inhibition as a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity. [ABSTRACT FROM AUTHOR]

Background: Cytokine release syndrome (CRS) represents a potentially lifethreatening and systematic inflammatory response where it is noted an increase of secretion of proinflammatory cytokines from lymphocytes, myeloid cells like macrophages, dendritic cells, and monocytes. This syndrome is characteristic of some conditions such as viral infections, administration of antibody-based therapy, auto-immune disease, and immunotherapy, especially in severe COVID-19 patients. Case reports: We presented two cases of COVID-19 patients in which the clinical picture significantly deteriorated during hospitalization, where the value of CRP, ferritin, LDH, and IL-6 dramatically increased, especially values of IL-6 were recorded over 2000. We treated them with third-generation cephalosporins, carbapenems, glycopeptides, metronidazole, anti-IL-6 inhibitor, low molecular weight heparin (LMWH), glucocorticoids, immunoglobulins (IVIG), and vitamins. Both patients were successfully treated and were discharged from the hospital with a recommendation for oral anticoagulant therapy. Conclusion: CRS is a complex syndrome. In the future, it is necessary to educate doctors about this syndrome, as well as to develop drugs whose goal would be to reduce the inflammatory response in already developed diseases. [ABSTRACT FROM AUTHOR]

We aimed to review the literature to introduce some effective plant-derived antioxidants to prevent and treat COVID-19. Natural products from plants are excellent sources to be used for such discoveries. Among different plantderived bioactive substances, components including luteolin, quercetin, glycyrrhizin, andrographolide, patchouli alcohol, baicalin, and baicalein were investigated for several viral infections as well as SARS-COV-2. The mechanisms of effects detected for these agents were related to their antiviral activity through inhibition of viral entry and/or suppuration of virus function. Also, the majority of components exert anti-inflammatory effects and reduce the cytokine storm induced by virus infection. The data from different studies confirmed that these agents may play a critical role against SARS-COVID-2 via direct (antiviral activity) and indirect (antioxidant and anti-inflammatory) mechanisms, suggesting that natural products are a potential option for management of patients with COVID-19 due to the lower side effects and high efficiency. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 instigated "cytokine storm" elicited upon infection is known to majorly cause lung injury and even mortality in severe cases. Early clinical prognosis to alleviate the exaggerated release of inflammatory cytokines is thus looked upon. Considering the recent attention and advantages of saliva as a clinical specimen, i.e. ease and painlessness of collection, which does not require trained staff and could allow self-sampling, the present study attempts to explore saliva for detection of IL-6, TNF-α and IL-10 which constitute major inflammatory genes that are elevated in COVID-19 using RT-PCR. Blood specimens of the same patients were also parallelly assessed to compare and validate the inflammatory marker expression. A total of 64 COVID-19 subjects who met the inclusion criteria were enrolled in this pilot study. Paired samples of blood and saliva from each patient were collected as per standard sampling protocols. RNA from all specimens were extracted using Qiagen RNA Blood Mini Kit and subjected to RT-PCR. IL-6, TNF-α and IL-10 expression were assessed in Ct (cycle threshold) values. It was observed that all 64 (100%) patients expressed IL-6 gene and TNF-α gene, whereas only 7 (5.19%) patients expressed IL-10 in both blood and saliva samples. The mean Ct values of IL-6 gene expressed in blood and saliva were 26.68 ± 2.26 and 28.53 ± 3.11 respectively. Similarly, the mean Ct values of TNF-α gene expressed in blood and saliva were 27.98 ± 2.45 and 28.92 ± 3.70 respectively. The observed mean Ct values of IL-10 gene expressed in blood and saliva were 31.26 ± 3.96 and 30.11 ± 4.12 respectively. Accordingly, the results indicate that inflammatory genes IL-6, TNF-α and IL-10 were detectable in both patient saliva as well as in blood. Moreover, mean Ct values of IL-6, TNF-α and IL-10 in both samples were found to be comparable. This finding thus suggests the possible use of saliva as an alternative specimen to blood for monitoring inflammation in COVID-19 patients. [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]

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection leads to the development of coronavirus disease 2019 (COVID-19), which causes endothelial dysfunction (ED), oxidative stress (OS), and inflammatory disorders. These changes cause hypoxia and cytokine storm with the development of cardio-pulmonary complications. Bioactive lipids and other polyunsaturated fatty acids participate in a vital role in the SARS-CoV-2 infection process. One of these mediators is the anti-inflammatory compound, lipoxin (LX). LXs are produced from arachidonic acid (AA) by collaboration between 5-lipoxygenase (5-LO) and 12–15 LO during cell interactions. Thus, our goal was to review the probable role of LXs in COVID-19 regarding the effects of LXs on the inflammatory signaling pathways that are linked with COVID-19 pathogenesis and complications. [ABSTRACT FROM AUTHOR]

Simple Summary: Septic shock is a life-threatening disease caused by a dysregulated host response to infection, affecting millions of people every year and killing more than 25% directly despite advances in modern medicine. This pathology is characterized by apoptosis-induced depletion of immune cells and immunodepression. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. There is no specific treatment but the early identification and diagnosis of the pathology as well as timely treatment can greatly improve patient outcomes. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of immune cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. The most important alteration observed in septic neutrophils is the activation of a survival program capable of resisting apoptotic death. As regards adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, favoring immunosuppression. Several promising therapies that target the host's immune response to sepsis are currently under evaluation. Innate and adaptive immune system cells play a critical role in the host response to sepsis. Sepsis is a life-threatening disease characterized by apoptosis-induced depletion of immune cells and immunodepression, which contribute to morbidity and mortality. Many alterations in the expression of surface markers of neutrophils and monocytes have been described in septic patients. The aim of this study was to inspect the recently published literature to inform the clinician about the most up-to-date techniques for the study of circulating leukocytes. The impact on cell phenotypes and on the function of leukocytes of extracorporeal and non-blood purification treatments proposed for sepsis were also analyzed. We conducted a systematic review using Pubmed/Medline, Ovid/Willey, the Cochrane Library, the Cochrane Controlled Trials Register, and EMBASE, combining key terms related to immunological function in sepsis and selected the most relevant clinical trials and review articles (excluding case reports) published in the last 50 years. The most important alteration in neutrophils during sepsis is that they activate an anti-apoptotic survival program. In septic monocytes, a reduced characteristic expression of HLA-DR is observed, but their role does not seem to be significantly altered in sepsis. As regards adaptive immunity, sepsis leads to lymphopenia and immunosuppression in patients with septic shock; this process involves all types of T cells (CD4, CD8 and Natural Killer), except for regulatory T cells, which retain their function. Several promising therapies that target the host immune response are currently under evaluation. During the worldwide pandemic caused by SARS-CoV-2, it was useful to study the "cytokine storm" to find additional treatments, such as the oXiris® filter. This therapy can decrease the concentration of inflammatory markers that affect the severity of the disease. [ABSTRACT FROM AUTHOR]

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

COVID-19 is one of the viral diseases that has caused many deaths and financial losses to humans. Using the available information, this virus appears to activate the host cell-death mechanism through Calpain activation. Calpain inhibition can stop its downstream cascade reactions that cause cell death. Given the main roles of Calpain in the entry and pathogenicity of the SARS-CoV-2, its inhibition can be effective in controlling the COVID-19. This review describes how the virus activates Calpain by altering calcium flow. When Calpain was activated, the virus can enter the target cell. Subsequently, many complications of the disease, such as inflammation, cytokine storm and pulmonary fibrosis, are caused by virus-activated Calpain function. Calpain inhibitors appear to be a potential drug to control the disease and prevent death from COVID-19. [ABSTRACT FROM AUTHOR]

Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm. [ABSTRACT FROM AUTHOR]

The respiratory illness triggered by severe acute respiratory syndrome virus-2 (SARS-CoV-2) is often particularly serious or fatal amongst patients with pre-existing heart conditions. Although the mechanisms underlying SARS-CoV-2-related cardiac damage remain elusive, inflammation (i.e. 'cytokine storm') and oxidative stress are likely involved. Here we sought to determine: 1) if cardiomyocytes are targeted by SARS-CoV-2 and 2) how inflammation and oxidative stress promote the viral entry into cardiac cells. We analysed pro-inflammatory and oxidative stress and its impact on virus entry and virus-associated cardiac damage from SARS-CoV-2 infected patients and compared it to left ventricular myocardial tissues obtained from non-infected transplanted hearts either from end stage heart failure or non-failing hearts (donor group). We found that neuropilin-1 potentiates SARS-CoV-2 entry into human cardiomyocytes, a phenomenon driven by inflammatory and oxidant signals. These changes accounted for increased proteases activity and apoptotic markers thus leading to cell damage and apoptosis. This study provides new insights into the mechanisms of SARS-CoV-2 entry into the heart and defines promising targets for antiviral interventions for COVID-19 patients with pre-existing heart conditions or patients with co-morbidities. • To determine if cardiomyocytes are targeted by SARS-CoV-2. • The role of inflammation and oxidative stress in promoting the viral entry. • The consequences on cell damage. [ABSTRACT FROM AUTHOR]

Background: Progressive neuronal death is the key pathological feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying the neuronal death in AD patients have not been fully elucidated. Necroptosis reportedly activates and induces neuronal death in patients with Alzheimer's disease (AD); however, the main mediators and mechanisms underlying necroptosis induction in AD remain elusive.Methods: The function of hyperphosphorylated tau (pTau) in inducing necroptosis in neuronal cell was examined using Western blotting, RT-PCR and flow cytometry. Tau-induced inflammation was identified via RNA sequencing and transwell assay. Pharmacological methods and CRISPR-Cas9 technology were used to verify the role of necrosome proteins in pTau-stimulated neuronal death and inflammation. TauP301S model mice were treated with Nec-1 s to evaluate the role of necroptosis in tau pathology.Results: Hyperphosphorylated tau could induce necroptosis in neuronal cells by promoting the formation of the RIPK1/RIPK3/MLKL necrosome. In addition, pTau significantly stimulated cell-autonomous overexpression of cytokines and chemokines via the intracellular nuclear factor kappa B (NF-κB) signaling pathway. Importantly, the RIPK1/RIPK3/MLKL axis was essential for the pTau-mediated NF-κB activation and cytokine storm. Furthermore, necroptosis stimulation, NF-κB activation, and cytokine induction have been detected in TauP301S mice and blocking necroptosis markedly ameliorated behavioral defects and excessive neuroinflammation in AD mice.Conclusions: Our study, for the first time, revealed that pTau contributes to neuronal death by inducing necroptosis and inflammation, mediated by activating the RIPK1/RIPK3/MLKL and NF-κB pathways, thereby delineating the hierarchical molecular network of neuronal necroptosis induction in AD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the use of tocilizumab in a community hospital setting for critically ill patients with severe COVID-19. Design: A retrospective case series Setting: Five community hospitals within 1 urban health system Patients: Adult patients whom received tocilizumab between March 27th, 2020 to April 30th, 2020 for severe COVID-19. Interventions: None. Measurements and Main Results: Sixteen patients in total were evaluated from the 5 community hospitals. The mean (± SD) age of the patients was 53.9 ± 9.2 years, 56% were men, and the most common comorbidities present on admission were hypertension (31%) and diabetes mellitus (25%). All patients received at least 1 other treatment modality for COVID-19 (steroids, hydroxychloroquine, or convaslescent plasma). Additionally, all patients on admission to intensive care units had severe COVID-19 with 56% requiring mechanical ventilation with a pre-tocilizumab median (IQR) Pao2: Fio2 of 84 (69 – 108.6), 19% requiring vasopressor support, and inflammatory markers (CRP, LDH, ferritin, and IL-6) were elevated. The median (IQR) tocilizumab dose was 400 mg (400-600) which correlated with a weight-based mean (± SD) dose of 5.4 mg/kg ± 1.3. Of the 16 patients that received tocilizumab, 8 (50%) were discharged home, 7 (44%) died, and 1 (6%) was still hospitalized at the end of data collection. Patients who died were more likely to be older 62 ± 2 years, female (57%), had a higher rate of mechanical ventilation (86%) and vasopressors (43%) use at baseline, and had a higher median (IQR) IL-6 level prior to tocilizumab administration 550 pg/mL (IQR 83-1924). There were no reported adverse drug reactions reported after the administration of tocilizumab for any patient. Conclusions: Our findings do not support the effectiveness of tocilizumab in treatment of severe COVID-19 infection in critically ill patients. [ABSTRACT FROM AUTHOR]

• An aminothiazole derivative X22 showed a significant reduction in the levels of inflammatory mediators including NO, TNF-α and IL-6 in RAW 264.7 cells stimulated with LPS. • MEP revealed that the reactive sites are located in CF 3 and NH 2 groups. These particular groups exhibit a strong propensity to engage in hydrogen bonding and dipole-dipole interactions. • Molecular docking studies revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids, Tyr151, Ser60, Gln61, and Arg179. • MD simulation data demonstrated that TNF-alpha exhibits effective binding to the active sites of proteins, resulting in the formation of a stable protein complex. Aminothiazole-based structures, including compounds like anakinra, nitazoxanide, amiphenazole, and tizoxanide, along with cytokine-blocking agents such as tocilizumab and siltuximab are currently under extensive investigation for their potential in managing severe COVID-19 by specifically targeting and inhibiting cytokines responsible for cytokine release syndrome (CRS). These targeted therapies have shown promising results in effectively mitigating the effects of severe COVID-19. Herein, we carried out a biological assessment of a novel aminothiazole-based derivative 5-(phenylthio)-4-(2-(trifluoromethyl) phenyl) thiazol-2-amine (X22) to gauge its potential as an anti-inflammatory agent. Utilizing in vitro assays, which included measuring nitric oxide (NO) inhibition and observing the production of LPS-induced pro-inflammatory cytokines (TNF-α and IL-6) in RAW 264.7 macrophages. Furthermore, the X22 was characterized by experimental FT-IR, NMR, and UV–visible spectral analysis. The optimized molecular geometry and vibrational wave numbers were calculated using the DFT and B3LYP/6–311++ G (d,p) basis set. The vibrational assignments were calculated using VEDA's Potential Energy Distribution (PED) program. 1H and 13C NMR were calculated by the GIAO method. Additionally, compounds HOMO-LUMO and HF interactions were studied. Subsequently, the MEP map was traced to find the reactive sites of X22. In addition, Mulliken population analysis and thermodynamic properties with respect to various temperatures were also calculated. All the theoretical predictions were carried out by using the DFT-B3LYP method at the level of 6–311++ G (d,p). Finally, the molecular docking interactions revealed that ligand (X22) binds to TNF-α and IL-6 via H-bonding with amino acids Tyr 151, Ser60, Gln61, and Arg179. These findings suggest that X22 could be a valuable therapeutic agent for mitigating the progression of severe SARS-CoV-2 infections. [Display omitted] [ABSTRACT FROM AUTHOR]

• Evidence indicates that a cytokine storm is involved in the pathophysiology of monkeypox. • We hypothesize that purinergic signaling plays a role in the cytokine storm seen in monkeypox. • Modulating purinergic receptors could help mitigate the cytokine storm. • Our findings offer fresh perspectives on the connection between purinergic signaling and human monkeypox. Some evidence has indicated that monkeypox can induce a cytokine storm. Purinergic signaling is a cell pathway related to the cytokine storm. However, the precise mechanisms that lead to cytokine storms in monkeypox infections and the possible involvement of purinergic signaling in the immune response to this virus remain unknown. In this review article, we aimed to highlight a body of scientific evidence that consolidates the role of the cytokine storm in monkeypox infection and proposes a new hypothesis regarding the roles of purinergic signaling in this immune-mediated mechanism. We further suggested some purinergic signaling modulators to mitigate the deleterious and aggravating effects of immune dysregulation in human monkeypox virus infection by inhibiting P2X3, P2X7, P2Y2, and P2Y12, reducing inflammation, and activating A1 and A2A receptors to promote an anti-inflammatory response. [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]

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3–5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy. [ABSTRACT FROM AUTHOR]

Inflammatory diseases have become increasingly prevalent throughout the world. Coronavirus disease 2019 (COVID‐19), which has recently become pandemic, also exhibits hyperinflammation and cytokine release syndrome. To address inflammation‐related diseases, numerous molecular targets have been explored in preclinical studies and clinical trials. Among them, the protease‐activated receptors (PARs) that belong to G protein‐coupled receptors are one of the most popular classes of drug targets, participating in inflammatory signalling and diseases. PARs activation can trigger downstream intracellular signalling to modulate a variety of inflammatory responses in multiple systems, including nervous, respiratory, digestive, circulatory, urinary and immune systems. Importantly, there are the Yin‐Yang effects, comprising anti‐ and pro‐inflammatory roles, of PARs activation in different types of inflammations, and these are context‐dependent. Alternatively, it was recently revealed that PARs not only modulate inflammatory‐related tumour progression, but also participate in inflammatory cytokine release related to COVID‐19 via direct interaction with severe acute respiratory syndrome coronavirus 2 protein, suggesting that PARs also participate in other diseases via inflammatory responses. In this review, we renew and discuss the findings of PARs as molecular targets for treating inflammatory diseases, highlighting the novel roles of PARs and facilitating a better understanding of their designated values in the specific inflammatory environment. [ABSTRACT FROM AUTHOR]

Some patients with COVID-19 pneumonia develop an associated cytokine storm syndrome that aggravates the pulmonary disease. These patients may benefit of anti-inflammatory treatment. The role of colchicine in hospitalized patients with COVID-19 pneumonia and established hyperinflammation remains unexplored. In a prospective, randomized controlled, observer-blinded endpoint, investigator-initiated trial, 240 hospitalized patients with COVID-19 pneumonia and established hyperinflammation were randomly allocated to receive oral colchicine or not. The primary efficacy outcome measure was a composite of non-invasive mechanical ventilation (CPAP or BiPAP), admission to the intensive care unit, invasive mechanical ventilation requirement or death. The composite primary outcome occurred in 19.3% of the total study population. The composite primary outcome was similar in the two arms (17% in colchicine group vs. 20.8% in the control group; p = 0.533) and the same applied to each of its individual components. Most patients received steroids (98%) and heparin (99%), with similar doses in both groups. In this trial, including adult patients with COVID-19 pneumonia and associated hyperinflammation, no clinical benefit was observed with short-course colchicine treatment beyond standard care regarding the combined outcome measurement of CPAP/BiPAP use, ICU admission, invasive mechanical ventilation or death (Funded by the Community of Madrid, EudraCT Number: 2020-001841-38; 26/04/2020). [ABSTRACT FROM AUTHOR]

Objective: Early diagnosis is important for severe diseases in COVID-19. Monocyte/high density lipoprotein ratio (MHR) is a new prognostic marker indicating inflammation. We aimed to investigate the relationship between MHR and diseases severity in COVID-19. Methods: Patients with laboratory confirmed COVID-19, were retrospectively analyzed. Clinical symptoms, signs and laboratory data on the first day of hospitalization were obtained from medical records of hospital. The clinical data of 301 patients were included in study. Cases were diagnosed on the basis of interim guidance of World Health Organization (WHO). Patients were classified into two groups as non-severe COVID-19 and severe COVID-19. MHR were calculated with laboratory data on the first day of hospitalization. The relationship between MHR level and COVID-19 severity was evaluated. Statistical analysis of the data was performed by using SPSS 25 (SPSS Inc., Chicago, IL, USA) package program. Statistical significance level was accepted as p<0.05. Results: One hundred ninety-six patients (65.1 %) had non-severe COVID-19,105 patients (34.9 %) had severe COVID-19. In our study, it was found that the mean age was higher in severe patients and comorbid diseases were more common. Although monocyte count values were not statistically significantly different, MHR was significantly higher in severe COVID-19 than non-severe COVID-19. Conclusions: Monocytes are very important to cytokine storm in COVID-19. Dyslipidemia can occur in viral infection because of inflammation. MHR can be used as an inflammatory marker in COVID-19. [ABSTRACT FROM AUTHOR]

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID‐19 infection. The pathogenesis of COVID‐19‐related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS‐CoV‐2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF‐α + IFN‐γ or a cocktail of TNF‐α + IFN‐γ + IL‐6, increased expression of ACE2/DPP4, accentuated the pro‐inflammatory senescence‐associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence‐like state. IL‐6 by itself failed to induce substantial effects on viral entry receptors or SASP‐related genes, while synergy between TNF‐α and IFN‐γ initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper‐inflammation, normalized SARS‐CoV‐2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine‐mediated viral entry receptor activation and links with senescence and hyper‐inflammation. [ABSTRACT FROM AUTHOR]

The inflammatory process is a biological response of the organism to remove injurious stimuli and initiate homeostasis. It has been recognized as a key player in the most severe forms of SARS-CoV-2, characterized by significantly increased pro-inflammatory cytokine levels, the so-called "cytokine storm" that appears to play a pivotal role in this disease. Therefore, the aim of this systematic review was to select clinical trials with anti-inflammatory plants and relate the activity of these plants to inflammatory markers of SARS-CoV-2 infection. PRISMA guidelines are followed, and studies of interest are indexed in PubMed and ClinicalTrials.gov databases. As a result, 32 clinical trials encompassing 22 plants were selected. The main anti-inflammatory mechanisms described in the studies are the inhibition of inflammatory cytokines, such as IL-6, TNF-a, IFN-γ, and IL-1; decreased CRP and oxidative marker levels; increased endogenous antioxidant levels; modulation of cardiovascular risk markers. The data found are not directly related to SARS-CoV-2 infection. However, they provide possibilities for new studies as plants have a wide array of phytochemicals, and detecting which ones are responsible for anti-inflammatory effects can provide invaluable contribution to studies aiming to evaluate efficacy in scenarios of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that hyperinflammatory syndrome and cytokine storm observed in COVID-19 severe cases are narrowly associated with the disease's poor prognosis. Therefore, targeting the inflammatory pathways seems to be a rational therapeutic strategy against COVID-19. Many anti-inflammatory agents have been proposed; however, most of them suffer from poor bioavailability, instability, short half-life, and undesirable biodistribution resulting in off-target effects. From a pharmaceutical standpoint, the implication of COVID-19 inflammation can be exploited as a therapeutic target and/or a targeting strategy against the pandemic. First, the drug delivery systems can be harnessed to improve the properties of anti-inflammatory agents and deliver them safely and efficiently to their therapeutic targets. Second, the drug carriers can be tailored to develop smart delivery systems able to respond to the microenvironmental stimuli to release the anti-COVID-19 therapeutics in a selective and specific manner. More interestingly, some biosystems can simultaneously repress the hyperinflammation due to their inherent anti-inflammatory potency and endow their drug cargo with a selective delivery to the injured sites. Drug delivery systems can be harnessed to fight against SARS-CoV-2 induced hyperinflammation by improving the properties of anti-inflammatory agents, smartly responding to the inflammatory site to selectively deliver their cargo, and may possess inherent anti-inflammatory potency. [Display omitted] • Hyperinflammatory syndrome and cytokine storm are narrowly associated with COVID-19 poor prognosis. • Targeting the inflammatory pathways is a rational therapeutic strategy to combat COVID-19. • Drug delivery systems can be harnessed to improve the properties of anti-inflammatory agents. • Drug delivery systems can be tailored to smartly respond to the specific stimuli of the inflammatory microenvironment. • Biomimetics and mesenchymal stem cells are promising therapeutics and drug carriers against COVID-19. [ABSTRACT FROM AUTHOR]

The rapid and widespread global pandemic of 2019 coronavirus disease (COVID-19) has had unprecedented negative health and economic impacts. Immune responses play a key role in the development of COVID-19, including the disruption of immune balance and cytokine storms caused by excessive inflammatory responses. Due to the effects of cancer itself and treatment, patients often accompanied by immunosuppression appear to be a susceptible population for COVID-19. Worryingly, COVID-19 with cancer is associated with a poor prognosis. Cancer patients are a vulnerable group, threatened by COVID-19, finding a way to combat COVID-19 for them is urgent. Immunonutrition is closely related to balance and strong immune function. Supplementary immunonutrition can improve the immune function and inflammatory response of cancer patients after surgery, which provides evidence for the role of immunonutrition in combating COVID-19. We reviewed possible mechanisms of immunonutrition against COVID-19, including enhancing immune cell function, increasing immune cell count, ameliorating excessive inflammatory response, and regulating gut microbiota. Immunonutrition supplementation in cancer patients may be beneficial to enhance immune function in the early stage of COVID-19 infection and control excessive inflammatory response in the late stage. Therefore, immunonutrition is a potential strategy for the prevention and treatment of COVID-19 in cancer. [ABSTRACT FROM AUTHOR]

Platelet-leukocyte crosstalk is commonly manifested by reciprocal links between thrombosis and inflammation. Platelet thrombus acts as a reactive matrix that recruits leukocytes to the injury site where their massive accumulation, activation and migration promote thrombotic events while triggering inflammatory responses. As a life-threatening condition with the associations between inflammation and thrombosis, COVID-19 presents diffuse alveolar damage due to exaggerated macrophage activity and cytokine storms. These events, together with direct intracellular virus invasion lead to pulmonary vascular endothelialitis, cell membranes disruption, severe endothelial injury, and thrombosis. The developing pre-alveolar thrombus provides a hyper-reactive milieu that recruits circulating leukocytes to the injury site where their activation contributes to thrombus stabilization and thrombosis propagation, primarily through the formation of Neutrophil extracellular trap (NET). NET fragments can also circulate and deposit in further distance where they may disseminate intravascular thrombosis in severe cases of disease. Thrombi may also facilitate leukocytes migration into alveoli where their accumulation and activation exacerbate cytokine storms and tissue damage, further complicating the disease. Based on these mechanisms, whether an effective anti-inflammatory protocol can prevent thrombotic events, or on the other hand; efficient antiplatelet or anticoagulant regimens may be associated with reduced cytokine storms and tissue damage, is now of interests for several ongoing researches. Thus shedding more light on platelet-leukocyte crosstalk, the review presented here discusses the detailed mechanisms by which platelets may contribute to the pathogenesis of COVID-19, especially in severe cases where their interaction with leukocytes can intensify both inflammatory state and thrombosis in a reciprocal manner. • Mutual interactions between platelets and leukocytes promote both thrombosis and inflammatory responses. • As the serious inflammatory condition, COVID-19 may also be associated with thrombotic events due to vascular inflammation or injury. • Direct and indirect vascular damage may occur due to virus invasion or leucocyte-dependent cytotoxic effect respectively. • Endothelialitis caused by cytokine storms may lead to vascular lesion and thrombosis in pre-alveolar vessels. • Pre-alveolar thrombi facilitate the migration of activated leucocyte, gating the sources of cytolytic and inflammatory agents in to the site of infection. • Therefore thrombosis may intensify the disease condition by the enhancements of cytokine storms and pulmonary damage. • Some clinical trials have shown evidence of reciprocal treatment of thrombosis and inflammation in COVID-19. • Exploring the direct cross-talk between inflammatory and thrombotic events sheds more light on the pathogenesis and treatment approaches of COVID-19. [ABSTRACT FROM AUTHOR]

The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine storm are known clinical phenomena observed following naturally disseminated adenovirus infection in immunocompromised hosts as well as when extremely high doses of adenovirus vectors are injected intravenously. This dose-dependent, cytokine-mediated toxicity compromises the safety of adenovirus-based vectors and represents a critical problem, limiting their utility for gene therapy applications and the therapy of disseminated cancer, where intravenous injection of adenovirus vectors may provide therapeutic benefits. The mechanisms triggering severe cytokine response are not sufficiently understood, prompting efforts to further investigate this phenomenon, especially in clinically relevant settings. In this review, we summarize the current knowledge on cytokine and chemokine activation in response to adenovirus- and adenovirus-based vectors and discuss the underlying mechanisms that may trigger acute cytokine storm syndrome. First, we review profiles of cytokines and chemokines that are activated in response to adenovirus infection initiated via different routes. Second, we discuss the molecular mechanisms that lead to cytokine and chemokine transcriptional activation. We further highlight how immune cell types in different organs contribute to synthesis and systemic release of cytokines and chemokines in response to adenovirus sensing. Finally, we review host factors that can limit cytokine and chemokine expression and discuss currently available and potential future interventional approaches that allow for the mitigation of the severity of the cytokine storm syndrome. Effective cytokine-targeted interventional approaches may improve the safety of systemic adenovirus delivery and thus broaden the potential clinical utility of adenovirus-based therapeutic vectors. [ABSTRACT FROM AUTHOR]