Excessive Production Of Proinflammatory Cytokines Research Articles

Profiling Differential Effects of 5 Selective Serotonin Reuptake Inhibitors on TLRs-Dependent and -Independent IL-6 Production in Immune Cells Identifies Fluoxetine as Preferred Anti-Inflammatory Drug Candidate

Excessive proinflammatory cytokine production induced by abnormal activation of Toll-like receptor (TLR) signaling, for example, by SARS-CoV-2 infection, can cause a fatal cytokine storm. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine, used to treat depression, were recently reported to reduce the risk of severe disease in patients with coronavirus disease 2019 (COVID-19), but the mechanisms of the anti-inflammatory effects of SSRIs, and which SSRI would be most suitable as an anti-inflammatory drug, remain unclear. Here, we examined the inhibitory effects of 5 FDA-approved SSRIs, paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, on the production of interleukin-6 (IL-6) induced by stimulation with multiple TLR agonists in murine macrophages and dendritic cells, and on the production of cytokines induced by concanavalin A in murine lymphocytes. In J774.1 murine macrophage cells, pretreatment with SSRIs significantly suppressed IL-6 release induced by TLR3 agonist poly(I:C), TLR4 agonist LPS or TLR9 agonist CpG ODN, but did not affect IL-6 release induced by TLR7 agonists imiquimod or resiquimod. In accordance with the results obtained in J774.1 cells, pretreatment with SSRIs also suppressed IL-6 release induced by a TLR3, TLR4 or TLR9 agonist in bone marrow-derived dendritic cells and peritoneal cells of C57BL/6 mice. On the other hand, interestingly, sertraline alone among the SSRIs amplified IL-6 production induced by TLR7 agonists in murine dendritic cells, though not in macrophages. Concanavalin A-induced production of IL-6 or IL-2 in murine lymphocytes was suppressed by SSRIs, suggesting that SSRIs also inhibit TLRs-independent IL-6 production. Since SSRIs suppressed both IL-6 production induced by multiple TLR agonists in macrophages or dendritic cells and TLR-independent IL-6 production in lymphocytes, they are promising candidates for treatment of patients with cytokine storm, which is mediated by overactivation of multiple TLRs in a complex manner, leading to the so-called IL-6 amplifier, an IL-6 overproduction loop. However, the 5 SSRIs examined here all showed different effects. Overall, our results suggest that fluoxetine may be the most promising candidate as an anti-inflammatory drug. An examination of the structural requirements indicated that the N-methyl group of fluoxetine has a critical role in the inhibition of IL-6 production.

Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review.

Coronavirus infection can have various degrees of severity and outcomes. In some cases, it causes excessive production of pro-inflammatory cytokines, a so-called cytokine storm, leading to acute respiratory distress syndrome. Unfortunately, the exact pathophysiology and treatment, especially for severe cases of COVID-19, are still uncertain. Results of preliminary studies showed that immunosuppressive therapy, such as interleukin (IL)-6, IL-1, and TNF-α antagonists commonly used in rheumatology, can be considered as treatment options for COVID-19, especially in severe cases. The review focused on the most common and currently studied monoclonal antibody drugs, as well as up-to-date data on the pathogenesis of COVID-19, host immune response against SARS-CoV-2 and its association with cytokine storm. It also covered effects of interleukin (IL)-6, IL-1, and TNF-α blockers on the course of coronavirus infection and outcome in patients treated for the main autoimmune disease and subsequently infected with COVID-19.

Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells.

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of β-amyloid (Aβ) and neurofibrillary tangles (NFTs). Apart from Aβ and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, “surveying” phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aβ plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aβ plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for in silico drug screening and gains further insight into the development of microglia-based therapeutic interventions for AD.

Molecular mechanisms of dexamethasone-mediated modulation of inflammatory and interferon responses in severe COVID-19 patients.

Abstract Severe COVID-19 is characterized by cytokine storm, an excessive production of pro-inflammatory cytokines, which results in acute lung damage and death. Dexamethasone (Dex), a corticosteroid administered as a standard of care for severe COVID-19, has been shown to reduce the onset of severe complications in these patients. However, the mechanisms underlying the beneficial effects of Dex are poorly understood. We conducted a transcriptomic analysis (NanoString) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild (no hospitalization) and severe (on ventilator in the ICU) disease. The latter group included patients ± Dex. Treatment of severe COVID-19 patients with Dex inhibited pro-inflammatory pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling and the genes involved in cytokine storm (IL-1, IL-6 and IFN-γ), which were altered in severe vs mild disease. Pro-inflammatory immune cell functions are regulated by calcium signaling, which in turn is under the control of Kv1.3 potassium channels, but their role in the complications associated with COVID-19 remains elusive. RT-qPCR experiments in PBMCs from COVID-19 patient cohorts showed an increase in Kv1.3 expression in severe patients that was significantly reduced by Dex treatment. In agreement with these findings, in vitro treatment with Dex reduced Kv1.3 protein abundance in CD3+, CD4+, CD8+ T cell and CD56dim NK cells in healthy donor (HD) PBMC, while NanoString showed inhibition of pro-inflammatory genes and cytokines. Functional studies showed that Dex significantly reduced Kv1.3 activity and IFN-γ in HD T cells. Thus, our findings suggest that Kv1.3 inhibition contributes to the immunosuppression by Dex. This work was supported by Senior Pilot Grant, University of Cincinnati, Department of Internal Medicine to LC, NIH (R38HL155775 to MC) and Biospecimens and associated data were provided by the Cincinnati COVID-19 Repository at the University of Cincinnati and Cincinnati Children’s Hospital Medical Center.

Sirt6 activation blocks LPS induced expression of inflammatory cytokines in cardiac cells

Sepsis induced myocardial dysfunction is a common complication that has been linked to an increased mortality. The activation of NFkB pathway and excessive production of pro‐inflammatory cytokines is considered to be one of the most important signaling pathway involved in the pathogenesis of sepsis. Earlier studies have shown that Sirt6, a member of class III of histone deacetylases, attenuates hyper‐activation of NFkB signaling that contributes to inflammation and the aging process. In the present study we tested the hypothesis whether pharmacological activation of Sirt6 can prevent LPS induced myocardial inflammation. Primary cultures of adult rat cardiac fibroblasts were treated with UBCS039, an allosteric activator of Sirt6, for 48 hours. The results showed a dose‐dependent increase in steady‐state levels of Sirt6 as well as deacetylation of its target H3K9 by Western analysis. A similar effect of UBCS039 treatment was observed in H9C2 cardiac myocytes. We also tested effects of UBCS039 on LPS induced NFkB activation and cytokine production in these cells. Our data showed that pretreatment of cardiac fibroblasts with UBCS039 for 48 hrs significantly reduced LPS (100ng/ml)‐induced phosphorylated levels of NFkB (pNFkB). By real‐time PCR analysis we found that LPS led to increased expression (4‐9 fold) of mRNA of IL‐6, IL‐1b, TLR4 and CD‐38 in cardiac fibroblasts within 6h of treatment. This effect of LPS in cardiac fibroblasts was completely blocked when cells were pretreated with UBCS039. These data thus indicated that pharmacological activation of Sirt6 is capable of blocking LPS induced inflammatory response in cardiac cells, and has the potential to alleviate sepsis induced myocardial dysfunction and related health consequences.

Endothelial PP2AC prevents endotoxemia‐induced acute lung injury by suppressing STAT3 activity

Acute lung injury (ALI) is a critical hypoxemic respiratory failure characterized by alveolar‐capillary damage, unchecked inflammation, vascular leak, and pulmonary edema secondary to endothelial barrier dysfunction. Identifying the candidate molecules targeting mechanisms for excessive production of proinflammatory cytokines and endothelial dysfunction are warranted for therapeutic intervention. Recent studies show that the signal transducers and activators of transcription 3 (STAT3) phosphorylation in critical for inflammatory cytokines production and systemic inflammation. Protein phosphatase 2A (PP2A) is a hetero‐trimeric, ubiquitously expressed Ser/Thr phosphatase. The phosphatase activity of PP2A is regulated by its catalytic C subunit (PP2AC). PP2A plays an essential role in modulating tissue inflammation by maintaining the phosphorylation/de‐phosphorylation balance of multiple proteins. So far, however, no studies have deciphered PP2AC isoform‐a function in regulating pulmonary vascular endothelial permeability and inflammatory signaling. We hypothesize that PP2AC expression in vascular endothelial cell (EC) protects the lung against sepsis‐induced lung injury. Wild‐type (WT) and endothelial specific PP2AC‐deficient mice (PP2ACCKO) were challenged with lipopolysaccharide. We found that lipopolysaccharide‐induced inflammatory response, characterized by up‐regulated level of IL‐1b, IL‐6, MPO activity and pulmonary vascular hyper‐permeability in lung tissue of PP2ACCKO mice was significantly elevated as compared to WT littermate control. Mechanistically, we showed that PP2AC deletion in mouse lung‐EC and in human lung‐EC markedly augmented Ser727‐phosphorylation‐mediated STAT3 activation and MMP9 level in response to lipopolysaccharide. Intriguingly, administration of a STAT3 inhibitor suppressed lipopolysaccharide‐induced production of MMP9 and proinflammatory cytokines IL‐1b, IL‐6, MPO activity and pulmonary vascular hyper‐permeability and thus rescued the augmented inflammatory phenotype in PP2ACCKO mice lung. In conclusion, these data showed the protective role of endothelial‐PP2AC in limiting endothelial barrier dysfunction and inflammation, and thereby it attenuates sepsis‐induced lung injury by preventing hyper‐activated STAT3 signaling.

Anti-Inflammatory Polyketides from an Alga-Derived Fungus Aspergillus ochraceopetaliformis SCSIO 41020.

A new linear polyketide, named aspormisin A (1), together with five known polyketides (2–6), were isolated from the alga-derived fungus Aspergillus ochraceopetaliformis SCSIO 41020. Their structures were elucidated through a detailed comprehensive spectroscopic analysis, as well as a comparison with the literature. An anti-inflammatory evaluation showed that compounds 2, 5, and 6 possessed inhibitory activity against the excessive production of nitric oxide (NO) and pro-inflammatory cytokines in LPS-treated RAW 264.7 macrophages in a dose-dependent manner without cytotoxicity. Further studies revealed that compound 2 was active in blocking the release of pro-inflammatory cytokines (IL-6, MCP-1, and TNF-α) induced by LPS both in vivo and in vitro. Our findings provide a basis for the further development of linear polyketides as promising anti-inflammatory agents.

Are Anti-Inflammatory Drugs Effective In Patients With COVID-19 Cytokine Storm: A Review

SARS-CoV-2 - Severe acute respiratory syndrome - Coronavirus-2 is one of the most infectious diseases, leading to a pandemic. COVID-19 has extensive involvement in the lower respiratory tract causing acute respiratory syndrome disease (ARDS). No exact treatment is available, so strategies for developing treatment include repurposing of drugs. Pathogenesis of COVID-19 is associated with a cytokine storm in lung alveoli, leading to extensive inflammation and hemorrhage in lung tissue(1). Excessive pro-inflammatory cytokine production contributes to the progression of ARDS, additional tissue damage, multi-organ failure, and death. As there is a correlation between cytokine storm and COVID-19, early management of cytokine storm can improve survival rate and reduce mortality. The authors of this article presented similarities in the pathophysiology of COVID-19 and other inflammatory diseases like rheumatoid arthritis, an overview of the common cytokines associated with both the diseases, and their inhibitory molecules that can be repurposed for the treatment of COVID-19.

Healthy versus Unhealthy Adipose Tissue Expansion: the Role of Exercise.

Although the hallmark of obesity is the expansion of adipose tissue, not all adipose tissue expansion is the same. Expansion of healthy adipose tissue is accompanied by adequate capillary angiogenesis and mitochondria-centered metabolic integrity, whereas expansion of unhealthy adipose tissue is associated with capillary and mitochondrial derangement, resulting in deposition of immune cells (M1-stage macrophages) and excess production of pro-inflammatory cytokines. Accumulation of these dysfunctional adipose tissues has been linked to the development of obesity comorbidities, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease, which are leading causes of human mortality and morbidity in modern society. Mechanistically, vascular rarefaction and mitochondrial incompetency (for example, low mitochondrial content, fragmented mitochondria, defective mitochondrial respiratory function, and excess production of mitochondrial reactive oxygen species) are frequently observed in adipose tissue of obese patients. Recent studies have demonstrated that exercise is a potent behavioral intervention for preventing and reducing obesity and other metabolic diseases. However, our understanding of potential cellular mechanisms of exercise, which promote healthy adipose tissue expansion, is at the beginning stage. In this review, we hypothesize that exercise can induce unique physiological stimuli that can alter angiogenesis and mitochondrial remodeling in adipose tissues and ultimately promote the development and progression of healthy adipogenesis. We summarize recent reports on how regular exercise can impose differential processes that lead to the formation of either healthy or unhealthy adipose tissue and discuss key knowledge gaps that warrant future research.

Melatonin in the treatment of perinatal pathology

The review presents the results of studies that have shown the effectiveness of melatonin use in the treatment of perinatal pathology based on oxidative stress and associated systemic inflammation with excessive production of pro-inflammatory cytokines. It is shown that the lack or absence of the circadian rhythm of epiphyseal maternal melatonin plays a key role in the development of oxidative stress in the single mother-placenta-fetus functional system. The article summarizes the results of experimental studies that reveal the mechanisms of melatonin influence (antioxidant, anti-inflammatory, immunomodulating), which provide the protection of the fetus from damage caused by oxidative stress and inflammation in pregnancy complications. The article presents the results of the use of melatonin in full-term and premature infants in addition to standard therapy of brain damage as a result of hypoxia-ischemia and asphyxia, respiratory distress syndrome, sepsis, and necrotizing enterocolitis. Currently ongoing international studies should determine the dose, duration, safety profile, short-term and long-term effects of melatonin in newborns of various gestational ages for its inclusion in treatment protocols for perinatal pathology.

Immune response against toxoplasmosis-some recent updates RH: Toxoplasma gondii immune response.

AimsCytokines, soluble mediators of immunity, are key factors of the innate and adaptive immune system. They are secreted from and interact with various types of immune cells to manipulate host body’s immune cell physiology for a counter-attack on the foreign body. A study was designed to explore the mechanism of Toxoplasma gondii (T. gondii) resistance from host immune response.Methods and resultsThe published data on aspect of host (murine and human) immune response against T. gondii was taken from Google scholar and PubMed. Most relevant literature was included in this study. The basic mechanism of immune response starts from the interactions of antigens with host immune cells to trigger the production of cytokines (pro-inflammatory and anti-inflammatory) which then act by forming a cytokinome (network of cytokine). Their secretory equilibrium is essential for endowing resistance to the host against infectious diseases, particularly toxoplasmosis. A narrow balance lying between Th1, Th2, and Th17 cytokines (as demonstrated until now) is essential for the development of resistance against T. gondii as well as for the survival of host. Excessive production of pro-inflammatory cytokines leads to tissue damage resulting in the production of anti-inflammatory cytokines which enhances the proliferation of Toxoplasma. Stress and other infectious diseases (human immunodeficiency virus (HIV)) that weaken the host immunity particularly the cellular component, make the host susceptible to toxoplasmosis especially in pregnant women.Conclusion The current review findings state that in vitro harvesting of IL12 from DCs, Np and MΦ upon exposure with T. gondii might be a source for therapeutic use in toxoplasmosis. Current review also suggests that therapeutic interventions leading to up-regulation/supplementation of SOCS-3, IL12, and IFNγ to the infected host could be a solution to sterile immunity against T. gondii infection. This would be of interest particularly in patients passing through immunosuppression owing to any reason like the ones receiving anti-cancer therapy, the ones undergoing immunosuppressive therapy for graft/transplantation, the ones suffering from immunodeficiency virus (HIV) or having AIDS. Another imortant suggestion is to launch the efforts for a vaccine based on GRA6Nt or other similar antigens of T. gondii as a probable tool to destroy tissue cysts.

Cytokine storm in COVID-19: from viral infection to immune responses, diagnosis and therapy.

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.

The role of metabolic syndrome in the development of osteoarthritis

Introduction. Knee osteoarthritis is a progressive degenerative disease of the entire joint that leads to functional limitations and reduced quality of life. The end-stage of the disease is associated with disability and a significant burden both for the patient and the society. Osteoarthritis and metabolic syndrome. Metabolic syndrome is a group of cardiovascular risk factors including diabetes and hyperglycemia, abdominal obesity, hypercholesterolemia, and hypertension. The adverse effects of the metabolic syndrome are associated with worsening of the clinical manifestations and disease prognosis through the combined effects of metabolic disorders. It has also been suggested that individual components of the metabolic syndrome may be an independent risk factor for knee osteoarthritis. Osteoarthritis and diabetes mellitus. Experimental and epidemiological evidence supports the role of type II diabetes mellitus in the pathogenesis of osteoarthritis. Chronic hyperglycemia leads to oxidative stress and excessive production of proinflammatory cytokines, while insulin resistance can act locally and systemically through chronic low-grade inflammation. Osteoarthritis and hypertension. The mechanism that explains the relationship between osteoarthritis and hypertension is unclear. Several potential pathways for subchondral bone damage due to hypertension have been described. Osteoarthritis and dyslipidemia. Experimental studies suggest that dyslipidemia may be involved in the pathophysiological process of osteoarthritis, while epidemiological studies show heterogeneous results. Conclusion. Patients with knee osteoarthritis require a holistic approach in which the emphasis is not only on symptomatic pain relief, but also on the treatment of metabolic disorders.

Carbon dots as nanocatalytic medicine for anti-inflammation therapy

Aberrant reactive oxygen species (ROS) generation is one of the crucial mediators in the pathogenesis of inflammation. So, the development of nanocatalytic medicine to catalyze the ROS-scavenging reactions in pathological regions are promising for anti-inflammatory therapy. Herein, a type of biocompatible metal free carbon dots is prepared via a hydrothermal method which can exhibit peroxidase (POD)-like, catalase (CAT)-like and superoxide dismutase (SOD)-like activities. It has been found that the carbon dots have the capability to efficiently deplete the excessive ROS such as peroxide (H2O2), superoxide anion (O2−) and hydroxyl radical (OH) for their abundant functional groups. After the tail injection in mice with liver inflammation induced by lipopolysaccharide, the carbon dots efficiently reduced the excessive production of ROS and proinflammatory cytokines in vitro. Both in vitro and in vivo results endowed the biocompatible carbon dots with great potential in nanocatalytic medicine for the treatment of disease.

Inflammasomes and SARS-CoV-2 Infection.

SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called “cytokine storm”. Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1β and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response.

IL-1β, IL-17A, and IL-10: A Novel Axis Linked to Immunological Dysfunction May Pre-Empt Early Diagnosis of Sepsis after Cardiac Surgery

INTRODUCTIONSepsis caused by a dysregulated host response to infection, is a serious healthcare problem that results in very high mortality every year-round the globe. When left untreated, sepsis can potentially turn fulminant, making early diagnosis and intervention an essential component of the therapeutic strategy. Proinflammatory cytokines are necessary for initiating an effective inflammatory response against infection, whereas their excess production has been associated with tissue injury in multiple organ systems leading to increased mortality. In contrast, anti-inflammatory cytokines seem to be a prerequisite for controlling and down regulating the initial inflammatory response. But a sustained release of these biomolecules leads to a turn-down of immune activation within the host organism. In the clinical conundrums associated with sepsis, it was often observed that pathogen-responsive cells were exposed to a complex cytokine milieu. The excess production of proinflammatory cytokines is essential for the survival, replication and activation of phagocytic and cytotoxic immune cells. In conjunction with this proinflammatory activity, anti-inflammatory cytokines are also released which are involved in the occurrence of cellular anergy and impaired response to aetiologic agents, causing a compensatory anti-inflammatory response syndrome (CARS).Current practice in cardiac surgery is to review laboratory test results (CRP, PCT, blood culture) and clinical criteria (SOFA and STS) 48 h after surgery to diagnose sepsis. CRP and PCT lack sensitivity and specificity, whereas blood culture requires a long turnaround time and lacks sensitivity. Sepsis being an interplay between pro and anti-inflammatory response, the relative expression of immune biomarkers may provide a useful criterion for early diagnosis of sepsis. Thus, we aimed at investigating the variations in circulating levels of prominent cytokines and their potential use as a diagnostic marker of adult sepsis post cardiac surgery.MATERIALS AND METHODSIn this double-blinded cohort study, blood samples of adult patients undergoing cardiac surgery were collected before surgery (D -1), and on the post-operative day 1 (D +1) after the approval from the appropriate Institutional Ethics Committee. Patients who were deemed risky by EuroSCORE II risk stratification were included and immuno-compromised as well as patients with active infection before surgery were excluded. Plasma levels of IL-1β, IL-5, IL-6, IL-10, IL-17A and TNFα were determined using cytometric bead assay by flow cytometry and the results were analyzed using FCAP Array™ software. The data sets were analyzed (GraphPad Prism 5.02) and a p value of < 0.05 was considered statistically significant.RESULTSThe study was conducted with 34 patients (n=34) and un-blinded after retrieval of data. The cohort has 8 patients diagnosed with sepsis and 26 without sepsis based on STS criteria. Demographic details for both groups are summarized in Table 1. Cytokine and other biomarker expression levels before (D-1) and after (D+1) Surgery is summarized in Table 2. At D +1, IL-1β, TNF-α, IL-17A and IL-10 showed significantly higher concentration in sepsis group compared to non-sepsis group (Fig 1B). CRP, PCT, WBC and differential blood count were not showing any discriminatory potential between sepsis and non-sepsis patients at D +1. The ROC curves of the above four cytokine expression levels at D+1 was analyzed between sepsis and non-sepsis groups. A plasma IL-1β level of 0.25 pg/ml had a sensitivity of 87.5 % and a specificity of 53.8 % and a plasma IL-17A level of 1.78 pg/ml had a sensitivity of 75 % and specificity of 46.2 %. In addition, IL-10 level of 8.99 pg/ml in plasma showed a diagnostic sensitivity of 87.5 % and a specificity of 53.8% (Fig 1C). Based on the current observation we proposed a model of inflammatory cytokine dynamics involving IL-1β, IL-17A and IL-10 suggesting their role, which may lead to the development of sepsis (Fig 1D).CONCLUSIONWe identified a significant up regulation of circulating inflammatory cytokines at 24 h in patients who developed sepsis after cardiac surgery, earlier than any noticeable changes in conventional sepsis biomarkers. These results suggest the possibility of inflammatory cytokines as a diagnostic marker and may be a potential therapeutic target as well. The study needs to be validated further on a larger cohort of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A RARE AND COMPLEX CAUSE OF IMPOTENCE POEMS SYNDROME

Although plasma cell neoplasms occupy a large place in hematology practice, POEMS syndrome is very rare. Serum lambda light chain elevation and polyneuropathy, together with organomegaly, endocrinopathy, and skin lesions are the main components of the syndrome. We share our case, which we diagnosed in our clinic, with the belief that it will contribute to the literature. A 51-year-old male patient, who had no history of co-morbidity, drug use, or exposure to toxic substances, was started on supportive treatment in February 2021, who first developed the complaint of impotence. Later, he applied to the neurology outpatient clinic with complaints of weakness and weakness in the feet. After detecting polyneuropathy in his evaluation, IgG Lambda monoclonal gammopathy was detected in serum immune electrophoresis in his evaluation for etiology. Thereupon, it started to be investigated in terms of plasma cell neoplasms. In the examinations performed, immunoglobulin levels, serum-urine kappa and lambda light chain levels, plasma increase in the bone marrow biopsies and a solitary 3.3 cm sclerotic lesion in the sacral region were detected in the PET-CT of the patient, whose ethology could not be diagnosed. A tru-cut biopsy was taken from the sclerotic lesion of the patient, who was thought to be a plasmacytoma and a 20% monoclonal IgG lambda plasma increase was detected. In his physical examination, it was seen that he had increased lesions (Figure-1) and acrocyanosis (Figure-2) on the skin for the last 3-4 months. The patient's current complaints and laboratory results were evaluated with a preliminary diagnosis of POEMS syndrome (Table-1). POEMS syndrome is a rare disease and its exact incidence is unknown. It is frequently seen in 5-6 decades, with a median age of 51 years, and 63% of cases are male patients [1]. Chronic and excessive production of proinflammatory and other cytokines (IL-1β, TNFα, IL-6, vascular endothelial growth factor (VEGF) etc.), microangiopathy, edema, effusions, increase in vascular permeability, increase in neovascularization are important in the pathophysiology of the disease.

Protein PGLYRP1/Tag7 Peptides Decrease the Proinflammatory Response in Human Blood Cells and Mouse Model of Diffuse Alveolar Damage of Lung through Blockage of the TREM-1 and TNFR1 Receptors.

Infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in many cases is accompanied by the release of a large amount of proinflammatory cytokines in an event known as “cytokine storm”, which is associated with severe coronavirus disease 2019 (COVID-19) cases and high mortality. The excessive production of proinflammatory cytokines is linked, inter alia, to the enhanced activity of receptors capable of recognizing the conservative regions of pathogens and cell debris, namely TLRs, TREM-1 and TNFR1. Here we report that peptides derived from innate immunity protein Tag7 inhibit activation of TREM-1 and TNFR1 receptors during acute inflammation. Peptides from the N-terminal fragment of Tag7 bind only to TREM-1, while peptides from the C-terminal fragment interact solely with TNFR1. Selected peptides are capable of inhibiting the production of proinflammatory cytokines both in peripheral blood mononuclear cells (PBMCs) from healthy donors and in vivo in the mouse model of acute lung injury (ALI) by diffuse alveolar damage (DAD). Treatment with peptides significantly decreases the infiltration of mononuclear cells to lungs in animals with DAD. Our findings suggest that Tag7-derived peptides might be beneficial in terms of the therapy or prevention of acute lung injury, e.g., for treating COVID-19 patients with severe pulmonary lesions.

Effect of Tilorone on the Dynamics of Viral Load and the Levels of Interferons and Interleukin-1β in the Lung Tissue and Blood Serum of Mice with Experimental Influenza.

We studied the effect of tilorone on the dynamics of IFNα, IFNγ, and IL-1β levels in the lung tissue and blood serum in relation to viral load in the lungs of BALB/c mice with pneumonia caused by influenza virus A/Aichi/2/68 (H3N2). Tilorone was administered per os in doses of 40, 150, and 540 μg per mouse 6, 30, and 78 h postinfection, which simulated the drug regimen used in the clinic for the treatment of influenza and acute respiratory viral infections in Russia and post-Soviet countries. Tilorone reduced viral load with the maximum amplitude (2-3 lg) after 1-2 administrations. The results of studying the dynamics of the cytokine levels in the infected animals in general support the previous hypothesis that, in repeated dosing, tilorone enhances the IFN response (compensates for its deficiency) at the early stages of acute respiratory viral infections and suppresses (damps) excessive production of IFN and proinflammatory cytokines at the later stages.