Serum IL-6 Concentrations Research Articles

Danshensu exerts cardioprotective effects in rats with acute myocardial infarction via reduction of infiltration of inflammatory cells and mitigation of myocardial fibrosis

Purpose: To investigate the mitigative impact of danshensu on heart tissues in acute myocardial infarction (AMI) rats, and the mechanism of action involved.
 Methods: Seventy-five male Sprague-Dawley (SD) rats were used in this study. After successful induction of myocardial infarction, the rats were divided into model group (MG), low-dose danshensu group (LDG; 15 mg/kg), middle-dose danshensu group (MDG; 30 mg/kg), and high-dose danshensu group (HDG; 60 mg/kg), with 15 rats per group. Rats in sham group (SG; n = 15) served as control. Serum levels of biochemical indicators and expressions of various proteins in myocardial tissue were determined using Western blotting, and compared amongst the rat groups.
 Results: Serum cTnI concentrations in MDG and HDG were significantly decreased, relative to the corresponding concentrations in MDG. There were significantly lower serum concentrations of IL-1 in MDG and HDG than in model rats. Rats in HDG had lower serum IL-6 concentration than MG rats, while TNF-α levels were down-regulated in MDG and HDG, relative to MG (p < 0.05).
 Conclusion: Danshensu protects the heart function of rats with AMI by decreasing inflammationderived cells and mitigating myocardial fibrosis. Thus, it may be useful in the management of AMI in humans but clinical trials are necessary to ascertain this.
 Keywords: Danshens; Acute myocardial infarction; Myocardial ischemia-reperfusion; Myocardial fibrosis

Analysis of current status and influencing factors of inflammatory factors among electrical workers in Hainan province

Objective: To analyze the level and influence factors of inflammatory factors among electrical workers in Hainan Province. Methods: A total of 509 electrical workers were selected as the research subjects with random cluster sampling in September 2020. Basic information was collected by questionnaire, the serum IL-6, IL-8 and TNF-α levels of the subjects were detected by Luminex.Mann-Whitney U test and Kruskal-wallis H test were used for univariate analysis. Ordinal logistic regression analysis was used for potential influencing factors of the level of inflammatory factors. Results: The median concentrations of IL-6, IL-8 and TNF-α in serum were 2.78, 9.77 and 8.18 pg/ml. Compared with women, male was a risk factor for the increase of IL-6 levels (OR=1.80, 95%CI: 1.08~3.00, P=0.024) . Compared with 51-60 years old, 21-31 years old (OR=0.27, 95%CI: 0.18~0.42, P<0.001) , 31-41 years old (OR=0.27, 95%CI: 0.17~0.43, P<0.001) and 41-51 years old (OR=0.64, 95%CI: 0.41~0.99, P=0.043) were protective factors for the increase of IL-8 level. Compared with day shift workers, shift work was a risk factor for the increase of IL-8 level (OR=1.73, 95%CI: 1.21~2.48, P=0.003) . Compared with women, male was a risk factor for the increase of TNF-α levels (OR=2.87, 95%CI: 1.70~4.86, P<0.001) . Compared with workers who exposed to 7 or more occupational hazard factors, exposed to 1~3 (OR=0.53, 95%CI: 0.30~0.92, P=0.024) occupational hazard factors were protective factors for the increase of TNF-α levels. Conclusion: The level of inflammatory factors was related to sex, age, work system and occupational environment, which can provide basic data for follow-up research on occupational population.

Gut microbial sodium butyrate alleviates renal ischemia-reperfusion injury by regulating HES1/PPARα

This study investigated the effect of gut microbial sodium butyrate (NaB) on renal ischemia-reperfusion injury (IRI) and its mechanism using a rat model of renal IRI and a HK-2 cell model of hypoxia-reoxygenation (HR) injury. The activity of malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues and HK-2 cells was detected. ELISA was performed to measure the concentrations of TNF-α, IL-1β, and IL-6 in serum and cell culture supernatant. TUNEL staining and flow cytometry were used to assess apoptosis in kidney tissues and HK-2 cells, respectively. UCSC and JASPAR predicted the binding sites between HES1 and PPARα promoter, followed by experimental verification of the binding. NaB pretreatment inhibited oxidative stress, inflammation, and apoptosis following renal IRI in vivo and in vitro. NaB suppressed the expression of HES1 and promoted that of PPARα. Overexpression of HES1 or knockdown of PPARα in HR-treated HK-2 cells inhibited the protective effects of NaB. HES1 repressed the expression of PPARα by binding PPARα promoter. In conclusion, NaB may alleviate renal IRI by promoting the transcription of PPARα via downregulation of HES1.

Oxidative stress, biochemical, and histopathological changes associated with acute lumpy skin disease in cattle.

Background and Aim:Lumpy skin disease (LSD) is a highly infectious endemic viral disease of cattle in Africa and the Middle East. The objectives of this study were to assess histopathological changes in cattle infected with LSD and measure serum malondialdehyde (MDA – oxidant) and total anti-oxidant capacity (TAC – anti-oxidant), trace elements (zinc, copper, and iron), cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor-alpha [TNF-α]), haptoglobin (Hp), serum amyloid A (SAA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), blood urea nitrogen (BUN), and creatinine concentrations.Materials and Methods:Blood samples were collected from a total of sixty native and mixed breed cattle; (healthy; n = 25) and (LSD diseased; n = 35). Serum concentrations of MDA and TAC were measured by colorimetric methods. Serum IL-1β, IL-6, IL-10, TNF-α, Hp, and SAA concentrations were determined using human-specific enzyme-linked immunoassay kits.Results:Serum MDA, cytokine (IL-1β, IL-6, and TNF-α), Hp, SAA, AST, ALT, CPK, BUN, and creatinine concentrations were significantly higher, while TAC, IL-10, zinc, copper, and iron concentrations were significantly lower in LSD compared to healthy cattle (p < 0.05). Cows and exotic mixed breed cattle were at higher risk of LSD oxidative stress than bulls and local breeds (p < 0.05). Age was not associated with the risk of LSD (p > 0.05). Histologically, there was extensive tissue necrosis, severe vasculitis, mononuclear cell infiltration, and intracytoplasmic inclusion bodies.Conclusion:LSD is associated with pro-oxidative and pro-inflammatory states from imbalances that favor pro-oxidant and pro-inflammatory factors in the detriment of anti-oxidant and anti-inflammatory factors, leading to organ dysfunction and ultimately death. Oxidative stress is more frequent in cows and mixed breed cattle than in bulls and local breeds.

Serum IL-6 concentration correlates with plaque vulnerability and rupture in patients with severe carotid stenosis

Background and Aims : Myocardial or cerebral infarction is frequently caused by rupture of a vulnerable plaque. While imaging modalities can measure the degree of vessel stenosis, evaluation of plaque vulnerability remains challenging. We investigated whether plaque vulnerability is associated with distinct blood parameters, which could identify patients at high risk for rupture.

Psychosocial and biological predictors of resident physician burnout

BackgroundA high proportion of health professionals in training suffer from work-related stress and may develop a burnout syndrome. ObjectivesTo study the incidence of burnout after the first year of residency in a teaching hospital and to identify baseline psychological, psychosocial work conditions, and biological risk factors. MethodologyWe assessed the following in a prospective cohort of residents at baseline (first month residence) and after 1 year: background factors (socio-demographics, psychiatric history), perceived stress score (Perceived Stress Scale), Maslach Burnout Inventory score, and psychosocial factors (Job Content Questionnaire). Blood samples were obtained to study serum cortisol, IL-6, and TNF-α concentrations. The cumulative incidence was modelled by multivariate log-binomial regression analysis. ResultsWe included 71 participants with a female majority (64.8%), age 26.4 (2.65) years, psychiatric history in 20%, and burnout in 13%. Among those without burnout initially (N = 59), it had developed by 1 year in 22% of residents. Increased job demand (RR = 1.259, 95%CI = 1.019–1.556, p = 0.033) and decreased cortisol levels (RR = 0.877, 95%CI = 0.778–0.989, p = 0.032) predicted burnout after 1 year of residency among medical trainees. ConclusionBurnout syndrome develops in 22% of residents by 1 year of training and can be predicted by increased work demands and decreased cortisol levels.

Increased allergic and asthmatic risks in children residing in industrial areas by surveying the pre-inflammatory (IgE, IL-4 and IL-13) biomarkers.

Toxic metal(loid)s can lead to high damages on human. This work was conducted to investigate the levels of metal(loid)s in PM2.5 and a total of 123 male children's (aged 6-9years) blood chosen from different areas in Ahvaz and their association with the pre-inflammatory (Immunoglobulin E and cytokines: IgE, IL-4 and IL-13) responses in serum cells. Six metal(loid)s (arsenic, cadmium, chromium, mercury, nickel and lead) in three regions including industrial (Padad), vehicle traffic (Golestan) and reference (Kianpars) areas were studied. Results showed the concentrations of As, Cr, Cd, Ni and Hg in the ambient air of industrial area (Padad) (P < 0.001), and Pb in vehicle traffic area (Golestan) were higher (p < 0.001). Moreover, the mean levels of IgE (mean = 146.44pg/200landa, P < 0.003), IL-4 (mean = 548.23pg/200landa, P < 0.001) and IL-13 (mean = 53.21pg/200landa, P < 0.001) in Padad were higher than Golestan and Kianpars. Our results suggest that living in industrial areas leads to accelerated synthesis of IgE, IL-4 and IL-13 in blood. The spatial distribution of children's serum IgE, IL-4 and IL-13 concentrations showed an abnormal increase of 240 to 400pg/200landa for IgE, 950 to 1400pg/200landa for IL-4 and 90 to 128pg/200landa for IL-13. Our results indicate children in the industrial area are prone to asthma, allergy, miRNA mutation, and other chronic diseases.

Inflammatory Markers Combined With Metalloproteinase-9, Neopterin, and S100B Concentrations May Indicate the Pathogenesis of Central Nervous System Diseases in Children.

The identification of central nervous system inflammation etiology leads to adjusted therapy. We analyzed the potential inflammatory and neuro-axonal damage markers in children. Our target was to correlate the findings with a disease's course or a sequalae risk and assess their clinical usefulness. The study included 96 children with symptoms of central nervous system inflammation who underwent diagnostics. The research group involved 24 children with autoimmune disorders and 31 with neuroinfection. The control group included patients with both etiologies excluded. We analyzed the results of routine laboratory tests together with chosen serum (neopterin, interleukin [IL]-1β, IL-6) and CSF (metalloproteinase [MMP]-9, S100B protein) markers. In the whole cohort, CSF MMP-9 correlated with CSF cytosis and serum IL-6 and CRP. In the undivided neuroinflammatory group, CSF S100B correlated with serum IL-6 and IgM concentrations. CSF cytosis was associated with CSF MMP-9 and serum neopterin levels. Among the infective patients, IL-6 was linked with increased CSF MMP-9. We conclude that astroglial protein S100B, neopterin, and cytokine concentrations may enable predicting long-term consequences, whereas CSF MMP-9 concentration may reflect the actual central nervous system injury regardless of etiology.

ОСОБЕННОСТИ ЦИТОКИНОВОГО СТАТУСА ПРИ АКУШЕРСКИХ И ПЕРИНАТАЛЬНЫХ ОСЛОЖНЕНИЯХ У ЖЕНЩИН С ВНУТРИПЕЧЁНОЧНЫМ ХОЛЕСТАЗОМ БЕРЕМЕННЫХ

Background. Intrahepatic cholestasis of pregnancy (COP) is the most common complication of pregnancy that occurs during the 2nd-3rd trimester and is accompanied by liver damage manifested as cholestasis and cytolysis. Objective. To establish the role of cytokine response in the pathogenesis of COP as well as its obstetric and perinatal complications. Material and methods. 87 pregnant women were examined: 57 with intrahepatic cholestasis of pregnancy and 30 patients of the comparison group. The levels of pro-inflammatory (interleukin 6) and anti-inflammatory (interleukin 4) cytokines were determined by enzyme-linked immunosorbent assay, and their prognostic significance as predictors of obstetric and perinatal complications in women with COP was estimated. Results. The course of COP is accompanied by a decrease in the concentrations of IL-6 and IL-4 cytokines and a lower ratio of IL-4/IL-6 (P(U)IL-6=0.041; P(U)IL-4=0.0007 and P(U)IL4/IL-6=0.008). The concentration of IL-6 in blood serum that is &gt; 2.53 pg/ml (Se=83.3 %, Sp=73.9 %; AUC=0.822; 95 % CI 0.636–0.938; p=0.004) and IL-4 concentration that is &gt; 41.99 pg/ml in symptomatic COP (Se=100.0 %, Sp=78.6 %; AUC=0.839; 95 % CI 0.593–0.965; p=0.011) are regarded as a risk factor for preterm labor (PL) in women with COP. The concentration of IL-6 &gt; 3.07 pg/ml in women with COP and negative vaginal discharge culture can be considered as a predictor of meconium staining of amniotic fluid (MSAF) (Se=100.0 %, Sp=62.9 %; AUC=0.770; 95 % CI 0.597–0.895; p=0.024). Conclusions. COP is accompanied by a lower level of IL-6; an atypical immune deviation with no shift towards the Th2 immune response that is characteristic of a normal pregnancy; as well as an imbalance in the cytokine response with a decrease in the anti-inflammatory link. Preterm birth in patients with COP is associated with higher levels of IL-6 during pregnancy. The release of meconium into amniotic fluid in women with COP (in the absence of significant pathogenic and opportunistic microflora according to the results of vaginal discharge culture) correlates with higher concentrations of IL-6 in the blood.

Dietary supplemental synbiotic – yucca extract compound preparation modulates production performance, immune status and faecal microflora diversity in laying hens

ABSTRACT This research was designed to assess the influence of a synbiotic – yucca extract compound preparation (MCC) on production performance, faecal microbiota and immune in laying hens. A total of 180, 27-week-old healthy Hy-Line Brown laying hens were divided into 2 treatments with 6 replicates (15 birds/per replicates), including control group (CN), and treatment group with 3.34 g MCC/kg diet (MCC). The results revealed that supplementation of MCC in diet resulted in a greater laying rate in hens. The concentrations of serum IL-2, IL-6 and TNF-α were lower than CN group, whereas the concentrations of IgG and IL-10 in serum were higher in the MCC group. Furthermore, at the genus levels, the abundance of Romboutsia, and Helicobacter was lower, however, the abundance of Lactobacillus was higher when the hens were fed MCC. Therefore, the addition of MCC positively impacted the production performance, immune and faecal microbial diversity of laying hens.

Diurnal Differences in Intracellular Replication Within Splenic Macrophages Correlates With the Outcome of Pneumococcal Infection.

Circadian rhythms affect the progression and severity of bacterial infections including those caused by Streptococcus pneumoniae, but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication of S. pneumoniae within splenic macrophages, we sought to investigate whether events within the spleen correlate with differential outcomes of invasive pneumococcal infection. Utilising murine invasive pneumococcal disease (IPD) models, here we report that infection during the murine active phase (zeitgeber time 15; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. This correlated with significantly higher pneumococcal burden within the spleen of active phase-infected mice at early time points compared to rest phase-infected mice. Whole-section confocal microscopy analysis of these spleens revealed that the number of pneumococci is significantly higher exclusively within marginal zone metallophilic macrophages (MMMs) known to allow intracellular pneumococcal replication as a prerequisite step to the onset of septicaemia. Pneumococcal clusters within MMMs were more abundant and increased in size over time in active phase-infected mice compared to those in rest phase-infected mice which decreased in size and were present in a lower percentage of MMMs. This phenomenon preceded significantly higher levels of bacteraemia alongside serum IL-6 and TNF-α concentrations in active phase-infected mice following re-seeding of pneumococci into the blood. These data greatly advance our fundamental knowledge of pneumococcal infection by linking susceptibility to invasive pneumococcal infection to variation in the propensity of MMMs to allow persistence and replication of phagocytosed bacteria. These findings also outline a somewhat rare scenario whereby the active phase of an organism’s circadian cycle plays a seemingly counterproductive role in the control of invasive infection.

The Efficacy of Encapsulated Gamma-Cyclodextrin/Tributyrin on Growth and Inflammation in a Dextran Sodium Sulfate-Challenge Piglet Model

ObjectivesInflammatory bowel diseases are common in adults, and their incidence is increasing in children. Butyrate, a short chain fatty acid, can improve gut health, but its bitterness limits incorporation into foods. Herein, the efficacy of tributyrin (TB), a butyrate analog, encapsulated with ɣ-cyclodextrin (ɣ-CD) on growth and intestinal inflammation in a piglet model of dextran-sodium sulfate (DSS)-induced colitis was investigated. MethodsTwo-day-old piglets were randomized to three diets: control (formula alone, CON, N = 41), CD (CON + 9.0 mM ɣ-CD, N = 41), or CDTB (CON + 9.0 mM ɣ-CD/TB, N = 43). Half of the piglets in each group received DSS (1.25 g/kg body weight) from postnatal day (PND) 14 to 18. Blood and intestinal samples were collected on PND 19 and 27. IL-6 and TNF-α concentration in serum and colon mucosa were assessed by ELISA and IL-6, TNF-α, IL-10 and IFN-γ gene expression in colonic tissue were measured by qPCR. A quantitative histological grading system was used to assess 4 independent parameters: epithelial lining, cell infiltration, crypt damage and extent of the intestinal section affected. ResultsAverage daily weight gain (WG) between PND2-10 and 10–19 were affected by diet (P < 0.05), while colitis led to lower WG from PND19-27. A diet and colitis interaction indicated that after PND22 CDTB-COL piglets weighed less than CON and CD (P = 0.051). Diet had no impact on the descending colon (DC) morphology in the colitis animals, but the severity of the DC inflammation increased from PND19 and 27 (P < 0.0001). TNF-α and IL-6 concentrations were elevated in the ascending colon (AC) at PND19, but by PND27 concentrations were similar to non-colitis levels. A similar pattern was found in the DC, except that IL-6 remained elevated on PND27. IL-6, TNF-α and IFN-γ gene expression were significantly higher in the DC of colitis vs. non-colitis animals on PND27. Diet and colitis had no effect on serum TNF-α and IL-6. ConclusionsThe piglet as a model of DSS colitis is a feasible alternative to rodents. Dietary ɣ-CD/TB reduced growth rate and did not ameliorate the inflammatory process of DSS-induced colitis in neonatal pigs. Herein, oral administration of encapsulated TB did not reduce DSS-induced tissue damage or inflammation, however, additional studies are needed to confirm these observations. Funding SourcesNIFA, ISDA 2017–67,017-26,519.

Elevated osteopontin and IFNy serum levels and increased neutrophil-to-lymphocyte ratio are associated with the severity of symptoms in schizophrenia

IntroductionInflammation and immune dysregulation could contribute to the pathogenesis of schizophrenia. Osteopontin (OPN) is a key cytokine-like molecule in cellular immune response and it can directly modulate the cytokine expression and survival of microglia. Furthermore, its mRNA expression is elevated in first episode psychosis. Imbalance of T-helper subtypes could also represent a vulnerability factor for schizophrenia.ObjectivesThe aim of this study was to evaluate the relevance of T-helper subtype associated cytokines, OPN and NLR in the assessment of the severity of schizophrenia.Methods22 patients with schizophrenia were assessed for the intensity of their symptoms by PANSS and CGI scores. Serum OPN, IFNy, IL-10 and IL-8 concentrations were measured by ELISA kits and NLR was calculated from blood count. Statistical evaluation was performed using Mann-Whitney U test, Student’s t test and Spearman correlation.ResultsWe found significant correlation between the level of OPN and PANSS-total, PANSS-general scores. IFNy level and NLR showed significant correlation with PANSS-total, PANSS-positive, PANSS-general and CGI score. Antipsychotic therapy only had significant effects on NLR and OPN levels, both of which were significantly reduced after long-term antipsychotic treatment.ConclusionsOur results indicate that elevated OPN and IFNy concentrations, and increased NLR are associated with severe symptoms in schizophrenia and suggest the importance of Th1 subtype in patients with high PANSS-positive and PANSS-general score. Antipsychotic treatment had significant effects on the level of OPN and NLR, but not on the level of IFNy. Overall our results strengthen the inflammation hypothesis of schizophrenia.DisclosureNo significant relationships.

The significance of surface neutrophilic MPO expression level in NETosis and NETosis-associated coagulopathies in covid-19 infected patients

IntroductionInflammatory response-induced coagulopathy is a common complication associated with severe form of covid-19 infection. Evidences suggest that neutrophil extracellular traps (NETs) play a significant role in triggering the immunothrombosis in this condition. We aimed to evaluate the diagnostic value of surface neutrophilic myeloperoxidase (MPO) as NETosis biomarker for predicting the risk of covid-19-associated coagulopathies. MethodsCovid-19 infection was assessed by real-time-PCR and plasma d-dimer levels were measured by ELFA. Based on the covid-19 infection and d-dimer level outcomes, patients were categorized into four groups. Any alteration in the serum level of IL-6, H3Cit and neutrophilic surface MPO were analyzed by CLIA, ELISA, and flow cytometry, respectively. ResultsH3Cit variations and different d-dimer values confirmed the association between NETosis and coagulopathies. Findings showed that the expression of neutrophilic MPO reduced in cases with NETosis, which was correlated with increased levels of H3Cit. ANC/MPO ratio was signified as a valuable marker to discriminate the covid-19 and non covid-19-associated coagulopathies and could be considered as a prognostic factor due to its noteworthy correlation with serum IL-6 concentration. ConclusionDeclined levels of surface neutrophilic MPO in NETosis correlate with covid-19-associated coagulopathies and increased IL-6 levels, as a potential biomarker of covid-19 disease severity.

Serum concentrations of leptin and adiponectin in dogs with chronic kidney disease.

BackgroundAn imbalance in adipokines is associated with the progression of chronic kidney disease (CKD) in humans. However, alterations in adipokines in dogs with CKD remain unclear.ObjectivesTo examine whether adipokine concentrations in serum differ between healthy dogs and dogs with CKD and to determine the correlation between serum adipokine concentrations and CKD severity in dogs.AnimalsTwenty dogs with CKD and 10 healthy dogs.MethodsIn this cross‐sectional study, serum concentrations of leptin, adiponectin, interleukin (IL)‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF)‐α were measured in healthy dogs and dogs with CKD, which were classified according to the International Renal Interest Society guidelines.ResultsSerum leptin concentrations were positively correlated with systolic arterial blood pressure (r = .41), creatinine concentrations (r = .39), and symmetric dimethylarginine concentrations (r = .73). Serum adiponectin concentrations (median [range]) in CKD dogs with borderline or non‐proteinuric (20.25 [14.9‐45.8] ng/mL) were significantly higher than those in proteinuric CKD dogs (13.95 [6.4‐22.1] ng/mL; P = .01). Serum IL‐6 (median [range]; 43.27 [24.30‐537.30] vs 25.63 [6.83‐61.03] pg/mL; P = .02), IL‐18 (median [range]; 25.98 [11.52‐280.55] vs 10.77 [3.53‐38.45] pg/mL; P = .01), and TNF‐α (median [range]) concentrations (11.44 [8.54‐38.45] vs 6.105 [3.97‐30.68] pg/mL; P = .02) were significantly different between proteinuric and borderline or non‐proteinuric CKD dogs.Conclusions and Clinical Importanceleptin and adiponectin concentrations in serum might be associated with severity of CKD and proteinuria in dogs with CKD, respectively.

CHARACTERISTICS OF IMMUNOREACTIVITY IN PATIENTS WITH VARIOUS FORMS OF DIABETIC FOOT ULCER

The article presents a comparative assessment of the levels of cytokines that regulate the differentiation of various macrophage phenotypes, as well as immunological responses in patients with diabetes. We examined and treated 245 patients who were allocated to two groups. The first group comprised neuropathic patients (comparison subgroup 1A without DFU, n=30 and subgroup 1B with DFU, n=80). The second group included patients with neuroischemic type 2 diabetes (comparison subgroup 2A without DFU, n=35 and subgroup 2B with DFU, n=100). As an indicator of hyperglycemia, the glycated hemoglobin level (HbA1c) was used, which was determined on the DCA 2000 device by the method of latex immunoagglutination inhibition using the “Hemoglobin A1c Reagent kit”. The concentration of cytokines TNF-α, IFN-γ, IL-6, and OPG in blood serum was determined on the first day of hospitalization before surgery using enzyme immunoassay test systems (OOO “Cytokine”, St. Petersburg) in accordance with the manufacturer's instructions. An imbalance of cytokines was revealed, indicating a shift in immunomodulatory responses, aggravation of metabolic and vascular disorders in tissues, accompanied by an inadequate course of the inflammatory and reparative process and the formation of a diabetic foot ulcer.

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

BackgroundSevere COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.MethodsThe potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.ResultsFamotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.ConclusionsThese observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

MO688: Peritoneal Protein Clearance, Inflammation, Nutrition and Overhydration in PD Patients: Looking for the Culprit

Abstract BACKGROUND AND AIMS Peritoneal protein loss has been for many years seen as a detrimental consequence of peritoneal dialysis (PD). Many studies correlated this leakage with mortality, malnutrition and inflammation. More recent knowledge has brought overhydration to this equation. This study aims to review classic and recent factors associated with peritoneal protein clearance and its consequences on overall mortality. METHOD Prevalent and incident PD patients were included. Interleukin 6 (IL-6; dialysate and serum) was obtained during a 3.86% glucose peritoneal equilibration test. Hydration and nutritional status was assessed by bioimpedance. Linear and Cox regression were performed. RESULTS A total of 78 patients were included (54 incident, 24 prevalent), the mean age was 54.6 ± 18.1 years, 65% were males, and the mean follow-up was 33.9 ± 29.3 months. The mean Charlson comorbidity index (CCI) was 4.4 ± 2.4. The residual GFR was 6.7 ± 3.6 mL/min/1.73 m2 and the D/P creatinine 0.65 ± 0.12. The IL-6 concentration in the dialysate was 24.9 ± 30.8 pg/mL and in serum was 37.3 ± 5.1 pg/mL. The phase angle was 5.4 ± 1.1°, overhydration 0.88 ± 0.94 L and peritoneal protein clearance 85.6 ± 54.7 mL/24 h. Overall, eight patients died. Linear univariable analysis showed positive associations between peritoneal protein clearance and (i) small solute transport, as measured by D/P creatinine, (ii) body composition, as measured by phase angle and overhydration and (iii) CCI. The peritoneal protein clearance also correlated positively with dialysate IL-6, but not with serum IL-6. By linear multivariable analysis, using the backward method, a significant positive association between peritoneal protein and overhydration (P &amp;lt; 0.001; IC:26.665–71.694) and also phase angle (P = 0.032; IC: 1.845–39.330) were validated. In the exploratory survival analysis, no relationship was found between mortality and peritoneal protein clearance. A univariable positive association was shown with serum IL-6 concentration, overhydration and CCI. A higher phase angle was associated with lower mortality. No relationship with dialysate IL-6 or D/P creatinine was found. In this early-stage PD population, with globally preserved residual kidney function, an effect of this variable on mortality was not evident. Cox regression, conditional backward method, showed CCI (OR: 1.896, IC: 1.235–2.913, P = 0.003), overhydration (OR: 10.034, IC: 1.426–70.587, P = 0.021) and peritoneal protein clearance (OR: 0.576, IC: 0.339–0.978, P = 0.041) were predictors for mortality. CONCLUSION A better nutrition status and overhydration are the major determinants of peritoneal protein clearance. The survival analysis showed that mortality is higher in overhydrated patients, with higher CCI, but not with higher peritoneal protein clearance. Inflammation, local or systemic, as assessed by IL-6 concentration, did not reveal to be such a strong prognosis predictor as overhydration in these PD patients.

Three important short-chain fatty acids (SCFAs) attenuate the inflammatory response induced by 5-FU and maintain the integrity of intestinal mucosal tight junction

Background5-Fluorouracil (5-FU) is a used chemotherapy drug for cancer, and its main side effect is intestinal mucositis which causes chemotherapy to fail. It was known that short-chain fatty acids (SCFAs) can inhibit immune cell release of various proinflammatory factors and inhibit excessive intestinal inflammation. However, the inhibitory effect of SCFAs on 5-FU-induced intestinal mucositis is still unclear.ResultsTo simulate the effects of SCFAs on immune and intestinal epithelial cells, the cells (THP-1 cells and Caco-2 cells) were pretreated with sodium acetate (NaAc), sodium propionate (NaPc) and sodium butyrate (NaB), then inflammation was induced by 5-FU. The expressions of reactive oxygen species (ROS), Beclin-1, LC3-II, NF-κB p65, NLRP3 inflammasome, proinflammatory/anti-inflammatory cytokines and mucosal tight junction proteins were determined. In our results, the three SCFAs could inhibit ROS expressions, NLRP3, Caspase-1, IL-1β, IL-6, IL-18, Beclin-1 and LC3-II, when induced by 5-FU. In a 5-FU-induced chemoentermuctis mouse model, Lactobacillus rhamnoides can increase the concentrations of three SCFAs in faeces and increase the concentrations of IL-1β, IL-6 and IgA in serum, and decrease the expressions of NLRP3 and IL-17 in spleen cells. The expressions of ZO-1 and Occludin in intestinal mucosa were significantly increased.ConclusionsThese results indicated that the three SCFAs can effectively suppress the inflammation of THP-1 cells and Caco-2 cells and maintain tight junction integrity in intestinal mucosal epithelial cells.

Macrophages in epicardial adipose tissue and serum NT-proBNP in patients with stable coronary artery disease

Coronary artery disease (CAD) is widely considered a chronic inflammatory disorder, and dysfunction of epicardial adipose tissue could be an important source of the inflammation. Amino-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) is a known marker of cardiovascular disorders of cardiac origin. Recent studies show that inflammatory stimuli may influence its secretion. Our purpose was to evaluate NT-proBNP serum concentration in relation to immune cell ratios in epicardial adipose tissue (EAT), and cytokine levels in the patients with stable CAD. Patients with stable CAD and heart failure classified into classes II–III, according to the New York Heart Association (NYHA) scale, scheduled for the coronary artery bypass graft (CABG) surgery, were recruited into the study (n = 10; 59.5 (53.0-65.0) y. o.; 50% males). The EAT and subcutaneous adipose tissue (SAT) specimens were harvested in the course of CABG surgery. Immunostaining with anti-CD68, anti-CD45, antiIL-1β and anti-TNFα monoclonal antibodies was performed to evaluate cell composition by differential counts per ten fields (400 magnification). Fasting venous blood was obtained from patients before CABG. Blood was centrifuged at 1500g, aliquots were collected and stored frozen at -40 °С until final analysis. Concentrations of NT-proBNP, IL-1β, IL-6, IL-10, TNFα were determined in serum samples by enzyme-linked immunosorbent assay (ELISA). We have found increased production of IL-1β and TNFα cytokines in EAT compared to SAT. Concentrations of NT-proBNP exceeded 125 pg/ml in 4 patients, and correlations between the CD68+macrophage counts in both EAT and SAT samples (rs= 0.762; p = 0.010 and rs= 0.835; p = 0.003, respectively). NT-proBNP levels showed positive relations with CD45+leukocyte counts (rs= 0.799; p = 0.006), and with IL-1β+cell numbers (rs= 0.705; p = 0.023) in EAT samples only. As for the serum biomarkers, NT-proBNP levels showed negative correlation with fasting glucose levels (rs= -0.684; p = 0.029), and positive correlation with serum IL-6 concentrations (rs= 0.891; p = 0.001). Increased serum concentrations of NT-proBNP in CAD patients correlate with accumulation of macrophages in EAT, which is associated with increased production of IL-1β in EAT and correlates with some metabolic parameters.