Blood IL-6 Concentrations Research Articles

Cholesterol to saturated fat index (CSI), metabolic parameters and inflammatory factors among obese individuals

BackgroundThe role of dietary fat quality in promotion of cardiovascular diseases is studies before. However, the results are inconsistent. Recently, cholesterol to saturated fatty acid index (CSI) is suggested as a novel indicator of the atherogenicity and thrombogenicity potential of a diet. However, due to limited number of studies, in the current cross-sectional study, we aimed to evaluate the role of CSI in metabolic and inflammatory response among obese individuals.MethodsIn the current cross-sectional study 488 obese individuals aged 18–50 years old were involved in volunteer based invitation from outpatient obesity clinics. Subjects underwent anthropometric assays including weight, height, waist circumference (WC) and body composition and their fasting blood sample were obtained for biochemical assessments including blood sugar, serum lipids, hs-CRP and IL-6 concentrations by commercial kits. Physical activity was also assessed by short form of international physical activity questionnaire (IPAQ).ResultsAccording to our results, being at the top tetile of CSI was associated with higher anthropometric indices including weight, height, WC, FFM, and basal metabolic rate (BMR) compared with those at the lowest tertile (P < 0.05). Similarly, those at the highest category of CSI had significantly higher levels of serum glucose and hs-CRP both in crude and adjusted models in ANCOVA and in multinomial logistic regression models (P < 0.05).ConclusionIn the current study, for the first time, we identified the possible triggering role of dietary cholesterol to saturated fat index in increasing serum glucose and hs-CRP levels. due to cross-sectional design of the current study, causal inference is impossible. Further studies will help for better scientific justification.

Prenatal exposure to intra-amniotic infection with Ureaplasma species increases the prevalence of bronchopulmonary dysplasia

Objectives The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with Ureaplasma species. Methods This was a single-center, retrospective cohort study. Patients with singleton pregnancies who underwent inpatient management at our department for preterm premature rupture of membranes (PPROM), preterm labor, cervical insufficiency, and asymptomatic cervical shortening at 22–33 gestational weeks were included. Amniocentesis was indicated for patients with PPROM or an elevated maternal C-reactive protein level (≥0.58 mg/dL). Patients with an amniotic fluid IL-6 concentration ≥3.0 ng/mL were diagnosed with intra-amniotic inflammation, while those with positive aerobic, anaerobic, M. hominis, and Ureaplasma spp. cultures were diagnosed with microbial invasion of the amniotic cavity (MIAC). Patients who tested positive for both intra-amniotic inflammation and MIAC were considered to have intra-amniotic infection. An umbilical vein blood IL-6 concentration >11.0 pg/mL indicated fetal inflammatory response syndrome (FIRS). The maternal inflammatory response (MIR) and fetal inflammatory response (FIR) were staged using the Amsterdam Placental Workshop Group Consensus Statement. Results Intra-amniotic infection with Ureaplasma spp. was diagnosed in 37 patients, intra-amniotic infection without Ureaplasma spp. in 28, intra-amniotic inflammation without MIAC in 58, and preterm birth without MIR/FIR and FIRS in 86 as controls. Following an adjustment for gestational age at birth, the risk of BPD was increased in patients with intra-amniotic infection with Ureaplasma spp. (adjusted odds ratio: 10.5; 95% confidence interval: 1.55–71.2), but not in those with intra-amniotic infection without Ureaplasma spp. or intra-amniotic inflammation without MIAC. Conclusion BPD was only associated with intra-amniotic infection with Ureaplasma species.

Intracerebral Hemorrhage Leads to Anemia By Disrupting Erythropoiesis and Erythromyeloblastic Islands

Intracerebral hemorrhage (ICH), caused by the rupture of a cerebral vessel and subsequent entry of blood into the brain parenchyma, is a major form of acquired brain injury and contributes a remarkable proportion of stroke-related morbidity and mortality. Due to the few proven effective emergency and preventive treatments, patients who survived suffer varying degrees of poor prognosis that affect their quality of life. There is an urgent need to explore the cellular and molecular basis of the differences in the severity and prognosis of ICH. Anemia is a common manifestation of ICH. However, the mechanisms underlying ICH-induced anemia as we as the correlation between anemia and ICH progression/prognosis remain unclear. In this study, we found that approximately 35.1% (39 of 111) of ICH patients exhibited anemia and that decreased hemoglobin levels were positively associated with higher scores on the National Institutes of Health Stroke Scale, which quantifies the degree of neurological deficit, at admission. Furthermore, patients with decreased hemoglobin levels at admission showed higher modified Rankin scale scores at 3 months, which reflect the global disability of daily living at this time, suggesting that anemia was associated with a more severe progression and poor patient prognosis. To investigate the effects of ICH on bone marrow (BM) erythropoiesis, we conducted experiments in 12-month-old mice with collagenase-induced striatal ICH. Our results showed that ICH caused apparent anemia on day 3, associated with larger hematomas in the striatum and more severe neurologic deficits. We first evaluated the phenotype of hematopoietic progenitors and found that mice suffering ICH exhibited increased granulocyte monocyte progenitors but a significant decrease in common myeloid progenitors and megakaryocyte erythrocyte progenitors compared to control mice, suggesting a reduced source of erythroid progenitors. Further analysis revealed that the colony-forming ability of erythroid progenitors and subsequent terminal differentiation was significantly suppressed after ICH. To assess whether ICH-induced suppression of erythropoiesis is associated with erythromyeloblastic islands (EMBIs), the niche for erythropoiesis/myelopoiesis, we performed ICH using 12-month-old EpoR-tdTomato-Cre mice and found that the number of BM EMBIs and EpoR + macrophages decreased significantly. Moreover, the number and proportion of developing erythroid cells surrounding EMBIs decreased while LY6G + cells representing granulocytes increased prominently, indicating an altered microenvironment, with EMBI favoring granulopoiesis over erythropoiesis after ICH. Studies have shown that inflammation plays a crucial role in secondary brain injury after ICH. We hypothesize that inflammatory cytokines may contribute to the suppression of erythropoiesis observed in ICH mouse models. To test this, we measured inflammatory factors in both peripheral blood and BM fluid using Quantibody Mouse Inflammation Array. In particular, IL-6 concentrations in peripheral blood and BM fluid in ICH mice were significantly higher than controls. Treatment with MR16-1, an IL-6 antagonist, alleviated ICH-induced anemia and improved BM erythropoiesis in ICH mice, as evidenced by increased peripheral red blood cells and hemoglobin levels, elevated numbers of erythroid progenitors and terminal erythroblast. MR16-1 treatment also improved BM EMBI formation and increased EpoR + macrophages. In addition, MR16-1 treatment effectively improved neurologic deficits and reduced brain hematoma after ICH. Administration of recombinant IL-6 to wild-type mice resulted in decreased levels of red blood cells and hemoglobin along with suppression of erythropoiesis in the BM. Collectively, these results suggest that ICH modulates erythropoiesis and erythromyeloblastic islands function to ultimately lead to anemia and reveal a possible therapeutic opportunity to reverse ICH-induced anemia and improve ICH prognosis by targeting IL-6.

The effect of Lignova sorbent to the concentration of interleukin-6 in the blood and bile in patients with mechanical jaundice of tumors etiology

The OBJECTIVE was to study changes of IL-6 concentration in the blood and bile in patients with MJ of tumor genesis by means of biliary sorption.METHODS AND MATERIALS. The investigation was conducted to study changes in the concentration of IL-6 in the blood and bile against the background of bile sorption in 105 patients with mechanical jaundice (MJ), the cause of obturation was a tumor of the periampullary zone. The patients are divided into two groups. The first group consisted of 51 patients, the second group included 54 patients. All patients of the main group underwent percutaneous perhepatic cholangiostomy for the purpose of decompression; bile sorption was performed using the domestic Lignov enterosorbent. The level of IL-6 in blood serum and bile was determined by enzyme immunoassay.RESULTS. The use of bile sorption in the treatment complex significantly changed the concentration of IL-6 in blood serum (P&lt;0.01) and bile. Determination of IL-6 in blood and bile makes it possible to more objectively assess the degree of cytokine-induced endogenous intoxication in response to ongoing therapeutic measures for tumors of the periampullary zone complicated by mechanical jaundice. The use of bile sorption contributes to a decrease in the concentration of the pro-inflammatory cytokine IL-6 in the blood and bile as an inducer of endogenous intoxication and a cascade of inflammatory processes in patients with tumors of the periampullary zone complicated by mechanical jaundice.CONCLUSION. Bile sorption application helps to decrease proinflammatory cytokine IL-6 concentration in blood and bile as an inductor of endogenous intoxication and inflammatory processes cascade.

Maternal SARS-CoV-2 Infection at Delivery Increases IL-6 Concentration in Umbilical Cord Blood.

SARS-CoV-2 infection in pregnant women may induce inflammation within the amniotic cavity and/or an increase in proinflammatory cytokines in fetal circulation. The aim was to investigate levels of IL-6 in maternal blood, umbilical cord blood, and amniotic fluid in pregnant women infected with SARS-CoV-2 at delivery. A single-center prospective observational case-control study of pregnant women diagnosed with SARS-CoV-2 infection at delivery was conducted. A total of 48 infected and 42 healthy women had IL-6 concentrations measured in their blood, amniotic fluid, and umbilical cord blood. The concentrations of IL-6 in maternal blood and amniotic fluid were similar in the study and control groups, while umbilical cord blood concentrations were significantly higher in SARS-CoV-2-positive women. The umbilical cord blood IL-6 concentration was related to composite neonatal morbidity. Maternal SARS-CoV-2 infection in pregnant women at delivery increases umbilical cord blood IL-6 concentration. The correlation between maternal and umbilical blood concentrations indicates a possibility of passage of IL-6 through the placenta. Perinatal alterations resulting from maternal SARS-CoV-2 infection at delivery carry a risk of impacting the health of infants even in asymptomatic course of infection.

An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of &gt;50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .

Association of interleukin-6 level and DNA polymorphism in type 2 diabetic patients in Kirkuk city

The basic inflammatory factor interleukin-6 plays an important role in the inflammatory response. It has been shown that IL-6 has a role in insulin resistance and T2DM. The IL-6 gene is found on chromosome 7p15-p21 in humans, it works via a receptor composed of two components, the IL-6 receptor, and gp130. Single nucleotide polymorphisms in the regulatory areas of IL-6R genes influence their expression levels and are linked to a higher risk of T2DM. There were 80 T2DM patients and 80 healthy people enrolled in the present work. Fasting blood glucose levels, HbA1C, and IL-6 concentrations were estimated in both groups. The allelic frequencies of 2 single nucleotide polymorphisms (rs2229238, rs4845625) were identified by PCR-SSP. In this study, we found that the fasting blood sugar levels, HbA1c, and IL-6 levels were statistically highly significant in patients in comparison with controls. In regarding the association of genotypic (CC, CT, TT) and allelic frequencies of rs2229238, and rs4845625 polymorphism of the gene IL6R, and prevalence of diabetes mellitus. The results of PCR-SPP products of rs2229238 (C/T) of the IL6R gene indicated the significant correlation the rs4845625 IL6R polymorphism with T2DM, where no significant association was observed between these genotypes (CC, CT, TT) and allelic (T) frequencies of rs2229238 as a risk factor and T2D.

Ursolic acid does not change the cytokine levels following resistance training in healthy men: A pilot balanced, double-blind and placebo-controlled clinical trial.

Ursolic acid (UA) is a natural compound that shows anti-inflammatory actions. However, no human studies have investigated the cytokine profile during the RT and UA consumption. The purpose of this study was to verify if UA is able to potentiate the anti-inflammatory activity after RT, reflecting in the reduction of blood inflammatory markers in healthy men. Twenty-seven participants were allocated to two groups: control (CON) (n=13) and UA (n=14). For 8weeks, each group performed RT and consumed capsules containing a placebo (400mg/day) or UA (400mg/day). Serum cytokine concentrations were evaluated before and after the training period. There was no difference in the serum cytokine concentrations of TNF-α, IL-10 and IL-6 (p>0.05). In conclusion, UA supplementation for 8weeks was not able to change the blood TNF-α, IL-10, and IL-6 concentrations in healthy men undergoing RT. However, further studies are warranted to investigate other inflammatory markers.

T cell counts and IL-6 concentration in blood of North African COVID-19 patients are two independent prognostic factors for severe disease and death.

The immune system plays a crucial role in the response against severe acute respiratory syndrome coronavirus 2 with significant differences among patients. The study investigated the relationships between lymphocyte subsets, cytokines, and disease outcomes in patients with coronavirus disease 2019 (COVID‐19). The measurements of peripheral blood lymphocytes subsets and cytokine levels were performed by flow cytometry for 57 COVID‐19 patients. Patients were categorized into two groups according to the severity of the disease (nonsevere vs. severe). Total lymphocytes, T cells, CD4+ T cells, CD8+ T cells, B cells, and natural killer cells were decreased in COVID‐19 patients and statistical differences were found among different severity of illness and survival states (P ˂ 0.01). The levels of IL‐6 and IL‐10 were significantly higher in severe and death groups and negatively correlated with lymphocyte subsets counts. The percentages of Th17 in the peripheral blood of patients were higher than those of healthy controls whereas the percentages of Th2 were lower. For the severe cases, the area under receiver operating characteristic (ROC) curve of IL‐6 was the largest among all the immune parameters (0.964; 95% confidence interval: 0.927–1.000, P < 0.0001). In addition, the preoperative IL‐6 concentration of 77.38 pg/ml was the optimal cutoff value (sensitivity: 84.6%, specificity: 100%). Using multivariate logistic regression analysis and ROC curves, IL‐6 > 106.44 pg/ml and CD8+ T cell counts <150 cells/μl were found to be associated with mortality. Measuring the immune parameters and defining a risk threshold can segregate patients who develop a severe disease from those with a mild pathology. The identification of these parameters may help clinicians to predict the outcome of the patients with high risk of unfavorable progress of the disease.

INFLUENCE OF THERAPY UPON LPS-INDUCED CYTOKINE SECRETION BY THE BLOOD-DERIVED INNATE IMMUNITY CELLS OF THE BRONCHIAL ASTHMA PATIENTS

Bronchial asthma (BA) is the most widespread chronic inflammatory disease. Since BA is associated with a systemic inflammation state, a comprehensive study of its effect in this disease, and influence of pathogenetic therapy should be performed, by studying the whole blood cytokine status of the patients suffering with BA. The cells from respiratory tract in acute-phase BA patients may produce pro-, as well as anti-inflammatory mediators. The anti-inflammatory mediators are able to suppress activity of immune cells in peripheral blood. Thus, the aim of present study was to evaluate eventual inflammation-associated and functional activity of immune cells from the patients’ peripheral blood in BA and following appropriate therapy. Bacterial lipopolysaccharide (LPS) a classical pro-inflammatory agent. We have studied an LPSinduced cytokine-induced ex vivo secretion model by peripheral blood immune cells, as a relevant test for their functional activity. The LPS-induced responses of whole blood cells from patients with proven BA diagnosis have been studied at pre-treatment time points, and following two weeks of basic anti-inflammatory therapy. According to clinical indications, the antagonists of CysLTR1, or combinations of glucocorticosteroids and β-adrenoreceptor agonists were administered by inhalation to BA patients. LPS-induced production of TNFα, IL-6, IL-8 (at 6 h) and IFNγ, IL-17A or IL-1β (at 24 h) by whole blood cells from BA patients or healthy volunteers has been assessed by ELISA technique. The cytokine production from non-stimulated whole blood cells from BA patients and healthy volunteers were used as the baseline control. IL-4 concentrations in plasma of BA patients and healthy volunteers were also measured. We have shown a decrease of IL-6 production in control blood samples from BA patients after two weeks of therapy. This may indicate the attenuation of the observed inflammatory process. The therapy applied did not influence the background levels and LPS-induced secretion of IL-1β, IL-1ra, IFNγ, and IL-8 in whole blood samples from BA patients. IL-4 plasma levels in BA patients were not changed after two weeks of therapy. It has been shown that whole blood from BA patients produced less TNFα and IL-8, both in control samples, and during their response to LPS, than the values obtained in healthy volunteers. These findings are in agreement with a notion that BA causes partial depression of innate immune cells activity. The increased LPS-induced TNFα secretion by the whole blood cells from BA patients has been observed following two weeks of basic anti-inflammatory therapy. We suggest that the increased LPS-induced TNFα secretion could be explained by partial restoration of peripheral blood immune cell activity associated with anti-inflammatory BA therapy. To elucidate the mechanism of increased LPS-induced TNFα secretion, we have estimated whole blood concentration of soluble CD14 (sCD14) in BA patients. No significant differences between sCD14 concentrations have been found. Obtained result presume existence of sCD14-independent mechanism of TNFα regulation by whole blood cells in response on LPS which may occur during anti-inflammatory therapy of BA. We suppose that basic anti-inflammatory therapy of BA does not simply reduce IL-6 concentration in peripheral blood, but may also partially restore the activity of innate immune cells in BA patients.

Influence of postoperative analgesia on systemic inflammatory response and postoperative cognitive dysfunction after femoral fractures surgery: a randomized controlled trial.

To investigate the possible effect of postoperatively applied analgesics-epidurally applied levobupivacaine or intravenously applied morphine-on systemic inflammatory response and plasma concentration of interleukin (IL)-6 and to determine whether the intensity of inflammatory response is related to postoperative cognitive dysfunction (POCD). This is a randomized, prospective, controlled study in an academic hospital. Patients were 65 years and older scheduled for femoral fracture fixation from July 2016 to September 2017. Inflammatory response was assessed by leukocytes, neutrophils, C reactive protein (CRP) and fibrinogen levels in four blood samples (before anesthesia, 24 hours, 72 hours and 120 hours postoperatively) and IL-6 concentration from three blood samples (before anesthesia, 24 hours and 72 hours postoperatively). Cognitive function was assessed using the Mini-Mental State Examination preoperatively, from the first to the fifth postoperative day and on the day of discharge. The study population included 70 patients, 35 in each group. The incidence of POCD was significantly lower in the levobupivacaine group (9%) than in the morphine group (31%) (p=0.03). CRP was significantly lower in the levobupivacaine group 72 hours (p=0.03) and 120 hours (p=0.04) after surgery. IL-6 values were significantly lower in the levobupivacaine group 72 hours after surgery (p=0.02). The only predictor of POCD in all patients was the level of IL-6 72 hours after surgery (p=0.03). There is a statistically significant association between use of epidural levobupivacaine and a reduction in some inflammatory markers. Postoperative patient-controlled epidural analgesia reduces the incidence of POCD compared with intravenous morphine analgesia in the studied population. NCT02848599.

Vactosertib, a TGF-ß Receptor I Kinase/ALK5 Inhibitor, Diminishes Tumor Progression and Bone Disease in a Mouse Model of Multiple Myeloma and Overcomes Resistance to Proteasome Inhibitors

Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by osteolytic bone disease and immunosuppression. Transforming growth factor-beta (TGF-β) supports MM progression through its role in stimulation of IL-6, Th17/regulatory T cell development, hematopoietic suppression, and its promotion of catabolic bone remodeling. Inhibition of the proteasome has emerged as a powerful strategy for treatment of MM. Proteasome inhibitors (PIs) have improved overall survival in patients with MM, but the majority develop drug resistance. Therefore, a novel therapeutic strategy is needed for better treatment of MM. Vactosertib (VACTOSERTIB) is an orally bioavailable small molecule inhibitor of the TGF-β type I receptor kinase (TβRI) currently in a phase I clinical trial (NCT03143985) in combination with the immunomodulatory drug, pomalidomide. In this study, we first investigate if Vactosertib is capable of diminishing myeloma progression either as a single agent or in combination with the PI, ixazomib.Methods: Expression levels of TGF-β1 and phospho-Smad2/3 was examined in human and mouse MM cells and bone marrow by Western blot and immunohistochemistry (IHC). Cellular and molecular assays were performed in human RPMI8226, ARH-77 and PIs-resistant RPMI8226 as well as murine 5T33MM cells via MTT, apoptosis, real-time PCR and Western blot. For preclinical evaluation, C57BL/KaLwRij mice bearing 5T33MM cells expressing luciferase were treated with Vactosertib, ixazomib, or the combination of Vactosertib plus ixazomib for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Peripheral blood IL-6 and monoclonal protein concentration, M-spike, were measured by ELISA. Fluorescence-activated cell sorting (FACS) analyses were used for immunological evaluation, such as myeloid derived suppressor cells (MDSCs), Foxp3+ regulatory T cells (Tregs) and NK cells. Femur trabecular bone density and microarchitecture were assessed by 3D micro-CT system.Results: We first evaluated the expression of the TGF-β1 ligand and its receptor activated signaling intermediates, Smad2/3 in bone marrow of patients with MM. There is an accumulation of the type 1 isoform of the TGF-β ligand within the tumor microenvironment (TME) and of phospho-Smad2/3 in myeloma cells within the bone marrow of patients (Figure 1). In vitro studies utilizing the TbRI inhibitor Vactosertib (TEW-7197) with murine 5T33MM, human RPMI8226 (Figure 2A), U266, ARH-77 cell lines, and tumor cells from patients with MM (Figure 2B) cultured demonstrate a dose-dependent reduction in cell viability in cultures of these MM cells continuously exposed to Vactosertib. Synergistic inhibition of Vactosertib in combination with PIs was also observed in parent (Figure 2C), bortezomib- (Figure 2D), ixazomib- (Figure 2E), and carfilzomib-resistant RPMI8226 cells (Figure 2F). We also found that there is an accumulation of the TGF-β1 within the TME and phospho-Smad2/3 within the MM at advanced stages in the bone marrow of C57BL/KaLwRij mice harboring the 5T33MM myeloma cells. Oral administration of Vactosertib as a single agent inhibited MM progression as measured by mortality (Figure 3A), peripheral blood monoclonal protein concentration and BLI (Figure 3B). While the expansion of CD11b+Gr-1+ MDSCs (Fig. 3C) and the population of Tregs (Fig. 3D) in the spleen were reduced, NK cells were increased by Vactosertib alone (Fig. 3E). Combination therapy of Vactosertib plus ixazomib exhibited a synergistic anti-tumor effect when compared to either Vactosertib or ixazomib alone by a decrease in mortality (Figure 4A) and significant reduction in both the BLI and M-spike before and after treatment (Figure 4B, C). Furthermore, Vactosertib single therapy enhanced the bone thickness and reduced trabecular separation in comparison to control mice.Conclusions: Taken together, our data demonstrate that Vactosertib (a small molecule inhibitor of the TGF-β type I receptor kinase) suppresses viability of human MM cells, and is associated with a potent anti-myeloma effect, suppressing bone resorption and modulating the MM TME in a immunocompetent preclinical model of MM. These data provide a rationale for clinical evaluation of the combination therapy of Vactosertib and ixazomib as a potential therapeutic strategy to improve outcomes in patients with MM. [Display omitted] DisclosuresKim:MedPacto: Other: Founder/CEO. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau.

Anti-arthritic properties of crude extract from Chenopodium ambrosioides L. leaves.

To evaluate the effect of hydroalcoholic crude extract (HCE) from Chenopodium ambrosioides leaves on the development of type II collagen-induced arthritis (CIA) and on pro-inflammatory cytokine balance. Collagen-induced arthritis was induced in DBA1/J mice. On the 21st day, the mice were treated orally with HCE or methotrexate, daily. Six weeks after beginning the treatment, the following measures were determined: lymphoid organs cell numbers, percentage of blood cells, IL-6, IFN-γ, TNF-α and IL-17 serum concentrations, activity of hepatic and kidney glutathione S-transferase, hepatic 7-ethoxyresorufin-O-deethylase activity, bone density and histopathology. Treatment of CIA mice with HCE 5mg/kg (HCE5) reduced the percentage of neutrophils and macrophages and the number of bone marrow cells and increased the lymphocyte numbers and the inguinal lymph node cellularity. This treatment inhibited the serum concentration of IL-6 and TNF-α, which may be related to the preservation of bone density and to the slight thickening of periarticular tissues, with minimal fibrosis and fibroblast proliferation in the joints. The CIA group presented advanced articular erosion and synovial hyperplasia. Phytochemical analysis showed mainly flavonols. HCE5 presented anti-arthritic potential and reduced IL-6 and TNF-α, which participate directly in the development and maintenance of the inflammatory process in rheumatoid arthritis.

NEFA-induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non-alcoholic steatohepatitis.

The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non‐alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non‐esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF‐α and IL‐6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), mitofusin‐2 (Mfn‐2) and OXPHOS complexes (human: COI and COIII; cow: COI‐IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC‐1α and Mfn‐2 overexpression significantly decreased the NEFA‐induced ROS production and TNF‐α and IL‐6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS‐JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS‐JNK/p38MAPK pathway. PGC‐1α or Mfn‐2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH.

Late preterm prelabor rupture of fetal membranes: fetal inflammatory response and neonatal outcome.

BackgroundTo characterize the influence of microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI) on the intensity of the fetal inflammatory response and the association between the presence of the fetal inflammatory response syndrome (FIRS) and short-term neonatal morbidity in the preterm prelabor rupture of membranes (PPROM) between the gestational ages of 34 and 37 weeks.MethodsOne hundred and fifty-nine women were included in the study. The umbilical cord blood interleukin (IL)-6 concentrations were determined using enzyme-linked immunosorbent assay kits. FIRS was defined based on the umbilical cord blood IL-6 concentration and the presence of funisitis and/or chorionic plate vasculitis.ResultsWomen with both MIAC and IAI had the highest median umbilical cord blood IL-6 concentrations and highest rates of FIRS. Women with FIRS had the higher rates of early-onset sepsis and intraventricular hemorrhage grades I and II when FIRS was characterized based on the umbilical cord blood IL-6 concentrations and the histopathological findings.ConclusionThe presence of both MIAC and IAI was associated with a higher fetal inflammatory response and a higher rate of FIRS. Different aspects of short-term neonatal morbidity were related to FIRS when defined by umbilical cord blood IL-6 concentrations and the histopathology of the placenta.

Role of purinergic signalling and proinflammatory cytokines in diabetes

Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are pre­sent on the pancreatic islet cells as well as on hepato­cytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell gran­ules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A 2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracel­lular ATP concentration. Ecto-NTPDases in cooperation with 5’-nucleotidase may significantly increase ecto-adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour ne­crosis factor-a (TNF-a) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes distur­bance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflamma­tory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90–100)

Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing.

The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.

The effect of different concentrations of sufentanil on interleukin-6 and tumor necrosis factor-α concentrations in peripheral blood induced by lipopolysaccharide

Objective Investigating the effect of different concentration of sufentanil on IL-6 and TNF-α concentrations in human peripheral blood induced by lipopolysaccharide(LPS). Methods Every blood sample were collected from 30 healthy volunteers. Using a completely randomized design grouping method. Samples were randomized assigned in eight groups. Venous blood 5 ml from every volunteers were collected. 100 μl of the venous blood from every sample were put in eight ethylenediaminete-traacetic acid-vitro ready tubes labeled(A, B, C1, C2, C3, D1, D2, D3) by using precision pipette. Groups are: group A for the saline group(control), group B joined LPS 100 mg/L, group C includes C1, C2, C3, respectively fentanyl 0.05, 0.50, 5.00 μg/L, group D includes the D1, D2, D3 fentanyl 0.05, 0.50, 5.00 μg/L and LPS 100 mg/L, respectively. The IL-6 and TNF-α ELISA kit were used to detect supernatant concentrations of IL-6 and TNF-α. Results Group A and group C in peripheral blood IL-6 and TNF-α concentration were not significantly different(P>0.05). Plus LPS of group B and group D of IL-6, of TNF-α concentrations were significantly increased(P<0.05). Group D and group B, the peripheral blood of IL-6 and TNF-α concentrations were significantly lower(P<0.05). Group D2, D3 peripheral IL-6 and TNF-α concentration reduction are greater than the group D1(P<0.05). Group D3 peripheral blood IL-6 and TNF-α concentration were greater than group D2 reduction(P<0.05). Conclusions LPS can promote isolated human peripheral blood inflammatory cytokine IL-6 and TNF-α concentration increasing. Sufentanil inhibited LPS-induced, IL-6 and TNF-α concentration increase in a dose-dependent manner from the peripheral blood. Sufentanil had no effect on IL-6 and TNF-α concentration the peripheral blood drawn away from people. Key words: Sufentanil; Lipopolysaccharide; Peripheral blood; Interleukin-6; Tumor necrosis factor-α

Evaluation of in-feed larch sawdust anti-inflammatory effect in sows.

The study aimed to investigate the possible anti-inflammatory activity of larch sawdust as feed supplement in lactating sows' diet and its possible effect on the prevalence of Postpartum Dysgalactia Syndrome under field conditions. In a Greek farrow-to-finish pig farm, fifteen sows were randomly and equally allocated to a negative control group (NC group), a positive control group (PC group), and a treatment group (LT group). The animals of the first two groups received 99% basic diet and 1% corn starch, while LT group animals received 99% basic diet and 1% larch sawdust. The whole trial period lasted 35 days (7 days prior to farrow - day of weaning). At parturition day, animals of the PC group received 2 ml of an anti-inflammatory drug intramuscularly (meloxicam, Metacam®, Boehringer Ingelheim Vetmedica), while the animals of both other groups, received 2 ml of normal saline. Results showed insignificant differences among experimental groups for parameters such as post-partum rectal temperature and piglets performance. On the contrary, a significant increase of mean milk lactation index was observed in LT and PC groups on the 4th day of lactation period, when compared with NC group (p=0.014). Additionally, mean IL-6 concentrations in blood in the LT group showed a tendency for reduction when compared with those found in NC, and insignificant difference (p>0.05) when compared with those observed in PC group 24 hours postpartum. Moreover, the respective TNFα mean level in the LT group at 24 and 72 hours after parturition was similar to that found in PC group, respectively) and significantly lower than that determined in the NC group (p=0.003, p=0.024. The results suggest a possible anti-inflammatory effect of larch sawdust in sows.

Intraamniotic inflammation and umbilical cord blood interleukin-6 concentrations in pregnancies complicated by preterm prelabor rupture of membranes

Objective: To evaluate umbilical cord blood interleukin (IL)-6 concentrations and the occurrence of fetal inflammatory response syndrome (FIRS) with respect to microbial invasion of the amniotic cavity (MIAC) and/or intraamniotic inflammation (IAI) in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). Methods: One-hundred-eighty-eight women with singleton pregnancies complicated by PPROM between gestational ages of 24 + 0 and 36 + 6 weeks were included in the study. Blood samples were obtained by venipuncture from the umbilical cord after the delivery of the newborn. The umbilical cord blood IL-6 concentrations were evaluated using ELISA kits. FIRS was defined as umbilical cord blood IL-6 > 11 pg/mL. Result: Women with MIAC and IAI had higher IL-6 concentrations than women without these complications (with MIAC: median 18.1 pg/mL versus without MIAC: median 5.8; p < 0.0001; with IAI: median 32.9 pg/mL, versus without IAI: median 5.8; p < 0.0001). Women with IAI with MIAC and women with IAI without MIAC had the highest umbilical cord blood IL-6 concentrations (medians: 32.6 and 39.4 pg/mL) and rates of FIRS (78% and 67%). Conclusions: IAI was associated with the highest umbilical cord blood IL-6 concentrations and rate of FIRS independent of the presence or absence of MIAC.