Monokine Induced By Interferon-gamma Research Articles

Associations of the circulating levels of cytokines with the risk of myeloproliferative neoplasms: a bidirectional mendelian-randomization study

ObjectiveIn the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms.MethodsA genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl).ResultsOur results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03–1.81, P = 0.032; OR = 1.55,95%CI = 1.09–2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002–0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018).ConclusionOur findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN.

Assessing the Causal Relationship between Genetically Determined Inflammatory Cytokines and Parkinson's Disease Risk: A Bidirectional Two-Sample Mendelian Randomization Study.

Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52-0.96, P = 0.027; OR: 1.18, 95%CI: 1.01-1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04-1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD.

Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study

BackgroundPrevious observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. MethodsSummary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. ResultsUnivariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10−6) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10−8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. ConclusionThis study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.

Causal associations between circulating inflammatory cytokines and blinding eye diseases: a bidirectional Mendelian randomization analysis.

Previous studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases. Summary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results. The IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 × 10-04, 95% CI: 5.198 × 10-07 - 2.129 × 10-01, p = 0.0151). This study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases.

Circulating levels of cytokines and risk of inflammatory bowel disease: evidence from genetic data.

Prior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research. We aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach. We selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn's disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation. Genetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn's disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines. Our study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.

IP-10 and MIG are sensitive markers of early virological response to HIV-1 integrase inhibitors.

Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH≥ 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels.

Salivary macrophage activation-related chemokines and mitogen-activated kinase kinase-degrading proteolytic activity in type 1 diabetes mellitus.

This cross-sectional study aimed to evaluate salivary concentrations of macrophage activation-related chemokines and mitogen-activated kinase kinase (MAPKK)-degrading proteolytic activity in children and adolescents with and without type 1 diabetes mellitus (T1DM). A total of 122 children and adolescents (65 T1DM patients, 50.8% female, mean age:10.9 years; 57 systemically healthy controls, 36.8% female, mean age: 9.5 years) were included in the study. Salivary concentrations of interferon gamma inducible protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, MCP-4, macrophage-derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon gamma (MIG), and macrophage inflammatory protein-1 alpha (MIP-1α) were quantified using a bead-based technique. MAPKK-degrading proteolytic activity was detected using fluorescent peptide substrates. The T1DM group had higher plaque index (PI%, p=0.032) and bleeding on probing (BOP%, p=0.045) scores, and lower decayed, missing, filled teeth (dmft/DMFT, p=0.002) index scores compared to the healthy controls. Compared to the controls, salivary MCP-1 (p=0.007), MCP-3 (p<0.001), MIG (p=0.007), and MIP-1α (p=0.033) concentrations were elevated whereas MCP-4 concentrations decreased (p<0.001) in the T1DM group. After adjusting for age, PI%, BOP%, and dmft/DMFT scores, significant differences in salivary concentrations of MIG (p=0.033) and MIP-1α (p=0.017) were observed between the groups. Moreover, protease activities directed to the cleavage sites of MEK23-18 (p=0.001), MKK6b7-22 (p=0.007), MKK451-66 (p=0.005), MKK7b37-52 (p=0.034), and MKK7b69-84 (p=0.009) were elevated in the T1DM group. T1DM disrupts the salivary macrophage activation-related chemokine profile and dysregulates proteolytic MAPKK cleavage. These findings can be an outcome of the impaired systemic immune response in T1DM.

The utility of inflammatory and endothelial factors in the prognosis of severe dengue

BackgroundSevere dengue is associated with a considerable risk of mortality, and there is currently a lack of appropriate prognostic biomarkers to predict its severity. Pathogenesis of severe dengue is characterized by overt inflammation, endothelial activation, and increased vascular permeability. The current study investigates the utility of endothelial, inflammatory, and vascular permeability factors as biomarkers to identify dengue severity, which could improve disease prognosis and management. MethodsThe dengue-positive subjects were classified based on seropositivity for NS1, IgM, and IgG. The samples in each group were quantified for basic clinical investigations. The levels of Interleukin-6 (IL-6), Tumor necrosis factor receptor 1 (TNFR1), EOTAXIN, Monocyte chemoattractant protein-1 (MCP-1), Monokine induced by interferon-gamma (MIG), Intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Thrombomodulin, and Angiopoietin-2 were estimated in all serum samples using the multiplex bead-based assay. ResultsIgG seropositive dengue patients showed abnormal laboratory characteristics and severe dengue symptoms. Among the studied markers, only IL-6, TNFR1, ICAM-1, VCAM-1, Thrombomodulin, and Angiopoietin-2 were significantly elevated in IgG seropositive patients compared to healthy controls. Increased IL-6 and TNFR1 levels were associated with decreased platelet count and elevated Hematocrit levels in IgG seropositive patients. Furthermore, ROC curve analysis indicated that IL-6, TNFR1, Thrombomodulin, and Angiopoietin-2 showed good potential for predicting dengue severity. ConclusionInflammatory markers IL-6 and TNFR1, and endothelial factors Angiopoietin-2 and Thrombomodulin, could serve as prognostic markers for severe dengue. These findings also encourage the future study of these biomarkers in the pathogenesis of severe dengue infection.

MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.

Circulating Cytokine and Chemokine Profiles ofTrypanosoma cruzi-Infected Women During Pregnancy and Its Association With Congenital Transmission

Trypanosoma cruzi, the causative agent of Chagas disease, can be transmitted to the offspring of infected women, which constitutes an epidemiologically significant parasite transmission route in nonendemic areas. It is relevant to evaluate differentially expressed factors in T. cruzi-infected pregnant women as potential markers of Chagas congenital transmission. Circulating levels of 12 cytokines and chemokines were measured by enzyme-linked immunosorbent assay or cytometric bead array in T. cruzi-infected and uninfected pregnant women in their second trimester of pregnancy and control groups of T. cruzi-infected and uninfected nonpregnant women. Trypanosoma cruzi-infected women showed a proinflammatory Th1-biased profile, with increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12p70, IL-15, and monokine induced by interferon-gamma (MIG). Uninfected pregnant women presented a biased response towards Th2/Th17/Treg profiles, with increased plasma levels of IL-5, IL-6, IL-1β, IL-17A, and IL-10. Finally, we identified that high parasitemia together with low levels of TNF-α, IL-15, and IL-17, low TNF-α/IL-10 ratio, and high IL-12p70 levels are factors associated with an increased probability of Chagas congenital transmission. Trypanosoma cruzi-infected pregnant women who did not transmit the infection to their babies exhibited a distinct proinflammatory cytokine profile that might serve as a potential predictive marker of congenital transmission.

РАННИЕ И АЛЬТЕРНАТИВНЫЕ МАРКЕРЫ РАЗВИТИЯ ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТИ У ПАЦИЕНТОВ С САХАРНЫМ ДИАБЕТОМ

Aim: to assess the relationship of proinflammatory cytokines and chemokines with the levels of natriuretic peptides in patients with diabetes mellitus (DM). Materials and methods. A total of 155 patients (14 men and 61 women) with type 1 and type 2 diabetes, aged 34 to 84 years, were examined. All patients underwent standard clinical and laboratory examination, with an assessment of the levels of pro-inflammatory cytokines (interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), chemokines (monokine induced by interferon-gamma (MIG), regulated upon activation, normal T cell expressed and presumably secreted (RANTES), growth factors (fibroblast growth factor-23 (FGF-23), vascular endothelial growth factor (VEGF-A), natriuretic peptides (B‐type natriuretic peptide (BNP), N‐terminal fragment of B‐type natriuretic peptide (proBNP). Renal function was assessed based on the levels of serum creatinine, glomerular filtration rate (GFR), which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio (A/C). An echocardiographic examination was conducted according to the standard protocol with the calculation of dimensional, volume and speed characteristics. Statistical data analysis was performed using smSTATA 14.2 for Mac (2018). Results. 57% DM patients had BNP and proBNP levels exceeding the diagnostic values of BNP &gt;35 pg/ml and/or proBNP &gt;125 pg/ml. The levels of BNP and proBNP positively correlated with the levels of homocysteine, uric acid, IL-6, С-reactive protein (CRP), high-sensitivity C-reactive protein (hsCRP), A/С, creatinine, cystatin C, TNF-alpha, chemokines (MIG, RANTES), growth factors (FGF-23, VEGF-A) (p &lt;0.05). According to multiple regression analysis, predictors for increased proBNP were IL-6, A/K, creatinine (ß=0.70, p&lt;0.001, ß=3.51, p=0.01, ß=0.97, p=0.01, respectively). ROC analysis determined the highest diagnostic significance of creatinine for the prediction of increased proBNP. The significance of IL-6 proved higher than A/С (AUC-0.777). Thus, when the level of IL-6 (AUC-0.789) was 3.1 mg/ml, the sensitivity and specificity for increased proBNP concentration were 71.9% and 71.2%, respectively. Conclusion. IL-6 might be an independent predictor of increased levels of natriuretic peptide in patients with diabetes. Further study of the role of pro-inflammatory cytokines in the development of cardiovascular diseases will make it possible to finally decode the mechanisms of their pathogenesis, which will further allow us to understand their complex effect on the body and obtain information for the development of new effective and safe specific medicines.

Salivary concentrations of macrophage activation-related chemokines are influenced by non-surgical periodontal treatment: a 12-week follow-up study

ABSTRACTBackground: During periodontal inflammation, bacteria induces chemokine expression and migration of various inflammatory cells. The aim of the study was to learn if periodontal treatment alters salivary concentrations of macrophage activation-related chemokines and if such alterations correlate with abundance of periodontitis-associated bacteria.Methods: Twenty-five patients with periodontitis completed the study (NCT02913248 at clinicaltrials.gov). Periodontal parameters and stimulated saliva samples were obtained at baseline and 2, 6 and 12 weeks after non-surgical periodontal treatment. Salivary concentrations of monocyte chemoattractant proteins (MCP-1-4), macrophage-derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP-1α) and interferon-inducible protein (IP-10) were quantified using the Luminex® xMAP™ technique and abundance of bacteria was quantified using next-generation sequencing.Results: The treatment improved all periodontal parameters and caused an increase in the concentrations of MCP-2, MDC and MIP-1α at week 12 compared to baseline, week 2 and week 6, respectively. Salivary concentrations of MCP-1-2, MDC, MIG, MIP-1α and IP-10 correlated with the abundance of specific periodontitis-associated bacteria.Conclusions: Periodontal treatment impacts salivary concentrations of MCP-2, MDC and MIP-1α, which correlate with the abundance of specific periodontitis-associated bacteria. This indicates that these chemokines reflect periodontal status and possess potential in illustrating a response to treatment.

Early Immunologic Response in Multiply Injured Patients With Orthopaedic Injuries Is Associated With Organ Dysfunction.

To quantify the acute immunologic biomarker response in multiply injured patients with axial and lower extremity fractures and to explore associations with adverse short-term outcomes including organ dysfunction and nosocomial infection (NI). Prospective cohort study. Level 1 academic trauma center. Consecutive multiply injured patients, 18-55 years of age, with major pelvic and lower extremity orthopaedic injuries (all pelvic/acetabular fractures, operative femur and tibia fractures) that presented as a trauma activation and admitted to the intensive care unit from April 2015 through October 2016. Sixty-one patients met inclusion criteria. Blood was collected upon presentation to the hospital and at the following time points: 8, 24, 48 hours, and daily during intensive care unit admission. Blood was processed by centrifugation, separation into 1.0-mL plasma aliquots, and cryopreserved within 2 hours of collection. Plasma analyses of protein levels of cytokines/chemokines were performed using a Luminex panel Bioassay of 20 immunologic mediators. Organ dysfunction was measured by the Marshall Multiple Organ Dysfunction score (MODScore) and nosocomial infection (NI) was recorded. Patients were stratified into low (MODS ≤ 4; n = 34) and high (MODS > 4; n = 27) organ dysfunction groups. The MODS >4 group had higher circulating levels of interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1 receptor antagonist (IL-1RA), and monokine induced by interferon gamma (MIG) compared with the MODS ≤4 group at nearly all time points. MODS >4 exhibited lower levels of IL-21 and IL-22 compared with MODS ≤4. Patients who developed NI (n = 24) had higher circulating concentrations of IL-10, MIG, and high mobility group box 1 (HMGB1) compared with patients who did not develop NI (n = 37). Temporal quantification of immune mediators identified 8 biomarkers associated with greater levels of organ dysfunction in polytrauma patients with major orthopaedic injuries. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Arborvitae (Thuja plicata) essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts

Arborvitae (Thuja plicata) essential oil (AEO) is becoming increasingly popular in skincare, although its biological activity in human skin cells has not been investigated. Therefore, we sought to study AEO's effect on 17 important protein biomarkers that are closely related to inflammation and tissue remodeling by using a pre-inflamed human dermal fibroblast culture model. AEO significantly inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1), intracellular cell adhesion molecule 1 (ICAM-1), interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell chemoattractant (I-TAC), monokine induced by interferon gamma (MIG), and macrophage colony-stimulating factor (M-CSF). It also showed significant antiproliferative activity and robustly inhibited collagen-I, collagen-III, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2). The inhibitory effect of AEO on increased production of these protein biomarkers suggests it has anti-inflammatory property. We then studied the effect of AEO on the genome-wide expression of 21,224 genes in the same cell culture. AEO significantly and diversely modulated global gene expression. Ingenuity pathway analysis (IPA) showed that AEO robustly affected numerous critical genes and signaling pathways closely involved in inflammatory and tissue remodeling processes. The findings of this study provide the first evidence of the biological activity and beneficial action of AEO in human skin cells.

Impact of heart rate variability, a marker for cardiac health, on lupus disease activity.

BackgroundDecreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.MethodsFifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied.ResultsBaseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables.ConclusionsImpaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1087-x) contains supplementary material, which is available to authorized users.

Role of Monokine Induced by Interferon Gamma in Discrimination and Prognosis of Patients With Chagas' Disease and Idiopathic Dilated Cardiomyopathy

Monokine induced by interferon gamma (MIG) is a chemokine that has been found to increase in the myocardium of mice infected with Trypanosoma cruzi. It is not known whether MIG is regulated in patients with Chagas' disease (CD) and idiopathic dilated cardiomyopathy (DCM). Therefore, we aimed to investigate the possible diagnostic and/or prognostic value of MIG in these patients. In this prospective cohort study, MIG was measured in patients with CD (n = 93) and DCM (n = 47) and in healthy control subjects (n = 24). MIG was found to be significantly increased in patients with CD and advanced heart failure (New York Heart Association III-IV). Although no significant increase in MIG levels was observed in patients with DCM, there was a significant correlation between MIG and left ventricular ejection fraction in patients with DCM. In contrast, despite the significant increase in patients with CD and advanced heart failure, MIG had no significant correlation with any of the echocardiographic parameters in CD. MIG also failed to predict mortality and necessity for heart transplant in patients with CD but showed a clear trend for patients with DCM. To the best of our knowledge, this is the first study to investigate MIG in patients with CD and DCM. The significant increase of MIG in patients with CD and advanced heart failure, the negative correlation between MIG and left ventricular ejection fraction, and the clear trend in discrimination using a cutoff value found in patients with DCM require further investigation to clarify the diagnostic and prognostic potential of MIG in these patients.

Elevated Urinary T Helper 1 Chemokine Levels in Newly Diagnosed Hypertensive Obese Children

Objective:Increasing evidence suggests that T helper (Th) cells play a significant role in the pathogenesis of hypertension. The aim of this study was to evaluate the effect of obesity and anti-hypertensive treatment on urinary Th1 chemokines.Methods:The study groups consisted of three types of patients: hypertensive obese, healthy, and non-hypertensive obese. Pre-treatment and post-treatment samples of the hypertensive obese group and one sample from the other two groups were evaluated for urinary chemokine: regulated on activation, normal T cell expressed and secreted (RANTES), interferon-gamma-inducible protein 10 (IP10), and monokine induced by interferon-gamma (MIG). In the hypertensive obese group, urine microalbumin: creatinine ratio was examined before and after treatment. We recommended lifestyle changes to all patients. Captopril was started in those who could not be controlled with lifestyle changes and those who had stage 2 hypertension.Results:Twenty-four hypertensive obese (mean age 13.1), 27 healthy (mean age 11.2) and 22 non-hypertensive obese (mean age 11.5) children were investigated. The pre-treatment urine albumin: creatinine ratio was positively correlated with pre-treatment MIG levels (r=0.41, p<0.05). RANTES was significantly higher in the pre-treatment hypertensive and non-hypertensive obese group than in the controls. The urinary IP10 and MIG levels were higher in the pre-treatment hypertensive obese group than in the non-hypertensive obese. Comparison of the pre- and post-treatment values indicated significant decreases in RANTES, IP10, and MIG levels in the hypertensive obese group (p<0.05).Conclusion:Th1 cells could be activated in obese hypertensive children before the onset of clinical indicators of target organ damage. Urinary RANTES seemed to be affected by both hypertension and obesity, and urinary IP10 and MIG seemed to be affected predominantly by hypertension.

Plasma chemokine as potencial biomarker of cardiac morbidity in Chagas disease (HUM8P.330)

Abstract The immune response appears to be associated with morbidity in Chagas disease. The aim of this study was to evaluate the plasma chemokine levels in well-defined clinical polar groups of chagasic patients and its relationship with morbidity. Patients infected with Trypanosoma cruzi were grouped as indeterminate (IND) and cardiac (CARD) forms ranging from 23 to 69 years of age. The IND group included 82 individuals without cardiac involvement, while the CARD group included 94 patients presenting dilated cardiomyopathy. Healthy non-chagasic individuals were included as a control group (NI). The plasma chemokine levels, such as inflammatory protein 10 (IP-10), monocyte chemoattractant protein (MCP) 1 and monokine induced by interferon gamma (MIG), proved to be the highest in the CARD group. However, no significant difference could be observed when comparing the RANTES expression in the IND and CARD groups. Correlation analysis showed that higher IP-10, MCP-1 and MIG expression was associated with worst cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. The findings of this study indicate that a fine balance between homeostatic and inflammatory chemokines might represent a key element in the establishment of the distinct forms of chronic Chagas disease. Moreover, this inference involves important implications to better understand the pathogenesis and clinical management of patients with Chagas disease.

(Invited) Planar Field Effect Transistor Biosensors: Toward Single Molecular Detection and Clinical Applications

Field effect transistor (FET) based biosensors that can translate directly specific bindings between receptors and target analytes to electrical signals have attracted considerable interests for label free, rapid, low-cost detection of biomolecules. However, it is challenging to detect biomarkers at low concentrations in physiological buffers with high ionic strengths due to the small Debye length. FET biosensors on a planar configuration are highly preferable because of the process compatibility with microelectronic manufacturing. III-nitride semiconductor materials have been considered as a promising candidate for biosensing applications due to their unique properties, such as chemical inertness, non-toxicity, and excellent thermal stability. In particular, III-nitrides FETs are ion-impermeable and highly stable in electrolytes, making them ideal for detection at ultralow concentrations in fluids with high ionic strengths. Here we present a recessed gate planar AlGaN/GaN heterojunction FET (HFET) for biodetection. The gate area of the AlGaN/GaN HFET was recessed by inductively coupled plasma (ICP) etching to shift the threshold voltage to near zero volt regime for sensitivity enhancement. As such, the device works at the subthreshold regime. The biosensing measurement was performed on a non-bias gate setting to eliminate the noise and electrochemical activities from the gate electrode. The signal-to-noise ratio of these recessed AlGaN/GaN FET biosensors is two orders of magnitude higher than that of the Si nanowire FET biosensors previously reported. Detection of streptavidin at concentration of 16 aM in PBS physiological buffer has been demonstrated. To the best of our knowledge, this is the highest sensitivity ever reported on a field effect-based biosensor in physiological buffer. These devices have demonstrated their potential in biochemical and clinical applications. We have successfully detected MIG (monokine induced by interferon gamma, an indicator of transplant rejection in patients when detected at a concentration level above nano Molar) in clinical samples. Utilizing of ion impermeable semiconductors like GaN opens up opportunities of FET-based biosensors for direct detection of biomarkers in physiological fluids at low concentrations for early disease diagnosis with excellent manufacturing compatibility.

IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome

Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.