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Special electromagnetic field-treated water (SEW) and far-infrared radiation (FIR) can reduce acute respiratory distress syndrome (ARDS) in rats inflicted by lipopolysaccharides (LPSs). However, little is known about its underlying molecular mechanism. Differentially expressed proteins (DEPs) of SEW and FIR interventions were obtained from a proteomics database. A total of 89 DEPs were identified. Enrichment analysis of DEPs was performed using the Database for Annotation, Visualization, and Integrated Discovery. These DEPs were associated with the responses to LPSs, acute inflammation, extracellular exosomes, glucocorticoids, and electrical stimuli. The protein-protein interaction network was set up using the STRING database. Modular analysis was performed using MCODE in the Cytoscape software. Proteins Haptoglobin, Apolipoprotein B, Transthyretin, and Fatty acid binding protein 1 were among the core networks. A tail vein injection of LPS was used to establish the rat model with ARDS. Parallel reaction monitoring confirmed Hp protein expression. Inflammatory pathway factors were detected using an enzyme-linked immunosorbent assay. This indicates that SEW and FIR can be considered as potential clinical treatment methods for ARDS treatment and that their functional mechanisms are related to the ability of alleviating lung inflammation through Hp protein adjustment.

Background Impaired gastric emptying (GE) is associated with morbidity in surgical critically ill children. The relationship between inflammation, gut barrier integrity (lipopolysaccharide binding protein [LBP]; zonulin), and GE has not been described in this cohort. Methods Children ≥2 years of age and requiring critical care after surgery were enrolled. Preoperative and postoperative levels of serum cytokines, LBP, and zonulin, and GE by the acetaminophen absorption test, were measured, allowing patients to serve as their own controls. Postoperative delayed GE was defined as a decrease in GE by ≥20% compared with preoperative GE. The following were examined : comparison between postoperative andpreoperative values, correlations between fold change (postoperative/preoperative) in study variables, and fold change in study variables between patients with and without postoperative delayed GE. Results Twenty patients, median age 14 years (12.25, 18), 12 female, were included. Eight of 20 patients had postoperative delayed GE. Postoperative interleukin‐6 (IL‐6), IL‐8, IL‐10, and LBP were increased, and zonulin was decreased (P‐values < .05). Fold change in IL‐10 and zonulin were inversely correlated (ρ −0.618, P = .004). Patients with postoperative delayed GE had greater fold increase in IL‐10 (P = .0159) and fold decrease in zonulin (P = .0160). Five of 7 (71%) patients with both fold increase in IL‐10 and decrease in zonulin had delayed GE. Conclusion Postoperative changes in IL‐10 and zonulin were associated with delayed GE in surgical critically ill children, which might suggest a mechanism to for delayed GE in postoperative inflammation and gut barrier dysregulation after surgery.

A high-concentrate diet destroys gram-negative bacteria in the cattle rumen, leading to elevated ruminal lipopolysaccharide (LPS) levels. LPS causes liver inflammation through the hepatic portal vein but little is known about the effects of rumen-derived LPS on liver function and the reproductive organs. In this study, we determined the effect of increasing rumen fluid LPS levels on liver function and genital LPS levels. Cows were assigned to control (CON; n=5) and high-concentrate diet (HC; n=7) groups. We observed that the ruminal LPS and haptoglobin (Hp) levels were significantly higher and albumin levels were lower in the HC group than in the CON group. In the HC group, The Hp levels and aspartate transaminase (AST) activity were significantly higher and the total cholesterol levels were significantly lower after high-concentrate diet feeding than before feeding. No differences were observed in LPS levels in the peripheral veins, hepatic veins, hepatic portal vein, uterine perfusate, and follicular fluids between the groups. In all samples, the LPS level in the hepatic portal vein blood positively correlated with the AST activity and serum amyloid A level. In conclusion, our results indicate that high-concentrate diets do not have a direct effect on the reproductive organs upon a moderate ruminal LPS level increase. However, an increased ruminal LPS influx into the liver might affect negatively liver function.

Background/aims Zonulin is the only known regulator of intestinal permeability. It is also considered as a potential inflammatory marker in several conditions such as diabetes and inflammatory bowel syndrome. The aim of the study was to investigate zonulin levels in patients with early stages of CKD and its possible correlation with inflammation, anemia and iron status parameters. Methods Eighty-eight patients with early stages of CKD and 23 healthy volunteers were enrolled in the study. Zonulin, hepcidin-25, soluble transferrin receptor, interleukin-6 and high-sensitivity C-reactive protein were measured using commercially available assays. Results Zonulin was significantly lower among patients with CKD in comparison with healthy volunteers. There were no statistically significant differences in zonulin concentration between patients with and without inflammation. Zonulin was significantly correlated with hepcidin only in patients with inflammation. Zonulin was neither related to iron nor related to ferritin. Conclusions Zonulin cannot be considered as an inflammatory marker in CKD. It does not play a role in the disturbances of iron metabolism in CKD. Its physiological role remains to be elucidated.

Background Increased permeability of the intestinal wall and intestinal dysbiosis may contribute to chronic systemic inflammation, one of the causes of accelerated atherosclerosis and cardiovascular morbidity and mortality burden in patients with chronic kidney disease. The aim of this study was to evaluate the association between markers of intestinal permeability and inflammation in haemodialysis (HD) patients. Methods Plasma concentration of zonulin, haptoglobin, TNFα, IL6, d-lactates and bacterial lipopolysaccharides (LPS) was assessed in blood samples obtained after overnight fast before midweek morning HD session in 150 stable, prevalent HD patients. Daily intake of energy and macronutrients was assessed on the basis of a food frequency questionnaire. Results Serum hsCRP level was increased in over 70% of patients. Plasma levels of zonulin [11.6 (10.9–12.3) vs 6.8 (5.8–7.8) ng/mL], IL6 [6.2 (1.0–10.3) vs 1.3 (1.0–2.0) pg/mL] and TNFα [5.9 (2.9–11.8) vs 1.6 (1.3–1.8) pg/mL], but not LPS and d-lactates were significantly higher in HD than in healthy controls. d-lactates and LPS levels were weakly associated with IL6 (R = 0.175; p = 0.03, and R = 0.241; p = 0.003). There was a borderline correlation between plasma zonulin and serum hsCRP (R = 0.159; p = 0.07), but not with IL6, LPS and d-lactates. In multiple regression, both serum CRP and plasma IL6 variability were explained by LPS (β = 0.143; p = 0.08 and β = 0.171; p = 0.04, respectively), only. Conclusion The weak association between plasma d-lactate, LPS and IL6 levels indicates that intestinal flora overgrowth or increased intestinal permeability contributes very slightly to the chronic inflammation development in HD patients.

// Jianjun Lu 1, 2, * , Yanhong Wang 3, * , Miansheng Yan 1, * , Pinning Feng 1 , Linjing Yuan 4 , Yuesu Cai 1, 5 , Xin Xia 2 , Min Liu 1 , Jinmei Luo 1, 3 , Laisheng Li 1 1 Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China 2 Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China 3 Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China 4 Department of Gynaecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China 5 Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, 523808, People’s Republic of China * These authors contributed equally to this work Correspondence to: Laisheng Li, email: lilaish@mail.sysu.edu.cn Jinmei Luo, email: luojm3@mail.sysu.edu.cn Keywords: haptoglobin, NSCLC, progression, prognosis, biomarker Received: April 26, 2016 Accepted: May 22, 2016 Published: May 27, 2016 ABSTRACT The overall survival time of non-small cell lung cancer (NSCLC) has not improved dramatically in recent decades. An important reason is the lacking of valuable biomarkers. Haptoglobin was reported to have activities of anti-inflammatory, anti-oxidant, autoimmune and tumor angiogenesis. However its potential role as a tumor biomarker was not well recognized. We used an immunoturbidimetry method to measure serum haptoglobin levels in 205 NSCLC patients, and 210 normal healthy controls. We found that serum haptoglobin levels were significantly elevated in NSCLC patients compared with normal healthy controls (1.985±1.039 mg/mLvs. 0.922 ± 0.495 mg/mL, respectively, P < 0.0001). Higher serum haptoglobin levels were associated with advanced TNM stage, lymph node metastasis, and distant metastasis. Area under receiver operating characteristic curve (ROC) for serum haptoglobin was 0.809 (95% CI: 0.767–0.852) at a specificity of 0.881 and sensitivity of 0.639. The optimal cut-off value of haptoglobin was 1.495 mg/mL for discriminating NSCLC from normal healthy controls. Kaplan-Meier log rank analysis revealed that the higher serum haptoglobin levels group had a poorer overall survival compared with lower haptoglobin group (the median survival was 12.0 weeks , 26.0 weeks, respectively, P < 0.01). Further univariate and multivariate Cox regression analysis showed that serum haptoglobin was an independent risk factor of prognosis of NSCLC patients ( P < 0.01, P = 0.01, respectively). In conclusion, our study suggests that serum haptoglobin may act as useful clinical serological biomarkers in progression and prognostic evaluation in NSCLC.

Haptoglobin (Hp) is an acute-phase protein that is produced by the liver to capture the iron that is present in the blood circulation, thus avoiding its accumulation in the blood. Moreover, Hp has been detected in a wide variety of tissues, in which it performs various functions. In addition, this protein is considered a potential biomarker in many diseases, such as cancer, including ovarian carcinoma; however, its participation in the cancerous processes has not yet been determined. The objective of this work was to demonstrate the expression of Hp and its receptor CCR2 in the ovarian cancer cells and its possible involvement in the process of cell migration through changes in the rearrangement of the actin cytoskeleton using western blot and wound-healing assays and confirming by confocal microscopy. Ovarian cancer cells express both Hp and its receptor CCR2 but only after exposure to ascitic fluid, inducing moderated cell migration. However, when the cells are exposed to exogenous Hp, the expression of CCR2 is induced together with drastic changes in the actin cytoskeleton rearrangement. At the same time, Hp induced cell migration in a much more efficient manner than did ascitic fluid. These effects were blocked when the CCR2 synthetic antagonist RS102895 was used to pretreat the cells. These results suggest that Hp-induced changes in the cell morphology, actin cytoskeleton structure, and migration ability of tumor cells, is possibly “preparing” these cells for the potential induction of the metastatic phenotype.

The aim of this study was the identification of proteins differentially represented in the serum proteome of seropositive dogs with (Group 1) and without (Group 2) clinical-pathologic signs consistent with ehrlichiosis compared to healthy control dogs. Serum samples were collected from 20 dogs of various breeds with naturally occurring ehrlichiosis (10 dogs belonged to Group 1 and 10 to Group 2) and 10 healthy dogs. Two-dimensional electrophoresis (2DE) of pooled serum for each of the group of dogs were run in triplicate. 2D image analysis showed 39 spots differently expressed between Group 1 and Group 2 compared with healthy ones. Mass spectrometry analysis allowed identification of 6 proteins: albumin, haptoglobin (Hp), alpha-l-antitrypsin (AAT), Retinol Binding Protein 4 (RBP-4), alpha-l-acid glycoprotein (AGP) and vitamin D-binding protein (VDBP). When a confirmatory study was performed for albumin, Hp, AAT and RBP-4 by using different assays, significant differences (P < 0.05) between diseased and healthy groups were observed. It can be concluded that there are significant changes in the serum proteome of dogs with ehrlichiosis with modifications in proteins related with the acute phase response such as Hp, albumin and AGP, with vitamin A transport such as RBP-4, with inhibitors of serine proteases and anti-inflammatory proteins such as AAT, and vitamin D metabolism and actin scavengers such as VDBP. "Ministerio de Economia y Competividad" of Spain Fundacion Seneca - 19894/GERM/15

Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p

Intake of different types of protein may be associated with differences in biomarkers among various populations. This work investigated the influence of protein intake from haem and non-haem animals as well as protein from plants on haematological and biochemical parameters in inflammation among apparently-healthy adults living in Greece, a Mediterranean country. Four hundred and ninety apparently-healthy subjects (46 +/- 16 years, 40% men), who consecutively visited Polykliniki General Hospital for routine examinations, voluntarily agreed to participate in the study (participation rate 85%). Demographic, anthropometric and lifestyle characteristics were recorded. Participants completed a valid, semi-quantitative food frequency questionnaire. Protein intake was classified into three sources: protein from haem animals, protein from non-haem animals, and protein from plant origin. Fasting blood samples were taken from all participants; uric acid, creatinine, lipids, cystatin C, haptoglobin, haemoglobin, haematocrit, iron, ferritin, white blood cells, monocytes, platelets, and C-reactive protein were measured. Protein intake from only haem animals was associated with increased haemoglobin and haematocrit levels (p < 0.05) whereas intake of protein from non-haem animals and plant origin was not associated with the investigated haematological and biochemical markers of low-grade chronic inflammation when lifestyle factors and overall dietary habits were taken into account. Intake of protein from only haem animals seems to be consistently associated with haematological markers. The confounding role of dietary habits and lifestyle variables on the tested parameters deserves further attention in future research.

// Jae-Han Kim 1 , Sung Hyeon Lee 2 , Sookyung Choi 2 , Unyong Kim 3 , In Seok Yeo 4 , Su Hee Kim 2 , Myung Jin Oh 3 , Hantae Moon 3 , Jua Lee 3 , Seunghyup Jeong 3 , Min Gew Choi 5 , Jun Ho Lee 5 , Tae Sung Sohn 5 , Jae Moon Bae 5 , Sung Kim 5 , Yang Won Min 5 , Hyuk Lee 5 , Jun Haeng Lee 5 , Poong-Lyul Rhee 5 , Jae J. Kim 5 , Su Jin Lee 5 , Seung Tae Kim 5 , Jeeyun Lee 5 , Se Hoon Park 5 , Joon Oh Park 5 , Young Suk Park 5 , Ho Yeong Lim 5 , Won Ki Kang 5 , Hyun Joo An 3 , Jung Hoe Kim 4 1 Department of Food and Nutrition, Chungnam National University, Yuseong-Gu, Deajeon, Korea 2 GLYCAN Co., Ltd., Healthcare Innovation Park, Bundang-Gu, Seongnam, Korea 3 Graduate School of Analytical Science and Technology, Chungnam National University, Yuseong-Gu, Deajeon, Korea 4 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-Gu, Daejeon, Korea 5 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Se Hoon Park, email: hematoma@skku.edu Keywords: stomach neoplasm, haptoglobin, N-glycan, glycoprotein, biomarker Received: October 05, 2016 Accepted: December 21, 2016 Published: December 29, 2016 ABSTRACT Based on our previous studies, differential analysis of N-glycan expression bound on serum haptoglobin reveals the quantitative variation on gastric cancer patients. In this prospective case-control study, we explore the clinically relevant glycan markers for gastric cancer diagnosis. Serum samples were collected from patients with gastric cancer ( n = 44) and healthy control ( n = 44). N-glycans alteration was monitored by intact analysis of Hp using liquid chromatography–mass spectrometry followed by immunoaffinity purification with the serum samples. Intensity and frequency markers were defined depending on the mass spectrometry data analysis. Multiple markers were found with high diagnostic efficacy. As intensity markers ( I -marker), six markers were discovered with the AUC > 0.8. The high efficiency markers exhibited AUC of 0.93 with a specificity of 86% when the sensitivity was set to 95%. We additionally established frequency marker ( f -marker) panels based on the tendency of high N-glycan expression. The AUC to conclude patients and control group were 0.82 and 0.79, respectively. This study suggested that N-glycan variation of serum haptoglobin were associated with patients with gastric cancer and might be a promising marker for the cancer screening.

Background The gut microbiota is interlinked with obesity, but direct evidence of effects of its modulation on body fat mass is still scarce. We investigated the possible effects of Bifidobacterium animalisssp. lactis 420 (B420) and the dietary fiber Litesse® Ultra polydextrose (LU) on body fat mass and other obesity-related parameters. Methods 225 healthy volunteers (healthy, BMI 28–34.9) were randomized into four groups (1:1:1:1), using a computer-generated sequence, for 6 months of double-blind, parallel treatment: 1) Placebo, microcrystalline cellulose, 12 g/d; 2) LU, 12 g/d; 3) B420, 1010 CFU/d in microcrystalline cellulose, 12 g/d; 4) LU + B420, 12 g + 1010 CFU/d. Body composition was monitored with dual-energy X-ray absorptiometry, and the primary outcome was relative change in body fat mass, comparing treatment groups to Placebo. Other outcomes included anthropometric measurements, food intake and blood and fecal biomarkers. The study was registered in Clinicaltrials.gov (NCT01978691). Findings There were marked differences in the results of the Intention-To-Treat (ITT; n = 209) and Per Protocol (PP; n = 134) study populations. The PP analysis included only those participants who completed the intervention with > 80% product compliance and no antibiotic use. In addition, three participants were excluded from DXA analyses for PP due to a long delay between the end of intervention and the last DXA measurement. There were no significant differences between groups in body fat mass in the ITT population. However, LU + B420 and B420 seemed to improve weight management in the PP population. For relative change in body fat mass, LU + B420 showed a − 4.5% (− 1.4 kg, P = 0.02, N = 37) difference to the Placebo group, whereas LU (+ 0.3%, P = 1.00, N = 35) and B420 (− 3.0%, P = 0.28, N = 24) alone had no effect (overall ANOVA P = 0.095, Placebo N = 35). A post-hoc factorial analysis was significant for B420 (− 4.0%, P = 0.002 vs. Placebo). Changes in fat mass were most pronounced in the abdominal region, and were reflected by similar changes in waist circumference. B420 and LU + B420 also significantly reduced energy intake compared to Placebo. Changes in blood zonulin levels and hsCRP were associated with corresponding changes in trunk fat mass in the LU + B420 group and in the overall population. There were no differences between groups in the incidence of adverse events. Discussion This clinical trial demonstrates that a probiotic product with or without dietary fiber controls body fat mass. B420 and LU + B420 also reduced waist circumference and food intake, whereas LU alone had no effect on the measured outcomes., Highlights • The probiotic B420 and synbiotic LU + B420 seem to control body fat mass in humans, especially in the abdominal area. • B420 and LU + B420 reduce waist circumference and energy intake, but only LU + B420 increases lean body mass. • Reduced body fat is associated with zonulin, a marker of epithelial permeability, supporting earlier preclinical findings. Concise results on probiotics for weight management are lacking. Stenman et al. show in a gold standard clinical study that the probiotic B420 with or without a fiber controls body fat, waist circumference and energy intake when taken in a dietary intervention of six months. Study participants maintained habitual diet and physical activity. Stenman et al. link the benefit to changes in serum zonulin, a potential gut permeability marker. The authors have previously shown in animal studies that these gut microbiota targeting products improve metabolic health in mice by strengthening gut barrier function. These effects are now translated to humans.

Summary Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co‐inheritance in SCA of alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co‐inheritance of these polymorphisms on CBFv in 601 stroke‐free Tanzanian SCA patients aged

Cell Death and Differentiation, 20 (11), ISSN:1350-9047, ISSN:1476-5403

Haem oxygenase 1 (HO-1) is an inducible protein that plays a major protective role in conditions such as ischaemia-reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO-1 expression and its correlation with the GT length polymorphism (GT(n)) in the promoter of the HO-1 gene.In a dose-escalation, randomized, placebo-controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GT(n) genotype received intravenous HA. HO-1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period.We found that the baseline mRNA levels of HO-1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose-dependent increase in the baseline corrected area under the curve values of HO-1 mRNA and protein over 48 h. The response of HO-1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups.HA is an effective inducer of HO-1 in humans irrespective of the GT(n) genotype. The potential therapeutic application of HA needs to be evaluated in clinical trials.