Methylglyoxal in Cardiometabolic Disorders: Routes Leading to Pathology Counterbalanced by Treatment Strategies.

Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation, followed by deleterious effects at the cellular and systemic levels, is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders, including metabolic syndrome, diabetes mellitus, and cardiovascular diseases. In this review, an interplay between pathways leading to MGO generation and scavenging is addressed in regard to this system's impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases, are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.

The concentration of resistin in perivascular adipose tissue after CABG and postoperative atrial fibrillation.

BACKGROUND: Postoperative atrial fibrillation occurs in up to 30% of patients after coronary artery bypass graft (CABG) and its cause is unknown. The aim of the study was to evaluate whether concentration of resistin in surrounding coronary artery perivascular adipose tissue (PVAT) is related to postoperative atrial fibrillation occurrence. METHODS: A total number of 46 patients (35 male, 11 female; median age 66.5) were qualified for elective CABG. Medical history, laboratory test results and echocardiographic parameters were noted. Patients were monitored up to 3 days after CABG and then were divided into groups with and without postoperative atrial fibrillation occurrence. Fragments of PVAT were collected intra-operatively: near the left anterior descending artery and main left coronary artery. The concentration of resistin was determined by Human Resistin Quantikine ELISA Kit and expressed as ng/g. A multivariate stepwise logistic regression analysis was performed to find variables related to postoperative atrial fibrillation occurrence. RESULTS: Postoperative atrial fibrillation occurred in 14 (30.4%) patients. The patients with and without postoperative atrial fibrillation were similar in age, gender, epicardial adipose tissue thickness and laboratory parameters. The concentration of resistin in PVAT near the left main coronary artery was significantly higher in patients with postoperative atrial fibrillation than in those without the complication (P = 0.03). In the multivariate stepwise logistic regression analysis the concentration of resistin above cut-off point 54 ng/g in PVAT near left main coronary artery was independently related to postoperative atrial fibrillation occurrence (OR: 7.7; 95% CI:1.4-42.2 p = 0.02). CONCLUSIONS: The higher concentrations of resistin in PVAT near the left main coronary artery which is located close to the left atrium are associated with postoperative atrial fibrillation.

Nonenzymatic Serum Antioxidant Capacity in IBD and Its Association with the Severity of Bowel Inflammation and Corticosteroids Treatment.

Background and objectives: Oxidative stress signalling plays a monumental role in inflammatory bowel disease (IBD). Reduction of oxidative stress might control inflammation, block tissue damage, and reverse natural history of IBD. We assessed the serum concentrations of free thiols (FT) and uric acid (SUA), together constituting a large part of nonenzymatic serum antioxidant capacity, as well as total antioxidant status (TAS) with reference to IBD phenotype, activity, co-occurrence of anemia, and treatment with azathioprine (AZA) and corticosteroids (CS). Additionally, we appraised the potential of uric acid, thiol stress, and TAS as mucosal healing (MH) markers in ulcerative colitis. Materials and methods: SUA, FT, and TAS were measured colorimetrically using, respectively, uricase, Ellman's and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) methods. Results: The study group consisted of 175 individuals: 57 controls, 71 ulcerative colitis (UC), and 47 Crohn's disease (CD) patients. When compared to controls, SUA levels were significantly lower in patients with CD, and FT and TAS levels were significantly lower in patients with CD and UC. In UC patients, SUA, FT, and TAS inversely correlated with the severity of bowel inflammation. As MH markers, SUA displayed better overall accuracy and higher specificity than FT. In active CD, FT, and SUA were significantly lower in patients with anemia. FT was significantly lower in patients treated with corticosteroids. Conclusions: IBD patients, regardless the disease phenotype, have systemic thiol stress, depleted total antioxidant capacity, and reduced concentrations of uric acid, reflecting, to various degrees, clinical and local disease activity as well as presence of anaemia, the most common extraintestinal manifestation of IBD. Evaluation of systemic total antioxidant status may be useful in noninvasive assessment of mucosal healing. Our findings on thiol stress provide an additional aspect on adverse effects of corticosteroids therapy.

Lipid peroxidation markers in Crohn's disease: the associations and diagnostic value.

BACKGROUND: Crohn's disease (CD) is an incurable and difficult to diagnose condition. While high sensitive C-reactive protein (CRP) remains the best biochemical marker, we evaluated the diagnostic usefulness of lipid peroxidation indices. METHODS: Malondialdehyde/thiobarbituric acid-reactive substances (MDA/TBARS), peroxidation potential (PP), lipid hydroperoxides (ROOH), oxidized-low density lipoprotein (oxLDL), and oxLDL antibodies (OLAB) were assessed in 52 CD patients and 99 volunteers and referred to clinical activity, inflammation, nutritional and antioxidant status. RESULTS: MDA/TBARS were higher in CD while oxLDL and PP decreased in active disease and ROOH and OLAB did not differ. oxLDL and PP negatively and OLAB positively correlated with CD activity. MDA/TBARS positively correlated with IL-6 and SOD-1 and negatively with catalase. IL-6 and SOD-1 explained 24% in MDA/TBARS variability. PP negatively correlated with CRP, platelets, and IL-6 and positively with glutathione peroxidase-1, paraoxonase-1, cholesterol, triglycerides, and albumins. Cholesterol and CRP explained 57% in PP variability. oxLDL negatively correlated with IL-1 and IL-6 and positively with glutathione peroxidase-1, paraoxonase-1, cholesterol, and albumins. Paraoxonase-1 explained 17% of oxLDL variability. OLAB positively correlated with IL-1 explaining 10% in its variability and negatively with cholesterol. MDA/TBARS were the best predictor of CD, comparable to CRP, with high specificity (MDA/TBARS sensitivity and specificity: 75% and 90%; CRP: 76% and 93%). Combined assessment of MDA/TBARS and CRP improved sensitivity (94%) corresponding with acceptable specificity (81%). CONCLUSIONS: MDA/TBARS are elevated in CD and may help to rule the disease out, while the combined evaluation with CRP may serve for CD confirmation. oxLDL and PP depended on substrate availability, decreased in CD.

Correlation of MMP-3 and MMP-9 with Crohn's disease activity in children.

BACKGROUND: Recently published data indicate that the inflammation in Crohn's disease (CD) may be accompanied by elevated levels of matrix metalloproteinases. AIMS: The goals of the present study were the estimation of MMP-3 and -9 concentrations in sera of children with Crohn's disease, the examination of correlation between the concentrations of MMP-3 and -9 and clinical activity of the disease in the relation to the control group and the evaluation of the utility of MMP-3 and -9 concentration measurements as markers of disease activity. METHODS: Serum concentrations of MMP-3 and -9 were estimated in 82 children (45 CD patients divided into severe, moderate and mild subgroups; 37 controls) and correlated with disease activity estimated by the Pediatric Crohn's Disease Activity Index (PCDAI), CRP, seromucoid and ESR. RESULTS: Mean MMP-3 concentrations were: 2.49 ng/ml (95% CI: 1.76-3.52) for mild, 16.44 ng/ml (95% CI: 10.34-26.15) for moderate, 5.25 ng/ml (95% CI: 2.73-10.11) for severe CD and 1.95 ng/ml (95% CI: 1.53-2.48) for the control group (differences between all three groups were statistically significant; P < 0.001). Median MMP-9 concentrations were: 2.14 ng/ml (95% CI: 0-8.9) for mild, 14.21 ng/ml (95% CI: 4.53-21.48) for moderate, 42.2 ng/ml (95% CI: 5.74-61.27) for severe CD and 1.3 ng/ml (95% CI: 0.7-2.18) for the control group. MMP-9 concentrations in moderate and severe CD differed from the concentrations in mild CD (P = 0.002) and control group (P = 0.0001). MMP-3 concentration significantly correlated with MMP-9, PCDAI and ESR, while MMP-9 concentration significantly positively correlated with MMP-3, PCDAI, and CRP. Diagnostic utilities of the tests were: MMP-3 accuracy 75%, positive likelihood ratio (LR+) = 4.11 and negative likelihood ratio (LR-) = 0.51, sensitivity 56%, specificity 87%, Youden index 0.43; for MMP-9, accuracy 73%, LR+ = 5.14 and LR- = 0.50, sensitivity 56%, specificity 89%, Youden index 0.45; and for CRP, accuracy 74%, LR+ = 8.56 and LR- = 0.54, sensitivity 49%, specificity 94%, Youden index 0.43. CONCLUSIONS: MMP-9 serum concentration increasing along with the activity of the disease, exhibiting high specificity and correlating well with the indices of inflammation might be of better usefulness in the prediction of CD activity status in children than MMP-3.

Modulatory Impact of Lamiaceae Metabolites on Apoptosis of Human Leukemia Cells.

Lamiaceae species are rich sources of biologically active compounds which have been applied in medicine since ancient times. Especially their antineoplastic properties have been thoroughly studied with respect to their putative application in chemoprevention and adjuvant therapy of cancer. However, the most known biological effects of Lamiaceae have been ascribed to their essential oil fractions, whereas their (poly)phenolic metabolites being also abundant in these plants, are much less recognized, nevertheless contributing to their beneficial properties, such as anti-cancer actions. The aim of this study was to evaluate the impact of dried aqueous extracts from common thyme (Thymus vulgaris L.) (ExTv), wild thyme (Thymus serpyllum L.) (ExTs), sweet marjoram (Origanum majorana L.) (ExOm), and peppermint (Mentha × piperita L.) (ExMp), as well as (poly)phenolic compounds: caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-ß-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictyol-7-O-rutinoside (Er), and arbutin (Ab), on unstimulated Jurkat cells, in comparison with their effect on staurosporine-stimulated Jurkat cells. Jurkat T cells were incubated with different concentrations of ExTv, ExTs, ExOm, ExMp, Lgr, LA, Er, Lr, RA, CA, or Ab. Subsequently, staurosporine was added to half of the samples and flow cytometry combined with fluorescence-activated cell sorting analysis was conducted, which allowed for the selection of early and late apoptotic cells. Both ExTs and ExOm stimulated apoptosis of Jurkat cells and enhanced the proapoptotic effect of staurosporine. Conversely, ExTv and ExMp demonstrated no clear effect on apoptosis. CA and RA raised the staurosporine-induced apoptotic effect. The impact of Er and Lgr on Jurkat cells showed fluctuations depending on the compound concentration. Neither Er nor Ab altered staurosporine-induced apoptosis in Jurkat cells, whereas Lgr seemed to weaken the proapoptotic action of staurosporine. The most evident observation in this study was the pro-apoptotic action of ExTs and ExOm observed both in staurosporine-unstimulated and stimulated Jurkat cells. Additionally, an enhancement of staurosporine-induced apoptosis by caffeic and rosmarinic acids was reported. Therefore, it might be concluded that these are the mixtures of biologically active polyphenols which often exert more pronounced beneficial effects than purified molecules.

HDL Accessory Proteins in Parkinson's Disease-Focusing on Clusterin (Apolipoprotein J) in Regard to Its Involvement in Pathology and Diagnostics-A Review.

Parkinson's disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid ß, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.

Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis - with impact on gastrointestinal tract.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seems to employ two routes of entrance to the host cell; via membrane fusion (with the cells expressing both angiotensin converting enzyme 2 (ACE2) and transmembrane peptidase/serine subfamily member 2/4 (TMPRSS2/4)) or via receptor-mediated endocytosis (to the target cells expressing only ACE2). The second mode is associated with cysteine cathepsins (probably cathepsin L) involvement in the virus spike protein (S protein) proteolytic activation. Also furin might activate the virus S protein enabling it to enter cells. Gastrointestinal tract (GIT) involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019 (COVID-19) patients exhibiting GIT symptoms, such as diarrhea, and presenting viral-shedding in feces. Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT (especially brush-border enterocytes), these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract. Additionally, in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT. However, also furin and cysteine cathepsins (cathepsin L) might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT. Moreover, cathepsin L (due to its involvement in extracellular matrix components degradation and remodeling, the processes enhanced during SARS-CoV-2-induced inflammation) might be responsible for the dysregulation of absorption/ digestion functions of GIT, thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.

Punicalagin in Cancer Prevention-Via Signaling Pathways Targeting.

The extract of pomegranate (Punica granatum) has been applied in medicine since ancient times due to its broad-spectrum health-beneficial properties. It is a rich source of hydrolyzable tannins and anthocyanins, exhibiting strong antioxidative, anti-inflammatory, and antineoplastic properties. Anticancer activities of pomegranate with reference to modulated signaling pathways in various cancer diseases have been recently reviewed. However, less is known about punicalagin (Pug), a prevailing compound in pomegranate, seemingly responsible for its most beneficial properties. In this review, the newest data derived from recent scientific reports addressing Pug impact on neoplastic cells are summarized and discussed. Its attenuating effect on signaling circuits promoting cancer growth and invasion is depicted. The Pug-induced redirection of signal-transduction pathways from survival and proliferation into cell-cycle arrest, apoptosis, senescence, and autophagy (thus compromising neoplastic progression) is delineated. Considerations presented in this review are based mainly on data obtained from in vitro cell line models and concern the influence of Pug on human cervical, ovarian, breast, lung, thyroid, colorectal, central nervous system, bone, as well as other cancer types.

Circulating leptin and inflammatory response in esophageal cancer, esophageal cancer-related cachexia-anorexia syndrome (CAS) and non-malignant CAS of the alimentary tract.

We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract.

Correlation between biomarkers (calprotectin, seromucoid, metalloproteinase-3 and CRP) and clinical and endoscopic activity of ulcerative colitis in children.

PURPOSE: The aim of the study was to compare the clinical activity and inflammatory markers with the endoscopic activity of ulcerative colitis (UC) and mucosal healing. PATIENTS AND METHODS: The study included 50 children aged 2-18 years (27 girls, 23 boys) diagnosed with UC at various stages of the disease; 8 children were assessed twice. In 20 children, colonoscopy revealed pancolitis, in 24 - left-sided colitis, and in 6 - ulcerative proctitis. The clinical activity of UC was assessed according to the Pediatric Ulcerative Colitis Activity Index (PUCAI). Endoscopic index of the colon inflammation was assessed according to the Rachmilewitz scoring. We assessed the clinical activity of UC, the concentration of fecal calprotectin (FC), seromucoid, metalloproteinase-3 (MMP-3) and C-reactive protein (CRP). RESULTS: The study demonstrated significant decrease in the clinical activity, FC, seromucoid and MMP-3 in endoscopic remission. We found a strong positive correlation between PUCAI, FC, serum seromucoid and serum MMP-3 with the endoscopic activity. However, we found no relationship between the concentration of CRP and the endoscopic activity of the disease. Among the studied markers, seromucoid exhibited the best performance in distinguishing between patients with endoscopic remission and endoscopically active disease. CONCLUSIONS: The examined inflammatory markers such as FC, as well as serum seromucoid and MMP-3 levels may be helpful in the assessment of large intestine mucosal healing.

Upregulated sulfatase and downregulated MMP-3 in thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) formation is accompanied by degradation of extracellular matrix components (EMC). Numerous matrix metalloproteinases (MMPs) have been implicated in the process, but the involvement of MMP-3 remains unclear. Additionally, the changes in proteoglycan (PG) structure can alter the signal transduction pathways in TAA, though the enzymatic systems which originate them are not fully understood. OBJECTIVES: To measure MMP-3 and sulfatase levels in aneurysmal tissue, comparing them with non-aneurysmal vessels, and to investigate possible correlations with patients' serum levels in order to evaluate their potential usefulness in aiding aneurysm detection and monitoring. MATERIAL AND METHODS: The study included 74 patients (TAA: n = 42; control group: n = 32). Sulfatase activity was measured colometrically and MMP-3 levels were measured immunoenzymatically. RESULTS: Sulfatase activities were higher (p = 0.03) and MMP-3 concentrations lower (p = 0.014) in aneurysmal tissue than in normal aortic tissue. Medium-sized dilatations were associated with lower tissue MMP-3 concentrations than small dilatations (p = 0.033). No differences in sulfatase activity or MMP-3 concentration in the serum of TAA patients were observed in comparison with the controls. The serum and tissue levels of MMP-3 were correlated (r = 0.41; p < 0.001). The serum levels of MMP-3 were significantly lower in the female patients than in the male patients (p = 0.006). CONCLUSIONS: Our studies confirmed the lower MMP-3 levels in aneurysmal tissue, but the lack of a statistically confirmed reduction of MMP-3 in the blood serum seems to preclude its usefulness for diagnostic purposes. Our study points to the differences in MMP-3 behavior between TAA and abdominal aortic aneurysms. Significantly higher sulfatase activity in TAA tissue suggests a possible impact of sulfatase on signal transduction pathways involved in aneurysm formation.

Clinical relevance of circulating midkine in ulcerative colitis.

BACKGROUND: Non-invasive biochemical markers are needed to support the diagnosis of ulcerative colitis (UC), an incurable disease of unknown pathology. Midkine is an angiogenic cytokine, chemotactic towards neutrophils and macrophages, and a T-regulatory cell suppressor. METHODS: Serum midkine was measured immunoenzymatically in 93 UC patients and 108 healthy subjects, and evaluated with respect to disease status, endoscopic, inflammatory and angiogenic activity. The diagnostic value of midkine was compared to C-reactive protein (CRP) using receiver operating characteristics (ROC) analysis. RESULTS: Midkine was higher (p<0.0001) in inactive (199 ng/L) and active UC (351 ng/L) compared with controls (93 ng/L), and reflected disease activity (r=0.427, p<0.001). Midkine was correlated with CRP, erythrocyte sedimentation rate (ESR), leukocytes, platelets, interleukin-6, paraoxonase-1, albumin, transferrin, iron, hemoglobin, and hematocrit. Midkine correlated with angiogenic factors: vascular endothelial growth factor-A and platelet-derived growth factor-BB. As a marker of UC, midkine showed a diagnostic accuracy of 85%, sensitivity of 72%, specificity of 82%, whereas CRP showed 83%, 65% and 91%, respectively. As a marker of active UC, midkine showed a diagnostic accuracy of 87%, sensitivity of 84%, specificity of 75%, whereas CRP showed 75%, 63% and 83%, respectively. Combined assessment of midkine and CRP improved sensitivity but substantially decreased specificity. CONCLUSIONS: UC is associated with increased circulating midkine, which corresponds with clinical, endoscopic, inflammatory and angiogenic activity, and anemia. Performance of midkine as a marker of UC or active UC was comparable to that of CRP.

Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas--implication for clinical evaluation of cancer patient.

The presence of lymph node metastasis (LNM) is an important factor in clinical evaluation of esophageal cancer patients. Biological markers able to support detection of metastatic lymph nodes are sought after. Interleukin-8 (IL-8) is overexpressed by many cancers and involved in cancer dissemination. We investigated the relationship between circulating IL-8 and clinicopathological features of esophageal squamous cell carcinoma (ESCC), and evaluated the diagnostic potential of IL-8, with reference to the key angiogenic and lymphangiogenic factors: vascular endothelial growth factors A and C (VEGF-A and VEGF-C). We found elevated IL-8 levels in ESCC patients, correlated with tumor size and cancer dissemination, especially LNM. Circulating IL-8 correlated with lymphangiogenic VEGF-C rather then angiogenic VEGF-A. The association weakened in metastatic cancers, suggesting divergent mechanism of IL-8 involvement in the dissemination process. The cytokine levels correlated with platelets and neutrophils, pointing at these cells as possible sources of circulating IL-8. We demonstrated IL-8 that positively correlated with inflammation status of ESCC patients. Circulating IL-8 was a better indicator of ESCC dissemination than VEGF-A or VEGF-C. Yet, the detection rates were not satisfactory enough to allow for the recommendation of IL-8 determination as an adjunct to the clinical evaluation of lymph node involvement in ESCC patients.

Th9 lymphocytes and functions of interleukin 9 with the focus on IBD pathology.

The work presents the newest knowledge on a new phenotype of T helper lymphocytes (Th9) and on Interleukin 9 (IL-9). Processes leading to transformation of naïve T lymphocyte into Th9 lymphocytes are presented, including the role of IL-4 and TGFß signaling. Involvement of transcription factor network in production of IL-9 is described. Other cells capable of expressing IL-9 and secreting IL-9 are portrayed. Diversity of IL-9 effects caused by activation of IL-9 receptors on various types of cells is presented. Principal effects of the activation of IL-9 receptor on T-cells seem to be antiapoptotic and stimulatory which leads to enhanced defense against parasitic infection and cancer development but, from the other side, it perpetuate chronic inflammation in autoimmune diseases and allergic processes. In the last years the role of IL-9 in autoimmune diseases such as rheumatic diseases and inflammatory bowel disease gained importance since the increased expression of this cytokine has been observed in animal models of intestinal inflammation and in groups of patients with ulcerative colitis. It was also noted that neutralization of IL-9 in animal models of ulcerative colitis leads to amelioration of inflammatory process, what could have significance in the treatment of this disease in humans in the future.

Diagnostic Potential of Systemic Eosinophil-Associated Cytokines and Growth Factors in IBD.

Despite the acknowledged contribution of eosinophils to the disease pathogenesis, available data on cytokines closely related to the peripheral eosinophils in inflammatory bowel disease (IBD) are scattered. We assessed the concentrations of eosinophil-associated cytokines and growth factors in the group of 277 individuals (101 patients with Crohn's disease (CD), 77 with ulcerative colitis (UC), 16 with irritable bowel syndrome (IBS), and 83 healthy controls) and referred to IBD activity and the levels of hsCRP. As compared to IBS patients or healthy controls, patients with CD had significantly higher levels of IL5, IL8, IL12(p70), GM-CSF, and TNFα and patients with UC, the levels of eotaxin, IL4, IL5, IL8, IL12(p70), IL13, GM-CSF, and TNFα were also higher. As compared to CD patients, patients with UC had significantly higher levels of eotaxin, IL4, IL5, IL8, and IL1. In turn, the concentrations of hsCRP were significantly higher in CD than UC. Except for IL13, all cytokines and hsCRP positively correlated with CDAI. In UC, a positive correlation with MDAI was observed for hsCRP, GM-CSF, IL12(p70), and IFNγ and a negative one for IL8. The concentrations of hsCRP, GM-CSF, IFNγ, IL12(p70), and RANTES were higher in UC patients with active than inactive disease whereas those of IL8 and TNFα were significantly lower. Eotaxin, determined individually or in a panel with IFNγ and hsCRP, showed fair accuracy in differentiating CD from UC. If confirmed on a larger representation of IBS patients, IL8 might support differential diagnosis of organic and functional conditions of the bowel. GM-CSF, in turn, demonstrated to be an excellent indicator of bowel inflammation and may be taken into consideration as a noninvasive marker of mucosal healing. In summary, eosinophil-associated cytokines are elevated in IBD, more pronouncedly in UC, and may support the differential diagnosis of IBD and aid in monitoring of mucosal healing.

Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC).

Tissue expression of VEGF-C correlates with lymph node involvement (LNI) in ESCC and serum VEGF-C (sVEGF-C) in a non-small cell lung cancer has been more accurate marker of LNI than chest CT. Despite LNI importance in ESCC, the usefulness of serum VEGF-C (sVEGF-C) as a disease and LNI marker in ESCC has not been investigated yet. We found elevated sVEGF-C in ESCC (17.40 vs. 10.57 ng/ml in controls, p<0.001). It proved to be a better ESCC marker than described elsewhere: CEA, CA19-9 and SCC-Ag, with: sensitivity--70%, specificity--81%, accuracy--83.7%. Analysis of sVEGF-C correlation with clinico-pathological cancer features revealed relation to LNI (N0: 15.77 vs. N1: 21.78 ng/ml, p=0.02), especially in advanced cancers. Serum VEGF-C as a marker of LNI was characterized by: sensitivity--76%, specificity--58%, accuracy--64.4%. No relation was observed between LNI and sVEGF-A or sVEGF-A/platelets (PLT). Because sVEGF-C was higher in N0 cancers (p<0.01), the tumor presence also up-regulates sVEGF-C. We found sVEGF-C correlation with PLT and WBC: R=0.36 and R=0.32 (p<0.01). Nevertheless, analysis of PLT and WBC dependence on cancer features implies that elevation of sVEGF-C in N1 cancers is not related to them.

Impact of weight loss on circulating IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C and midkine in gastroesophageal cancer patients.

OBJECTIVE: Proinflammatory cytokines are involved in cancer-related weight loss, but the involvement of VEGF-A, VEGF-C, IL-8 and midkine in gastroesophageal cancer patients remains unknown. DESIGN AND METHODS: Serum IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C, and midkine were evaluated in 96 cancer patients and 42 controls using ELISAs and were related to the occurrence of weight loss, patient's age, gender and BMI, cancer TNM status and blood cell counts. RESULTS: All cytokines were elevated in cancer patients with further up-regulation of IL-6, IL-8, midkine and VEGF-A in cachexia. Underweight, midkine and VEGF-A were found independent indicators of weight loss. Primary tumor seems to be a major source of pro-cachectic cytokines, yet neutrophils and platelets also contribute to cytokine elevation. CONCLUSIONS: IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies, although a detailed mechanism underlying cytokine involvement needs to be elucidated.

Reduced Transferrin Levels in Active Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an inflammatory disease of unclear etiopathogenesis and challenging diagnosis, frequently complicated by anemia and malnutrition. C-reactive protein (CRP) remains the only biochemical marker of clinical relevance. The aim of this study was to test hypothesis that transferrin, coinfluenced by inflammation, malnutrition, anemia, and oxidative stress, may better reflect global IBD patient's condition than any other more specific index. Transferrin and other indices of inflammation, anemia, malnutrition, and oxidative stress were measured in 137 IBD patients (Crohn's disease (CD): n = 63 and ulcerative colitis (UC): n = 74) and 97 controls. Transferrin is reduced in active CD and UC and negatively correlates with the disease activity scores (CD: ρ = -0.49; UC: ρ = -0.52). In UC, transferrin correlates negatively with CRP, erythrocyte sedimentation rate (ESR), leukocytes, platelets, interleukin-6, interleukin-10, and TNF-α and positively with albumins, cholesterol, hemoglobin, hematocrit, erythrocytes, iron, and paraoxonase-1. In CD, transferrin correlates negatively with CRP, leukocytes, platelets, interleukin-1, and interleukin-6 and positively with albumins, iron, catalase, glutathione peroxidase-1, superoxide dismutase-1, and paraoxonase-1. The associations with inflammation and anemia/malnutrition were more pronounced in UC and with oxidative stress in CD. As UC activity marker, transferrin outperforms ESR and hemoglobin, indices used in calculating the disease clinical severity score.

Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis.

AIM: To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker. METHODS: Serum IL9 as well as other cytokines (IL1ß, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP® technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method. RESULTS: Systemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1ß and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD. CONCLUSION: The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.