Erythropoiesis and Iron Parameters in Transfusion-dependent and Nontransfusion-dependent Thalassemias.

INTRODUCTION: To clarify mechanisms of ineffective erythropoiesis on iron metabolism, studies on erythroid factors that regulating hepcidin suppression have been carried out. The aim of the current study is to identify associations between erythropoiesis and iron homeostasis parameters in ß-thalassemias. MATERIALS AND METHODS: This study consisted of 83 subjects: 21 thalassemia major (TM), 20 thalassemia intermedia (TI), 20 thalassemia trait (TT), and 22 healthy subjects (HS). Erythroferrone (ERFE), hepcidin, growth differentiation factor-15 (GDF15), erythropoietin (EPO), and iron status parameters were measured. RESULTS: Our results showed that TM and TI patients had higher hepcidin than the TT and control groups. The hepcidin/ferritin in TM patients was significantly lower than the other groups. GDF15 in TM and TI patients was significantly higher than in the TT and control groups. Also, TI group had significantly higher ERFE concentration and EPO activity when compared with the TM, TT, and HS groups. EPO activity showed positive correlation with ERFE and GDF15 concentrations. We could not find any correlation between ERFE and hepcidin concentrations. CONCLUSIONS: ERFE may be one of the parameters used to demonstrate erythropoietic activity level in thalassemias. More detailed studies are needed to clarify the role of ERFE in iron metabolism in the patients with thalassemias.

Lysophosphatidic acid represses autophagy in prostate carcinoma cells.

Lysophosphatidic acid (LPA) is a small signaling phospholipid that mediates diverse functions including cell proliferation, migration, and survival by engaging LPA-agonized G-protein coupled receptors. Autophagy is a survival mechanism in response to nutrient depletion or organellar damage that encloses idle or damaged organelles within autophagosomes that are then delivered to lysosomes for degradation. However, the relationship between LPA and autophagy is largely unknown. The purpose of this study is to elucidate whether LPA affects autophagy through the ERK1/2 and (or) the Akt-mTOR signaling pathways. In this study, we investigated the effect of LPA on autophagy-regulating pathways in various prostate-derived cancer cells including PC3, LNCaP, and Du145 cells grown in complete medium and exposed to serum-free medium. Using Western blotting and ELISA, we determined that LPA stimulates the ERK and mTOR pathways in complete and serum-free medium. The mTOR pathway led to phosphorylation of S6K and ULK, which respectively stimulates protein synthesis and arrests autophagy. Consistent with this, LPA exposure suppressed autophagy as measured by LC3 maturation and formation of GFP-LC3 puncta. Altogether, these results suggest that LPA suffices to activate mTORC1 and suppress autophagy in prostate cancer cells.

Evaluation of d-dimer, CXCL8, homocysteine, eosinophil cationic peptide, 25(OH)-vitamin D and immunomodulatory OX-2 levels in allergic patients.

OBJECTIVES: Studies on sCD200 (OX-2), 25-hydroxyvitamin-D (25(OH)D), homocysteine (hcy), eosinophil cationic peptide (ECP), d-dimer, CXCL8 and fractional exhale nitric oxide concentrations in allergic patients in Mediterranean regions under various climatic conditions have not been performed. In this report, blood samples were taken in May and June during times of high air pollination. This study was performed to compare serum biomolecule concentrations in allergic patients and matched controls and to evaluate the characteristics of allergic disease. METHODS: The study participants (n = 129) included 25 healthy individuals (controls) and 104 allergic patients. Consecutive patients with managed allergic disease (Group II, III, IV and V) above the age of 18 years were included. RESULTS: In the control group, there was a significant positive correlation between ECP level and body mass index (BMI). Positive correlations among ECP, IgE and OX-2 levels were detected in Group IV. In Group V patients, positive correlations between age and IgE and between BMI and 25(OH)D were identified. Statistical analysis revealed positive correlations among basophil, eosinophil and OX-2 levels, and a negative correlation between ECP and age in Group V. CONCLUSION: Overall, these data suggest that hcy, 25(OH)D and OX-2 may be useful biomarkers for conventional clinical measurements.

Proteomics pattern of peritoneal sApo-2L but not CD200 (OX-2) as a possible screening biomarker for metastatic ovarian, endometrial and breast carcinoma.

PURPOSE: The purpose of this study was to evaluate the soluble Apo-2L (sApo-2L) levels in the ascitic fluid and to study its potential in detecting malignant ascites and soluble CD200 (sCD200,sOX-2) levels so as to predict its clinical usage for detecting stage 4 metastatic endometrial, ovarian and breast cancer in serum samples. METHODS: Ascitic fluid from 53 and blood from 25 subjects without known malignancy on admission were collected. There were 14 breast cancer (BC), 17 ovarian cancer (OC) and 19 endometrial cancer (EC) patients diagnosed later on. Blood samples for sApo-2L, sCD200, liver function tests and CEA, CA-19.9 and CA-125 were always taken and assayed in the morning. RESULTS: Significantly low levels of sApo-2L were observed in peritoneal fluid from OC and EC patients compared to benign peritoneal fluid from control individuals. Positive correlation was observed between sApo-2L and aspartate aminotransferase (AST) in benign peritoneal fluid and sCD200, and creatinine and sCD200 and platelets in OC patients; also, sCD200 and CEA in EC patients and sCD200 and blood urea nitrogen (BUN) in healthy subjects. CONCLUSIONS: Our data indicate that low proteomics pattern of sApo-2L but not sCD200 is a good biochemical marker. Further decline in the level of sApo-2L was seen in EC compared to OC. Since higher levels of sApo-2L were seen with higher levels of AST, the liver might be involved in its metabolism. The positive correlation detected between sCD200 and creatinine, platelets, CEA and BUN needs to be elucidated.

Blood eosinophil and platelet levels, proteomics patterns of trail and CXCL8 correlated with survival in bevacizumab treated metastatic colon cancers.

STrail (soluble TNF-related apoptosis-inducing-ligand) has also been observed where the cytotoxic effects of antiangiogenic agents are increased in clinical phase II and III studies when these agents are combined with TRAIL related therapies. Recent studies have shown that CXCL8 and its receptors are significantly up-regulated in CRC and act as regulators of proliferation, angiogenesis, and metastasis. sTRAIL, CXCL8, CEA, together with complete blood count parameters (hemoglobine, platelet, eosinophil, basophil, neutrophil, lymphocyte) were recorded in the beginning and every three months afterwards for a period of 4 years. The study population comprised 21 of the 42 patients with metastatic colorectal cancer (MCRC), undergoing 18 FDG-PET/CT scanning prior to treatment. Progression free survival was 262 days and overall survival was 1148 days. Overall survival was higher in patients whose Karnofsky Performance scores were above 86% (p = 0.003). Progression free survival was higher in patients whose blood eosinophil counts at 0, 6, and 9 months were higher than the mean levels of corresponding values (p-values are 0.016, 0.032, and 0.001, respectively). Another significant positive correlation was found between the platelet levels at 9 months and progression free survival (p = 0.019). There were significant changes (p < 0.05) prior to treatment and three months later for sTRAIL (p = 0.0060) and CXCL8 (p = 0.00001), based on the Wilcoxon matched pairs signed rank test. Generally, sTRAIL values increased during therapy, while a decrease was observed for CXCL8 without any significant differences for other variables.

Anti-IgE monoclonal antibody (omalizumab) is effective in treating bullous pemphigoid and its effects on soluble CD200.

Herein, we report a case of a man with pruritic bullous pemphigoid (BP) and very high levels of total IgE (5000 kU/L) who was refractory to standard aggressive immunosuppressive regimens (systemic steroids, daily cyclophosphamide) for BP but responded rapidly to systemic anti-IgE (omalizumab). Our patient is a 28 year-old white male. On admission 70% of his body surface area was involved with large bullae overlying urticarial plaques, involving his upper and lower extremities, chest, and abdomen. The circulating level of sCD200 was 48.45 pg/mL in serum and 243 pg/mL in blister fluid. During the second month of follow-up, the patient's sCD200 level decreased to 26.7 pg/mL. After the second round of omalizumab (300 mg), frequency of exacerbations decreased and after the 13th round it had completely disappeared.

Serum soluble CD200 level was higher in patients with bullous pemphigoid during the active phase of the disease than for healthy individuals.

BACKGROUND: CD200 is a novel immunosuppressive molecule, existing both as cell membrane bound and as a soluble form in serum (sCD200), which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was found in serum and blister fluid in a patient with bullous pemphigoid and that anti-IgE therapy impacted those levels. We therefore planned this study to evaluate the soluble serum CD200 levels of bullous pemphigoid patients and compare it with that of healthy controls. We also analysed the association between the sCD200 levels and the clinical severity of the disease in bullous pemphigoid patients. METHODS: We investigated 5 consecutive patients with bullous pemphigoid, and 15 healthy controls were included in this study. Assessment of clinical examination and measurement of laboratory investigation were performed on the same day. Bullous pemphigoid patients were also assessed for Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Concentrations of anti-BP180 and soluble CD200 in the serum samples were quantified using ELISA kits. RESULTS: The serum soluble CD200 level was observed to be statistically significantly higher in patients with BP (77.6 +/- 15.7 pg/mL) compared with healthy controls (26.1 +/- 6.7 pg/mL), (p < 0.001). Nevertheless, there was no statistically significant correlation between serum soluble CD200 levels and clinical severity scores and Anti-BP180 values (p = 0.402, p = 0.395, respectively). However, there was a statistically significant correlation between ABSIS and Anti-BP180 levels in patients with BP (p = 0.036). CONCLUSIONS: CD200 might play a role in the immune response in the pathogenesis of bullous pemphigoid. However, we do not know the exact mechanism of CD200 in the disease initiation and/or progression.

Evaluation of soluble CD200 levels in type 2 diabetic foot and nephropathic patients: association with disease activity.

BACKGROUND: CD200 (OX-2) is a novel immune-effective molecule, existing in a cell membrane-bound form, as well as in a soluble form in serum (s OX-2), which acts to regulate inflammatory and acquired immune responses. MATERIAL AND METHODS: We planned this study to evaluate the sOX-2 levels of type 2 diabetic foot (group B), and compare it with that of healthy controls (group A). The patient group had the following values: DM period: 27.9±10.3 year [mean ±SD], HbA1c: 9.52±2.44% [mean ±SD]. RESULTS: Blood samples for sCD200 measurement were always taken in the morning between 8 and 10 A.M.. The results were reported as means of duplicate measurements. Concentrations of sOX-2 in the serum samples were quantified using an ELISA kit. Serum hs-CRP levels were measured using an hs-CRP assay kit. The sOX-2 level in group B was 173.8±3.1 and in group A was 70.52±1.2 [p<0.0001). In subgroup analysis of T2DM-DFI patients, we noticed that sOX-2 levels were higher in WGS (Wagner grading system) I and II patients than in WGS III and IV patients. The HbA1c, BUN, creatinine, hs-CRP levels, and sedimentation rates were higher in the patient group (p<0.0001, p<0.001, p<0.001, p<0.005, and p<0.0001, respectively). CONCLUSIONS: We suggest that there are vascular, immunologic, and neurologic components in DFI, whereas autoimmune diseases and inflammatory skin disorders have only an immunologic component. This is possibly evidence of a pro-inflammatory effect seen in DFI as a vascular complication.

Serum lipid peroxidation markers are correlated with those in brain samples in different stress models.

OBJECTIVE: Stress can stimulate increased production of oxygen radicals. We investigated the correlations between serum levels of lipid peroxidation markers and those in brain samples in different stress models. METHODS: Animals (n = 96) were divided equally into eight groups: a control group and groups treated with vitamin E (Vit E); exposed to immobilisation stress; exposed to immobilisation stress and treated with Vit E; exposed to cold stress; exposed to cold stress and treated with Vit E; exposed to both immobilisation and cold stress; and a final group exposed to both immobilisation and cold stress and treated with Vit E. Thiobarbituric acid-reactive substance (TBARS) in brain samples and levels of TBARS, corticosterone, conjugated dienes (CD), lipids, and paraoxonase-1 (PON1) activity in serum were analysed. RESULTS: Serum corticosterone (p < 0.001), CD (p < 0.05), lipid (p < 0.05) levels, and brain TBARS (p < 0.05) levels were significantly higher in all stress groups than in controls, and the elevated levels were reversed in the Vit E-treated stress groups (p < 0.05). Serum PON1 activity was not different among the groups (p > 0.05). Serum TBARS levels increased significantly in all stress groups (p < 0.05), but this elevation was only reversed in the group exposed to both immobilisation and cold stress and treated with Vit E (p < 0.001). CONCLUSION: These results suggest that serum levels of lipid peroxidation markers can be determined readily and may be useful as indicators to evaluate the effects of oxidative stress in the brain.

Effect of atorvastatin on atherosclerotic plaque formation and platelet activation in hypercholesterolemic rats.

We aimed to investigate whether atorvastatin influenced the CD40-CD40L pathway in atherosclerosis formation in rats fed a high cholesterol diet. Thirty-six male Wistar rats were divided among 4 groups as follows: control (C), statin (S), 5% cholesterol fed (HC), and statin-administered hypercholesterolemic (HCS). Serum levels of lipids, soluble CD40L, platelet factor 4, and interleukin-6 were assayed with commercial kits. The number of platelets expressing surface P-selectin, CD40, and CD40L were determined by flow cytometry. Aortas were examined for fatty streaks. In the HC group, we observed a significant increase in serum lipid levels and platelet activation markers compared with the control group. Rats in the HCS group had a significant decrease in lipid levels and downregulation in the number of platelets expressing surface P-selectin, CD40, and CD40L compared with the HC group. We observed decreased fatty streak formations in aortas in HCS rats. A positive correlation was found for platelet activation markers and atherosclerotic fatty streak formations. Regression analysis revealed that the predictor of atherosclerosis was CD40L. Our study suggests that in a rat hypercholesterolemic model, statin treatment may influence the CD40-CD40L dyad, and that this effect is parallelled by a suppression of progression of atherosclerotic plaque formation.

Association of circulating sTRAIL and high-sensitivity CRP with type 2 diabetic nephropathy and foot ulcers.

BACKGROUND: Hyperglycemia is among the potent factors that may induce or facilitate apoptosis. TNF-Related Apoptosis-Inducing Factor (TRAIL) is known for its apoptotic and immunomodulatory effects that have recently been correlated with diabetes. We examined serum-soluble TRAIL (sTRAIL) and high-sensitivity CRP (hs-CRP) levels and their association with various distinct parameters in type 2 diabetic nephropathy patients with diabetic foot disease. MATERIAL/METHODS: Twenty-two diabetic nephropathy patients with foot ulcers were enrolled in our study. Patients had been diagnosed with diabetes at age 24±10.58 years. Circulating sTRAIL and Hs-CRP levels were compared with control values, and possible correlations were investigated with parameters such as age, Wagner's Grade (WG), BMI, HbA1c, and creatinine. RESULTS: Serum sTRAIL levels were significantly reduced in the patient group, compared to healthy subjects. High HsCRP levels correlated with age, and WGS correlated with BMI and creatinine levels. CONCLUSIONS: Significantly suppressed sTRAIL levels in diabetic nephropathy patients with foot ulcers compared to healthy controls suggest a protective role for TRAIL in the disease setting.

There might be a role for CD200 in the pathogenesis of autoimmune and inflammatory skin disorders.

BACKGROUND: Soluble CD200 (sCD200) is a novel immuno-effective molecule, which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was present in serum and blister fluid in a patient with bullous pemphigoid and a patient with toxic epidermal necrolysis. We therefore planned this study to evaluate the sCD200 levels of autoimmune and inflammatory skin disorder patients and to compare them with that of healthy controls. MATERIAL/METHODS: Our study included 30 consecutive patients with psoriasis vulgaris, 15 with pemphigus vulgaris, and 15 healthy controls. Clinical examination and laboratory tests were performed on the same day. Psoriasis patients were also assessed with the Psoriasis Area and Severity Index (PASI) and pemphigus patients were assessed using the Pemphigus Disease Area Index (PDAI). Levels of sCD200 in the serum samples were quantified using ELISA kits. RESULTS: The serum sCD200 level was observed to be statistically significantly higher in patients with psoriasis vulgaris (96.7±15.8) compared to patients with pemphigus vulgaris (76.2±14.6), (p<0.001) and healthy controls (26.8±7.0) (p<0.001). The serum sCD200 levels were observed to be statistically significantly higher in patients with pemphigus vulgaris compared with that in healthy controls (p<0.001). In addition, there was a statistically significant correlation between serum sCD200 levels and PDAI (r=0.987, p=0.001). Nevertheless, there was no statistically significant correlation between serum sCD200 levels and PASI (r=0.154, p=0.407). CONCLUSIONS: sCD200 might play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders. However, it remains to be fully elucidated how sCD200 can orchestrate inflammatory response in psoriasis and pemphigus.

Effects of omalizumab on eosinophil cationic peptide, 25-hydroxyvitamin-D, IL-1ß and sCD200 in cases of Samter's syndrome: 36 months follow-up.

CONTEXT: The historic triad of nasal polyposis, asthma and intolerance to aspirin and related chemicals, recently designated as Samter's syndrome, is an inflammatory condition of unknown pathogenesis. This study surveyed the levels of chosen serum eosinophil cationic peptide (ECP), soluble CD200 (SCD200), interleukin (IL)-1ß, high sensitive C-reactive protein (hs-CRP) and 25-hydroxyvitamin-D (25(OH)D) in the aspirin-induced asthmatic patients treated with anti-IgE therapy to investigate their roles in the pathogenesis of disease perpetuation and anti-IgE therapy's impact on them. METHODS: Medical history, lung function tests and measurement of fractional exhale nitric oxide concentrations were performed on the same day. Concentrations of IL-1ß and SCD200 in the serum samples were quantified using ELISA kits. Total and specific IgE and hs-CRP levels were enumerated by fluoroenzyme immunoassay. Serum levels of 25(OH)D were quantified by a radioimmunoassay. RESULTS: We had three patients of severe persistent allergic asthma with Samter's syndrome. Levels of total IgE, ECP, fractional exhale nitric oxide concentrations, SCD200, IL-1ß and hs-CRP were decreased while 25(OH)D was increased after starting the treatment of anti-IgE. CONCLUSIONS: To our knowledge, this is the first time an association between omalizumab use and Samter's syndrome has been documented. As a conclusion allergic nasal symptoms (sneezing, postnasal drip) and asthma symptoms were decreased in patients, but no change was seen on nasal polyposis development after omalizumab treatment.

The effect of trans-resveratrol on platelet-neutrophil complex formation and neutrophil burst in hypercholesterolemic rats.

Transresveratrol (t-resveratrol; 3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic compound found in fresh grapes, grape juice and wine, and has been found to reduce the total cholesterol level in hypercholesterolemic rats. The objective of the present study was to assess the effects of t-resveratrol on platelet-neutrophil complex formation and neutrophil reactive oxygen species (ROS) status in control and hypercholesterolemic rats using a modified flow cytometric method. Rats (n=80) were divided into five groups (control, ethanol, resveratrol, hypercholesterolemic and resveratrol-administered hypercholesterolemic groups), comprising 16 animals per group. Serum levels of lipids and H2O2 were determined using commercially available kits, while platelet-neutrophil complex formation and neutrophil ROS status were determined using a modified flow cytometric method. Serum total cholesterol and low-density lipoprotein cholesterol levels were found to be increased and the high-density lipoprotein cholesterol level was found to be decreased in the HC group compared with the control group (P<0.001). Treatment of HC rats with t-resveratrol significantly lowered total cholesterol and low-density lipoprotein cholesterol levels (P<0.001). In the hypercholesterolemic group, levels of serum H2O2 platelet-neutrophil complex formation and neutrophil ROS status were significantly increased (P<0.001). On the other hand, in the resveratrol-administered hypercholesterolemic group, serum H2O2 levels, platelet-neutrophil complex formation and neutrophil ROS status were decreased compared with the hypercholesterolemic group (P<0.001). Serum H2O2 levels, platelet-neutrophil complex and neutrophil ROS status were positively correlated with one another. The present study is the first to demonstrate the protective effect of t-resveratrol against hypercholesterolemia-induced platelet-neutrophil complex formation and neutrophil ROS burst. Further investigations on its plausible role in antihypercholesterolemic treatment are warranted.

Total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations in patients with severe persistent allergic asthma: its relation to omalizumab treatment.

BACKGROUND: Asthma is a chronic inflammatory disease and omalizumab is indicated for moderate-to-severe persistent asthma. The results of many studies have shown that oxidative stress is involved in asthma pathogenesis. However, there is no data available to evaluate the alterations in total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations. OBJECTIVES: The objective was to determine whether treatment with omalizumab in severe allergic asthma influences systemic levels of oxidative stress markers. METHODS: The first group of 14 patients included 6 male and 8 female subjects with severe persistent asthma, having a mean age of 42.4 years. The second group included 14 newly diagnosed allergic asthma patients with a mean age of 43.8 years. All patients were followed in the Immunology and Allergy Clinic of the Antalya Education and Training Hospital and were evaluated by clinical status. A third group of 14 age-sex matched healthy controls were also included. Serum samples were collected and stored at -70 degrees C until use for the determination of total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations. Serum IgE levels, ANA (antinuclear antibody), RF (rheumatoid factor), hepatitis markers, C3, C4, and eosinophil levels were evaluated in all patients. All assays were carried out in duplicate. RESULTS: The mean IgE levels were as follow: Group I: 459.785 IU/mL; Group II: 124.8 IU/mL, and Group III: 39.88 IU/mL. Total antioxidant capacity levels of Group IB, group II, and group III were lower than the IA group. Total antioxidant capacity levels of groups II and III were higher than in group IB. Hydrogen peroxide concentrations in group IB were lower than in group IA, while concentrations in group II were higher than in group IB. The malondialdehyde concentration of group IB was lower than in all other groups. The malondialdehyde concentration of group III was higher than all other groups. The malondialdehyde concentration of group II was lower than in group III. The total nitric oxide level of group IB was lower than all other groups. The total nitric oxide level of group III was higher than all other groups, while that of group II was higher than for both groups IA/IB. CONCLUSIONS: To monitor the omalizumab treatment efficacy in severe allergic asthma patients, total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations might be new markers.

Soluble trail as a marker of efficacy of allergen-specific immunotherapy in patients with allergic rhinoconjunctivitis.

BACKGROUND: Allergic rhinitis is a common health problem affecting the immune system. The homeostasis of the immune system is regulated by apoptosis. In this study, serum circulating soluble TRAIL levels of allergic rhinoconjunctivitis patients before and after allergen-specific immunotherapy were evaluated. MATERIAL/METHODS: The sTRAIL levels of pre- and post-treated allergic rhinoconjunctivitis patients (n=25) were compared to age- and sex-matched healthy individuals (n=25). sTRAIL levels were measured by ELISA. The skin prick test (SPT) results were recorded before and after treatment. RESULTS: The sTRAIL levels between the pre-treated and control groups were significantly different (p<0.0001). However, there was no significant difference between the post-treated group and healthy individuals (p=0,801). SPT was a statistically significant difference between the values of the research group before and after immunotherapy (grasses mixture, barley mixture, Oleaauropeae, D. Pteronyssinus, D. farinae). CONCLUSIONS: The sTRAIL levels were decreased after allergen-specific immunotherapy to healthy levels and may be of use as a marker of efficacy of immunotherapy in allergic rhinoconjunctivitis patients.

Systemic levels of ceruloplasmin oxidase activity in allergic asthma and allergic rhinitis.

CONTEXT: The role of ceruloplasmin oxidase activity (COA) involving the interaction of oxidant and antioxidant balance in allergic diseases is still unknown. OBJECTIVE: Our study was designed to examine the changes in COAs in severe persistent asthma-allergic rhinitis, new diagnosed allergic asthma-allergic rhinitis and allergic rhinitis patients. METHODS: The study included 20 age- and sex-matched healthy individuals as control (Group I); Group II included 15 newly diagnosed allergic asthma-allergic rhinitis; Group III included 15 patients with severe persistent asthma-allergic rhinitis and in the fourth group there were 20 patients with allergic rhinitis. Group III was divided in two groups, severe persistent asthma-allergic rhinitis who were pre-(III-A) and post-treated (III-B) with omalizumab. Group IV was divided to two groups, pretreatment (IV-A) and posttreatment (IV-B) with specific subcutaneous immunotherapy modalities. All the posttreatment measurements were 12 months after the therapy. All the patients were assessed by the skin prick test, high sensitive C-reactive protein (hs-CRP) and COA. RESULTS: There were significant differences between Group I and Groups III-A, III-B, IV-A and IV-B; Group II and Groups III-A, III-B, IV-A and IV-B; Group III-A and Groups III-B, IV-A and IV-B; Group III-A and Groups IV-A and IV-B; and Group IV-A and IV-B. Interestingly, there was a correlation between the hs-CRP and COA levels in Group III-A. CONCLUSIONS: Our data suggest that hs-CRP and COA levels might be an indicator of an inflammation and important in revelation of patients with allergy related diseases, especially of asthma patients.

DNA methylation or histone modification status in metastasis and angiogenesis-related genes: a new hypothesis on usage of DNMT inhibitors and S-adenosylmethionine for genome stability.

Metastasis is a leading cause of mortality and morbidity in cancer. This process needs angiogenesis. The biology underlying cancer, metastasis, and angiogenesis has been investigated so as to determine the therapeutic targets. Invasive and metastatic cancer cells have undergone numerous genetic and epigenetic changes, manifested by cytoskeletal changes, loss of adhesion, and expression of proteolytic enzymes that degrade the basement membrane. Additionally, in endothelial cells, some epigenetic modifications occur during the formation of angiogenesis. Researchers have used some methylation inhibitors, histone deacetylase inhibitors, or methylating agents (such as S-adenosylmethionine, SAM) against cancer and angiogenesis. Although they are effective to beat these diseases, each one results in differentiation or changes in genome structure. We review epigenetically modified genes related with angiogenesis and metastasis in cancer and endothelial cells, and suggest a new proposal. This hypothesis has discussed the importance of the usage of DNA methylation inhibitors together with SAM to prevent tumor progression and genome instability or changes resulting in additional diseases.

Inhibition of angiogenesis by S-adenosylmethionine.

Metastasis is a leading cause of mortality and morbidity in cancer. One of the steps in metastasis process is the formation of new blood vessels. Aberrant DNA methylation patterns are common in cancer cells. In recent studies, S-adenosylmethionine (SAM), which is a DNA methylating agent, has been found to have inhibitory effects on some carcinoma cells in vivo and in vitro. In the present study, we have used SAM to investigate whether it is effective against angiogenesis in vitro. Our results have shown that SAM can reduce the formation and organization of capillary-like structures of endothelial cells in tumoral environment. Besides, we have found SAM can block endothelial cell proliferation and the migration of cells towards growth factors-rich media. In conclusion, our study suggests that SAM may be used against angiogenesis as a natural bio-product.

KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia.

Hyperthermia is known to serve as a powerful tool in the treatment of prostate cancer which is commonly diagnosed in men. Quercetin and KNK437, Hsp70 inhibitors, play an important role in blocking thermotolerance in some cancer cells. In the present study we investigated the effects of KNK437 and quercetin on the acquisition of thermotolerance and heat-induced apoptosis. Also, it was examined whether the possible mechanism triggering apoptotic pathway included caspase-3 activation in prostate cancer cells. For this purpose, PC-3 and LNCaP cells were treated with hyperthermia following pretreatment with or without KNK437 or quercetin. Thermotolerance was investigated by colony formation assay in these cells, while Hsp70 mRNA levels were measured by real time RT-PCR. Sandwich ELISA was used for detection of Hsp70 protein levels. Apoptosis was detected by flow cytometric annexin V binding assay and by western blot analysis of procaspase-3 and cleaved poly (ADP-ribose) polymerase levels. In our study, KNK437 and quercetin inhibited thermotolerance in a dose-dependent manner in PC-3 cells. KNK437 and quercetin decreased heat-induced accumulation of Hsp70 mRNA and protein in PC-3 and LNCaP cells. KNK437 and quercetin pretreatment enhanced the apoptotic effect of hyperthermia in both cells. We found that KNK437 was more effective than quercetin in inducing apoptotic cell death, activation of caspase-3, and cleavage of PARP in prostate cancer cells. We suggest that KNK437 is a useful agent for enhancing the efficiency of hyperthermic therapy which has less toxic side-effects in prostate cancer.