From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression

Purpose

Uremic toxins produced by gut microbiota (indoxyl sulfate—IS, p-cresyl sulfate—p-CS, and indole-3-acetic acid—IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) expression in HD patients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-κB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HD patients.

Methods

Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HD patients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF-κB expressions were analyzed by RT-qPCR.

Results

HD patients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-κB and low Nrf2 expression. Uremic toxins were positively correlated with NF-κB expression (IS, ρ = 0.58, p < 0.003; p-CS, ρ = 0.71, p < 0.001; IAA, ρ = 0.62, p < 0.001) and negatively with Nrf2 (IS, ρ = ? 0.48, p = 0.01; p-CS, ρ = ? 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-κB expression. In RAW 264.7 culture, NF-κB mRNA expression was stimulated by IS, while Nrf2 was downregulated.

Conclusions

Thus, uremic toxins may stimulate NF-κB mRNA and decrease Nrf2 expression in HD patients and, consequently, trigger inflammation and oxidative stress.

     

Prognostic Impact of CD133 mRNA Expression in 48 Glioblastoma Patients Treated with Concomitant Radiochemotherapy: A Prospective Patient Cohort at a Single Institution

Background

Cancer stem cells are thought to represent the population of tumorigenic cells responsible for tumor development. The CD133 antigen has been described as a putative stem cell marker in malignant brain tumor that could identify such a tumorigenic population in a subset of glioblastoma. To date, the correlation between CD133 expression in primary glioblastoma and patient prognosis is not clearly established. To address this question we investigated the relationship between CD133 mRNA expression and patient outcome in a glioblastoma patient cohort.

Materials and Methods

The quantitative expression of CD133 stem cell antigen mRNA using real-time QRT-PCR was assessed in a cohort of 48 consecutive primary glioblastoma patients treated by chemoradiation with temozolomide.

Results

On multivariate survival analysis, high CD133 mRNA expression was a significant (P = 0.007) prognostic factor for adverse progression-free and overall survival independent of extent of resection (P = 0.012) and MGMT methylation status (P = 0.002). Patient age was also an independent prognosticator of overall survival (P = 0.037). Furthermore, according to the conjoined expression of CD133 mRNA and MGMT status, the patients were categorized into 3 groups with homogenous prognosis.

Conclusions

These findings constitute conclusive evidence that the measurement of the mRNA expression of CD133 stem cell antigen actually impacts the survival of GBM patients.     

Malondialdehyde and CA II autoantibody levels are elevated in children with undescended testes

Purpose

In the pathogenesis of sub-fertility/infertility and testicular cancer related to undescended testes, oxidative stress, inflammation and autoimmunity are important factors. Therefore, the present study was designed to determine serum oxidative stress markers and carbonic anhydrase (CA) II autoantibodies in boys with undescended testes (UDT), and to investigate the relationship between these parameters.

Methods

Serum CA II autoantibody titers, malondialdehyde (MDA), ischemia modified albumin (IMA), protein carbonyl content and soluble CD40 ligand (sCD40L) levels were measured in 59 boys with UDT and 30 healthy subjects.

Results

MDA levels were significantly higher in the UDT group compared with the control group (p = 0.003). There was no significant difference between serum IMA, sCD40L or protein carbonyl levels. CA II autoantibody titers in the UDT group were significantly higher compared with those of the control group (p = 0.048). A weak positive correlation was determined between anti-CA II antibody titers and MDA and IMA levels (p = 0.041, p = 0.005, respectively).

Conclusions

MDA is the most reliable and decisive biochemical marker displaying oxidative damage in undescended testes, and an autoimmune response may be triggered by oxidative stress against CA II during the UDT process.     

An ignored cause of inflammation in patients undergoing continuous ambulatory peritoneal dialysis: periodontal problems

Aim

We aimed to assess whether there is a significant relation between periodontal health status and inflammation in uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and also to reveal the efficiency of periodontal treatment in patients with various degrees of periodontal problems.

Patients and methods

Overall, 68 patients undergoing CAPD were included in the study. Clinical indices and measurements were obtained at baseline and panoramic radiographies were used for the diagnosis. According to the baseline values, patients were stratified into four groups according to the severity of periodontal problems as follows: healthy/gingivitis, slight-to-moderate, and severe periodontitis. A control examination was performed 3 months after the periodontal treatment for only 43 patients. Clinical and laboratory parameters before and after treatment were compared.

Results

The frequency of periodontal disease was found to be high in uremic patients on CAPD. The frequency and severity of periodontitis was also found to be significantly (p < 0.01) higher in patients with high sensitive C-reactive protein levels and longer duration of peritoneal dialysis (p < 0.01). In addition, the periodontitis rate was found to be higher in patients with cardiovascular disease (p < 0.05) and diabetes mellitus (p < 0.01).

Conclusion

A meticulous periodontal examination should be a routine part of management of the uremic patients on CAPD because periodontal disease could be one of the hidden sources of unexplained inflammatory status.     

Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model

Background

Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model.

Methods

32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal^® for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real-time PCR, immunohistochemical staining, and western blot.

Results

Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p < 0.05). CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001).

Conclusion

PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model.

     

Gender differences in oxidative and nitrosative stress parameters in kidney transplant patients on tacrolimus-based immunosuppression

Background

Cardiovascular (CV) morbidity and mortality rates are still higher after kidney transplantation than in general population. It is known that oxidative and nitrosative stress may contribute to the progress of CV disease in a post-transplant period, but still gender aspect has not been elucidated completely. The aim of this study was to analyze the gender differences in the oxidative and nitrosative stress parameters, as well as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels among kidney transplant patients on tacrolimus-based immunosuppression.

Methods

Our research included 35 patients (20 men and 15 women) with renal transplant and 25 healthy volunteers. Patients were on chronic immunosuppressive regimen, which included tacrolimus, mycophenolate mofetil and prednisone. In order to estimate oxidative and nitrosative stress, we determined plasma levels of thiobarbituric acid-reactive substances (TBARS), activity of catalase (CAT), levels of total (protein and non-protein) sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), ADMA and SDMA, as well as nitrite/nitrate (NOx) ratio.

Results

TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p < 0.05, p < 0.01 and p < 0.05, respectively). There were no gender-dependent differences in AOPP, ADMA, SDMA and NOx in kidney transplant patients. Correlation analysis, Pearson and Spearman, showed significant correlations between tested oxidative and nitrosative stress parameters in male kidney transplant patients. Alternatively, in female patients, there were no significant correlations between tested parameters.

Conclusion

Our findings show that men might be more prone to oxidative damage than women. ADMA, the proven marker of CV morbidity and mortality, may be more significant in male kidney transplant patients concerning oxidative stress control of its level and function.     

Peptide Absorption After Massive Proximal Small Bowel Resection: Mechanisms of Ileal Adaptation

Background

Protein absorption occurs as di- and tri-peptides via H⁺/peptide co-transporter-1 (PepT1).

Aim

The aim of this study is to identify mechanisms of ileal adaptation after massive proximal enterectomy.

Hypothesis

Ileal adaptation in uptake of peptides is mediated through upregulation of PepT1 gene expression.

Study Design

Rats underwent 70% jejunoileal resection. Total mucosal cellular levels of messenger RNA (mRNA) and protein and transporter-mediated uptake per centimeter of the di-peptide glycyl-sarcosine (Gly-Sar) were compared in remnant ileum 1 and 4 weeks postoperatively to control and to 1-week sham laparotomy rats. Histomorphology, food consumption, and weights of rats were monitored.

Results

After 70% resection, although mRNA per cell for PepT1 decreased at 1 week (p?=?0.002), expression of mRNA at 4 weeks and protein at 1 and 4 weeks in remnant ileum were unchanged (p?>?0.1). Ileal Gly-Sar uptake (V _max??nanomoles per centimeter per minute, i.e., number of transporters per centimeter) increased at 1 and 4 weeks compared to control and 1-week sham (p?<?0.05 each); K _m (i.e., transporter function) was unchanged. Villous heights (millimeters) in remnant ileum increased at 1- and 4-week time points over controls (0.45 and 0.57 vs 0.21, resp; p?<?0.001).

Conclusions

Ileal adaptation to proximal resection for peptide absorption occurs through cellular proliferation (hyperplasia) and not through cellular upregulation of PepT1 mRNA or protein per enterocyte.     

Gastric Bypass and Sleeve Gastrectomy: the Same Impact on IL-6 and TNF-α. Prospective Clinical Trial

Background

Due to the association between the quantity of adipose tissue and concentrations of interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), this work aimed to assess the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) procedures on serum IL-6 and TNF-α concentrations.

Methods

This study evaluated serum IL-6 and TNF-α levels, as well as routine anthropometric and biochemical values, before and 1 year post-bariatric surgery. Fifty percent of patients (n?=?24) underwent RYGB, and 50 % (n?=?24) underwent SG. Prior to bariatric surgery, IL-6 and TNF-α mRNA expression levels in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were investigated in obese women.

Results

There was a significant reduction (p?<?0.05) in all anthropometric and routine biochemical measurements in patients in the RYGB and SG groups 1 year post-surgery. The serum concentrations of IL-6 and TNF-α were reduced following surgery in both groups (p?<?0.05). No differences in the relative expression levels of IL-6 and TNF-α were found between SAT and VAT prior to bariatric surgery.

Conclusions

RYGB and SG procedures demonstrated a similar impact on adipokine levels in women 1 year post-surgery. Both techniques may improve the course of chronic diseases and the state of inflammation associated with obesity.     

Oxidative stress markers in laparoscopic versus open colectomy for cancer: a double-blind randomized study

Background

Colorectal cancer as well as colorectal surgery is associated with increased oxidative stress through different mechanisms. In this study the levels of different oxidative stress markers were comparatively assessed in patients who underwent laparoscopic or conventional resection for colorectal cancer.

Methods

Sixty patients with colorectal cancer were randomly assigned to undergo laparoscopic (LS) or open surgery (OS). Lipid, protein, RNA, and nitrogen damage was investigated by measuring serum 8-isoprostanes (8-epiPGF_2α), protein carbonyls (PC), 8-hydroxyguanosine (8-OHG), and 3-nitrotyrosine (3-NT), respectively. The primary end point of the study was to analyze and compare serum levels of the oxidative stress markers between the groups.

Results

Postoperative serum levels of 8-epiPGF_2α, 3-NT, and 8-OHG were significantly lower in the LS group at 24 h after surgery (p < 0.05). At 6 h postoperatively, the levels of 8-epiPGF_2α and 3-NT were significantly lower in the LS group (p < 0.05). No difference in the levels of PC was found between the two groups at any time point. In the OS group, postoperative levels of 8-epiPGF_2α were significantly lower than the preoperative values (p < 0.01). In the LS group, the postoperative values of 8-epiPGF_2α, 3-NT, and 8-OHG were significantly lower than the preoperative values (p < 0.05).

Conclusion

Laparoscopic surgery for colorectal cancer is associated with lower oxidative stress compared to open surgery. 8-epiPGF_2α was the most suitable marker for readily defining the oxidative status in patients who underwent surgery for colorectal cancer.     

Propofol attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production through p38 MAPK and SAPK/JNK in alveolar epithelial cells

Purpose

Propofol is widely used in sedation and surgical procedures involving patients with acute lung injury (ALI), a common complication in critically ill patients. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in pathological changes in ALI. The present study investigated the anti-inflammatory effect and mechanism of propofol on MCP-1 production and mitogen-activated protein kinase (MAPK) phosphorylation induced by lipopolysaccharide (LPS) in alveolar epithelial cells (AECs).

Methods

AECs were treated with 1 μg/ml LPS for 30 min, 1 h, 6 h, or 24 h following pretreatment with 12.5–100 μM propofol for 30 min. Cytokines and chemokines secretion were profiled using cytokine array, and mRNA and protein levels of MCP-1 were measured by RT-PCR and ELISA. The phosphorylation of p38 MAPK, p44/42 MAPK, SAPK/JNK, ATF-2, and c-Jun were measured by Western blot analysis.

Results

Propofol at 50 and 100 μM dose-dependently inhibited MCP-1 mRNA expression (P < 0.05), and also propofol at 50 μM decreased extracellular MCP-1 protein levels (P < 0.05) compared to the LPS group. Propofol at 12.5–50 μM inhibited LPS-induced phosphorylation of p38 MAPK, p44/42 MAPK, SAPK/JNK, ATF-2, and c-Jun in AECs.

Conclusions

Propofol at clinically relevant concentrations attenuated LPS-induced MCP-1 mRNA expression and secretion by inhibiting the phosphorylation of p38 MAPK, SAPK/JNK, ATF-2, and c-Jun exerting its anti-inflammatory effects in AECs. These results suggest that propofol may modulate inflammatory response at clinically achievable concentrations in ALI.     

Iron Deficiency After Roux-en-Y Gastric Bypass: Insufficient Iron Absorption from Oral Iron Supplements

Background

Roux-en-Y gastric bypass (RYGB) may reduce the absorption of iron, but the extent to which this absorption is impeded is largely unknown. First, we determined the prevalence of iron deficiency following RYGB and explored the risk factors for its development. Second, we examined to what extent oral iron supplements are absorbed after RYGB.

Methods

Monocentric retrospective study in 164 patients (123 females, 41 males; mean age 43 years) who underwent RYGB between January 2006 and November 2010 was done. Pre- and postoperative data on gender, age, BMI, serum levels of iron, ferritin, hemoglobin, vitamin B₁₂, 25-hydroxy vitamin D, and use of proton pump inhibitors and H₂ antagonists were collected. Generalized linear mixed models were used for the analysis of the data. In 23 patients who developed iron deficiency after surgery, an oral challenge test with 100 mg FeSO₄·7H₂O was performed.

Results

Following RYGB, 52 (42.3 %) female patients and 9 male (22.0 %) patients developed iron deficiency (serum ferritin concentration ≤20 μg/L). The prevalence of iron deficiency was significantly higher in females than males (p?=?0.0170). Young age (p?=?0.0120), poor preoperative iron status (p?=?0.0004), vitamin B₁₂ deficiency (p?=?0.0009), and increasing time after surgery (p?<?0.0001) were also associated with iron deficiency. In the oral iron challenge test, only one patient out of 23 showed sufficient iron absorption.

Conclusions

Iron deficiency is extremely frequent after RYGB and is linked with different risk factors. Iron supplementation seems essential, but the effect of oral tablets may be limited as absorption of oral iron supplements is insufficient post-RYGB.     

Serum gamma-glutamyltransferase levels are inversely related to endothelial function in chronic kidney disease

Backgrounds

Gamma-glutamyltransferase (GGT) is an enzyme responsible for the extracellular catabolism of the antioxidant glutathione and recently implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is a prodromal feature of atherogenesis. Since oxidative stress is highly present in uremia and causally linked to endothelial dysfunction, we hypothesized that GGT may be a factor implicated in this process.

Methods

Serum GGT and C-reactive protein (CRP) levels, estimated glomerular filtration rate (eGFR), and 24-h proteinuria were measured in 214 nondiabetic stages 3–5 CKD patients. The endothelium-dependent vasodilatation (FMD) of the brachial artery was assessed by using high-resolution ultrasound. We investigated the relationship between FMD and circulating serum GGT.

Results

Serum GGT levels were negatively associated with FMD (r = ?0.41, p < 0.001) and eGFR (r = ?0.34, p < 0.001) in univariate analysis. Multivariate regression analysis showed that the association between GGT and FMD persisted after adjustment for age, sex, smoking, renal function (eGFR), inflammation (CRP), proteinuria, and homeostatic model assessment index.

Conclusion

Circulating GGT levels significantly associate with endothelial dysfunction, an important early feature of the atherogenic process. GGT might be an early marker of oxidative or other cellular stress that it is possibly directly related to the pathogenesis of endothelial dysfunction.     

Resistin expression correlates with steatohepatitis in morbidly obese patients

Background

Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients.

Methods

Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student’s t test.

Results

Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (>4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p < 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051).

Conclusions

In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis.     

Expression parameters of the metabolic pathway genes pyruvate dehydrogenase kinase-1 (PDK-1) and DJ-1/PARK7 in renal cell carcinoma (RCC)

Purpose

Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance.

Methods

RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal–Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models.

Results

PDK-1 mRNA expression was up-regulated as compared to normal tissue (p < 0.001). Differences were observed by tumor stage (p < 0.05) with a trend toward lower expression with increasing stage (p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31–0.94). No associations observed for DJ-1/PARK7 expression.

Conclusions

PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up-regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype.     

The effects of iron on FGF23-mediated Ca–P metabolism in CKD patients

Background

Fibroblast growth factor 23 (FGF23) is an important counterregulatory hormone for phosphate homeostasis. Since it has been reported that iron administration induces hypophosphatemic osteomalacia by triggering FGF23 synthesis, we hypothesized that iron administration might lead to a further increase in FGF23, resulting in alterations to Ca–P metabolism in a stage 5 CKD population.

Methods

This cross-sectional study was performed in a single center, and involved 73 hemodialysis patients (47.7 ± 15.74 years old, 68.5 % men), 29 peritoneal dialysis patients (44.55 ± 15.05 years old, 62.1 % men), and 55 healthy (43.57 ± 14.36 years old, 55.6 % men) subjects. The dialysis group was subcategorized according to iron therapy administration into users and nonusers.

Results

The median iFGF23 level was significantly higher in the dialysis population than in the healthy controls [88.050 (25.2–1038.3) pg/ml versus 46.95 (2.4–356) pg/ml (p < 0.001)]. In the dialysis population, a significantly lower median iFGF23 level was observed in iron therapy users than in nonusers [87.6 (25.2–1038.3) versus 119 (51.6–1031); respectively, p = 0.045]. A significant negative association between iron administration and iFGF23 level was revealed by both univariate (r = ?0.237, p = 0.016) and multivariate (β = ?0.221, p = 0.032) analysis. No association was found between iFGF23 and serum ferritin and iron levels. Also, there was no association between iron therapy and serum phosphate level.

Conclusion

In contrast to what is seen for the general population, this study showed that there was a negative relationship between iron administration and serum iFGF23 level in a dialysis population. We can therefore conclude that if high levels of FGF23 are harmful, iron therapy may have a beneficial effect on bone metabolism by reducing FGF23 levels in a dialysis population.     

Changes in Myostatin Signaling in Non-Weight-Losing Cancer Patients

Background

Myostatin is a negative regulator of skeletal muscle mass. We recently demonstrated that myostatin expression is upregulated in an experimental model of cancer cachexia, suggesting that modulations of this pathway might play a pathogenic role in cancer-related muscle wasting. The present study was designed to investigate whether myostatin signaling is modulated in the muscle of non-weight-losing (nWL) patients with lung and gastric cancer.

Methods

Myostatin signaling was studied in muscle biopsies obtained during surgical procedure from nWL patients affected by gastric (n = 16) or lung (n = 17) cancer. Western blotting was applied to test both the total expression of myostatin and the expression of phosphorylated form of GSK-3beta and Smad2/3.

Results

In patients with gastric cancer, the expression of both myostatin and phosphorylated GSK-3beta (p-GSK3β) were significantly increased. By contrast, in patients with lung cancer, myostatin levels were comparable to controls, whereas the expression of p-GSK3β significantly decreased in patients with disease stage III/IV.

Conclusions

Myostatin signaling is altered in nWL cancer patients. Different tumor types may give rise to different patterns of molecular changes within the muscle, which occur even before cachexia becomes clinically apparent.