Adenocarcinoma Contains More Immune Tolerance Regulatory T-cell Lymphocytes (Versus Squamous Carcinoma) in Non-small-Cell Lung Cancer

Background

Regulatory T lymphocytes (Tregs) are known to have host-immune dampening effects in many tumors and to be associated with increased tumor recurrence. Pharmacologic therapies have been developed to target these cells and hence strengthen the host’s immune system. The FoxP3 gene is a marker of Tregs and can be visualized with immunohistochemistry (IHC). We investigated the presence and pattern of Tregs in non-small-cell lung tumors to determine possible therapeutic targets in lung cancer.

Methods

We selected archival samples of primary lung carcinoma and benign inflamed lung from 32 surgical resections. We created a tissue array containing duplicate cores from the N1 and N2 nodal stations from 16 of the cases along with paired benign lung and tumor. We used whole-slide analysis for the other 16 cases. We used FoxP3 IHC to visualize Tregs in all lymphoid tissue present and to assess the quantity and pattern within the tissues.

Results

All lymphoid tissue contains Tregs, but adenocarcinoma had significantly higher levels than both inflammatory lung controls and squamous carcinomas (p ≤ 0.008). Benign N1 lymph nodes (from patients with lung cancer) showed higher numbers of Tregs for adenocarcinoma versus squamous carcinoma.

Conclusions

These findings reveal that Tregs are present in all lung tissues examined, but with significant enrichment in adenocarcinoma. This may lead to a more permissive microenvironment for adenocarcinoma and may explain aggressive patterns of tumor spread for this histology. Lung cancer patients with adenocarcinoma histology may benefit most from Treg-targeted therapy.     

Lentivirus-delivered ZEB-1 small interfering RNA inhibits lung adenocarcinoma cell growth in vitro and in vivo

Purpose

To explore the relationship between the expression of ZEB1 gene and the proliferation ability of lung adenocarcinoma cells.

Methods

Immunohistochemistry, Western blot and Real-time PCR were used to detect the expression of ZEB1 gene in lung adenocarcinoma tissue and cell lines compared with adjacent noncancerous region and the human lung fibroblast cell HLF cells. The lentivirus RNA interference technique was used to knock down the expression of ZEB1 in lung adenocarcinoma A549 and H1299 cell lines. Cell cycle and cell apoptosis were measured by FCM assay. In vivo, four groups of 4-week-old nude mice were subcutaneously injected with the stably transfected (ZEB-si, scr-si) cells at a single site to investigate the effect of ZEB1-siRNA in the nude mice tumor growth. In situ apoptosis was detection by TUNEL assay.

Results

ZEB-1 was highly expressed in lung adenocarcinoma tissue and cell lines compared with adjacent noncancerous region and the human lung fibroblast cell HLF cells. ZEB1-siRNA could decrease lung adenocarcinoma cell proliferation by delaying S-phase entry and induce cell apoptosis, which led to the inhibition of the tumorigenicity of A549 and H1299 cell lines. Further investigation showed that injecting the ZEB1-siRNA cells into the nude mice could significantly decrease the tumor growth.

Conclusion

Knockdown of ZEB-1 expression by lentivirus-delivered siRNA may provide a novel therapeutic target for the treatment of lung cancer.     

The potential role of extracellular regulatory kinase in the survival of patients with early stage adenocarcinoma

Background

Lung cancer is among the most common types of neoplasias, and adenocarcinoma is the most frequent histological type. There is currently an extensive search for prognostic biomarkers of nonsmall cell lung cancer (NSCLC).

Methods

We analyzed the correlation of clinical data and patient survival with the levels of activated extracellular regulatory kinase (ERK) in histological samples of surgically resected early stage lung adenocarcinoma. We randomly selected 36 patients with stage I or II lung adenocarcinoma who underwent pulmonary lobectomy between 1998 and 2004. Patients were divided into the following two groups according to immunohistochemical profile: a group with <15% ERK-positive tumor cells and a group with ≥15% ERK-positive tumor cells. For data comparison, an enrichment analysis of a microarray database was performed ({"type":"entrez-geo","attrs":{"text":"GSE29016","term_id":"29016"}}GSE29016, n=72).

Results

Activated ERK levels were ≥15% and <15% in 21 (58%) and 15 (42%) patients, respectively. There were no statistically significant differences in age, sex, smoking history, and body mass index (BMI) among the groups stratified by ERK levels. The survival rate was lower in the ERK ≥15% group than in the ERK <15% group (P=0.045). Enrichment analyses showed no correlation between variations in gene expression of ERK in patients with adenocarcinoma and survival rates in patients with stage I and combined stage II + III disease.

Conclusions

Our findings suggest that high ERK positivity in cells from biological samples of lung adenocarcinoma is related with tumor aggressiveness and a poorer prognosis.     

Oxidative DNA damage and β-catenin expression in colorectal cancer evolution

Purpose

Oxidative DNA damage is one of the mechanisms associated to initial colorectal carcinogenesis, but how it interacts with β-catenin, an adherence protein related to cancer evolution, is not clear. This study investigates the relationship between oxidative DNA damage and β-catenin expression in normal mucosa and colon tumor tissue (adenoma and adenocarcinoma) in colorectal adenocarcinoma evolution.

Method

One hundred and 13 samples were studied. Hematoxylin–eosin determined histological grade. β-Catenin expression was analyzed by immunohistochemistry. The oxidative DNA damage was evaluated using comet assay technique. The coefficient for rejection of the nullity hypothesis was taken to 5 %. Kruskal–Wallis, Spearman test, and partial correlation were used to analyze the data.

Results

There was oxidative DNA damage increase in colorectal cancer evolution (p?<?0.01). Histological grade was correlated with oxidative DNA damage (p?<?0.01). There were differences in β-catenin expression among normal, adenoma, and adenocarcinoma tissue with progressive increase of β-catenin expression (p?<?0.00). Histological grade was correlated to β-catenin expression (p?<?0.00). There was a relationship (p?<?0.00) between β-catenin and histological grade while controlling for the effect of oxidative DNA damage.

Conclusion

The findings of this study make it possible to establish a relationship between oxidative DNA damage and β-catenin expression in normal mucosa and colorectal tumor tissue. Additionally, they show a causal relationship between variations of β-catenin in different tissues analyzed while controlling for the effect of oxidative DNA damage.     

Antioxidant status and GST gene polymorphisms in antitubercular treatment-induced hepatotoxicity patients

Introduction

Hepatotoxicity is a serious adverse effect of antituberculosis treatment (ATT). Glutathione S-transferase (GST) is involved in the detoxification of toxic metabolites produced as a result of ATT, increased oxidative stress and decreased antioxidant levels, and differences in the GST polymorphism may be one of the causes of ATT-induced hepatotoxicity.

Aim

This study was undertaken to study the relationship among antioxidant status, oxidative stress and GST gene polymorphisms in the development of ATT-induced hepatotoxicity in Indian patients.

Methodology

Two hundred fifty TB patients attending clinics in the Gastroenterology and Thoracic Department, PGIMER, Chandigarh, were enrolled. Liver marker enzymes, markers of oxidative stress, levels of antioxidants and identification of GSTT1, GSTM1 and GSTP polymorphisms were performed using standard protocols.

Results

Of the 250 patients, 160 were males. Of the 160 males, 18 (11.3 %) had ATT-induced hepatotoxicity and 142 no hepatotoxicity, while of 90 females, 12 (13.3 %) had hepatotoxicity and 78 no hepatotoxicity. Patients who developed ATT-induced hepatotoxicity had significantly higher oxidative stress compared to those who did not develop hepatotoxicity at between 1 and 2 months of treatment. Among antioxidants, catalase did not show any significant difference at 2 and 4 months of treatment. The presence of GSTM1 was higher in hepatotoxicity patients as compared to non-hepatotoxicity patients, while GSTT1 and GST1/M1 were lower.

Conclusion

Therefore, in this study, the possible association of oxidative stress with ATT-induced hepatotoxicity was observed. A role of the GST polymorphism in ATT-induced hepatotoxicity was also found and thus could possibly identify the groups at highest risk of developing ATT-induced hepatotoxicity.     

Metachronous carcinomas in colorectum and its clinicopathological significance

Purpose

The study was designed to examine the significance of colorectal metachronous carcinoma in a large cohort of patients.

Methods

Over a mean follow-up period of 10?years, the clinicopathological features, microsatellite instability (MSI) and clinical follow-up of 56 patients with metachronous colorectal carcinoma were analysed.

Results

The prevalence of metachronous colorectal carcinoma was 2.1?%. The metachronous colorectal carcinomas appeared between 7 and 246?months (mean?=?66?months) after surgical resection of the index colorectal carcinomas. Thirty-six per cent (n?=?20) of the metachronous carcinoma occurred more than 5?years after the operation of the index carcinoma. Of the 56 patients, 20?% (n?=?11) of the metachronous colorectal carcinomas were mucinous adenocarcinoma. Cancers detected in the secondary operations (metachronous colorectal carcinomas), when compared with the primary index cancers, were smaller, showed higher proportions of mucinous adenocarcinoma and more often located in the proximal colon. Patients with metachronous colorectal cancers had higher prevalence of mucinous adenocarcinoma, loss of staining for MSI markers and better survival rates than other patients with colorectal cancers.

Conclusions

Patients with metachronous colorectal carcinomas have characteristic features, and attention to these features is important for better management of this group of cancer.     

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

Aims/Hypothesis

To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1?? [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance.

Methods

Rats were fed either a low-fat or high-fat diet (HFD) for 4?weeks. In vivo electroporation was used to overexpress Pgc-1?? in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1?? on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic?Ceuglycaemic clamp.

Results

Pgc-1?? gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1??. In rats fed a HFD, increasing the levels of Pgc-1?? partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences.

Conclusions

Our data show that an increase in Pgc-1?? expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.     

Solid predominant histology predicts EGFR tyrosine kinase inhibitor response in patients with EGFR mutation-positive lung adenocarcinoma

Background

The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) differs in patients with lung adenocarcinoma harboring EGFR-activating mutations. Although lung adenocarcinoma with EGFR-activating mutations has heterogeneous morphologic features, the predictive role of histologic subtype of lung adenocarcinoma with regard to the effectiveness of EGFR-TKIs in patients with EGFR-activating mutations has not been well defined.

Methods

Among 134 postoperative recurrence patients with lung adenocarcinoma harboring EGFR-activating mutation (L858R or exon 19 deletion) treated with EGFR-TKIs, we retrospectively analyzed 61 patients treated with EGFR-TKIs as first-line chemotherapy. All the tumors were classified according to the new histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) into the following subtypes: lepidic, papillary, acinar, micropapillary, or solid predominant subtype. We evaluated the correlation between the histologic subtype and the clinical efficacy of EGFR-TKIs.

Results

In overall response rate, adenocarcinoma with solid predominant subtype is significantly worse than with non-solid predominant subtype (61 vs. 88 %, P = 0.03). The median progression-free survival (PFS) and overall survival after EGFR-TKI treatment were significantly shorter for the patients with solid predominant subtype than for those with non-solid predominant subtype (median PFS of 7.7 vs. 13.5 months, P = 0.002, and median OS of 21.5 vs. 31.0 months, P = 0.028).

Conclusions

This study indicated that among patients with lung adenocarcinoma harboring activating EGFR mutations treated with EGFR-TKIs, solid predominant subtype according to IASLC/ATS/ERS classification is a response predictor for EGFR-TKI.     

Reduced Oxidative Stress in STEMI Patients Treated by Primary Percutaneous Coronary Intervention and with Antioxidant Therapy: A Systematic Review

Purpose

Coronary reperfusion by primary percutaneous coronary intervention (PCI) has been established as an essential therapy of ST-elevation myocardial infarction (STEMI). Although the coronary intervention is undoubtedly beneficial, reperfusion itself can induce processes resulting in additional myocardial damage—a phenomenon known as ischemia-reperfusion injury (IRI). Oxidative stress is one of the major factors contributing to IRI. This systematic review focuses on the effect of antioxidant therapy on reperfusion triggered oxidative stress and myocardial IRI in patients with STEMI.

Methods

We performed a systematic search in EMBASE and Pubmed and included eight randomised clinical trials evaluating edaravone, allopurinol, vitamin c, nicorandil, N-acetylcysteine, glucose-insulin-potassium, atorvastatin and deferoxamine.

Results

Administration of edaravone, allopurinol, atorvastatin and nicorandil as a supplement to primary PCI significantly reduced oxidative stress and myocardial damage as well as improved cardiac function and clinical outcomes. Treatment with deferoxamine and N-acetylcysteine reduced the oxidative stress but an effect on the clinical outcome parameters could not be shown.

Conclusions

Preliminary studies of edaravone, allopurinol, atorvastatin and nicorandil seems promising though larger clinical trials with a wider range of clinical outcome parameters and trials of higher methodological quality should confirm the clinical benefits before a general recommendation can be given. Moreover, the included studies revealed a complex link between oxidative stress and cardiac function and/or cardiac adverse events and in order to further elucidate the detrimental role of oxidative stress in IRI in relation to primary PCI the assessment of oxidative stress and the clinical outcome parameters should be standardized.     

Salivary markers of oxidative stress in patients with obstructive sleep apnea treated with continuous positive airway pressure

Purpose

Obstructive sleep apnea syndrome (OSAS) is characterized by elevated oxidative stress. Measurement of oxidative stress in saliva seems to be promising in long-term treatment monitoring of OSAS patients. In this study, our aim was to investigate whether short-term continuous positive airway pressure (CPAP) treatment would influence oxidative stress in saliva.

Methods

Patients with diagnosed OSAS (16 women, 28 men) underwent polysomnography during the first night and CPAP treatment during the second night. Saliva samples were taken in the evening and morning on both days. Markers of oxidative stress and antioxidant status were analyzed in saliva.

Results

Evening concentrations of the salivary thiobarbituric acid reacting substances (p?p?p?Conclusion Salivary markers of oxidative stress and antioxidant status do not change significantly after one night treatment with CPAP. On the contrary, after 1 month with CPAP therapy, reduced markers of oxidative stress were reported. Therefore, the future studies should be focused on finding the optimal sampling frequency to clarify the potential of saliva for the monitoring of OSAS treatment.     

Interventionelle bronchologische Therapie

Background

Chronic obstructive pulmonary disease (COPD) is an incurable progressive disease which is characterized by an irreversible occlusion of the small airways. Especially when pharmaceutical treatment attempts do not bring the desired success in patients with severe COPD, a new therapeutic concept for causal treatment of pulmonary emphysema is now available: endoscopic lung volume reduction. A differentiation is made between reversible occlusive treatment with endobronchial valves and irreversible nonocclusive procedures, such as thermoablation, bronchial glue, stents and spirals.

Methods

A systematic comparison of the most important procedures for lung volume reduction with respect to clinical outcome and complication profile was carried out based on a literature search and clinical experience.

Results

A complete occlusion in heterogeneously distributed lung emphysema and complete fissures are the most important predictive markers for successful valve therapy. The most important complication is the high rate of pneumothorax. The similarly effective irreversible procedure can be a possible therapy option for patients with collateral connections between the lung lobes but the current evidence from studies is insufficient for final conclusions to be drawn.

Conclusion

In summary interventional bronchological measures represent a new therapy option for COPD patients with severe emphysema and advanced disease stage. However, none of the procedures are currently suitable for broad application in the clinical routine.     

Lower albumin levels in African Americans at colon cancer diagnosis: a potential explanation for outcome disparities between groups?

Background and aim

Colorectal cancer is the third most common cancer and 3rd leading cause of cancer-related death in the USA. African Americans (AA) have inferior outcomes when matched for diagnosis stage and socioeconomic situation. Nutritional status, at diagnosis and its contribution to the observed cancer outcome disparity, between AA and non-Hispanic whites (nHw) has not been evaluated to date. The aim of the investigation was to determine if differences in nutritional surrogate markers, such as serum albumin and body mass index (BMI), exist at the time of colorectal cancer diagnosis between AA and nHw.

Methods

The University of Florida College of Medicine-Jacksonville endoscopy database was reviewed for all patients with a biopsied colorectal mass between January 2000 and December 2007. Patients were excluded if histology did not reveal colorectal adenocarcinoma or albumin/BMI was unavailable. Demographic data, tumor location, serum albumin within 60?days of diagnosis, presence of diabetes along with serum HbA1c were obtained.

Results

During the study period, 321 patients had colorectal masses discovered and 156 met entry criteria. There was no difference between ethnic groups regarding gender distribution, tumor location, diabetes presence, or BMI. Mean albumin was significantly less in AA compared to nHw (p?Conclusions Lower albumin levels in AA indicate poorer nutritional status at colorectal cancer diagnosis compared to nHw. This may contribute to the outcome disparities observed between AA and nHw. Aggressive nutritional interventions to reverse this disparity should be evaluated.     

L-citrulline Prevents Alveolar and Vascular Derangement in a Rat Model of Moderate Hyperoxia-induced Lung Injury

Background

Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of l-arginine to l-citrulline in endothelial cells. We investigated whether administering l-citrulline by raising the serum levels of l-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury.

Methods

Newborn rats were exposed to FiO₂?=?0.6 or room air for 14?days to induce lung derangement and then were administered l-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed.

Results

Serum l-arginine rose in the L-citr?+?hyperoxia group (p?=?0.05), as well as the Von Willebrand factor stained vessels count (p?=?0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the l-citr?+?hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with l-citrulline under exposure to hyperoxia (p?=?0.0001). Lung VEGF and eNOS increased in the l-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p?=?0.003).

Conclusions

We conclude that administering l-citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.     

Individual risk assessment in bladder cancer patients based on a multi-marker panel

Purpose

To investigate whether a combined application of urine cytology (CYT) and molecular markers for bladder cancer (BC) can predict tumor aggressiveness.

Methods

The study comprised 2,113 patients who underwent urethrocystoscopy and transurethral resection of the bladder. CYT, fluorescence in situ hybridization (FISH), immunocytology (uCyt+) and nuclear matrix protein 22 test (NMP22-ELISA) were performed. Results of the individual tests and of a multi-marker panel were correlated with pT-stages and tumor grades.

Results

Five hundred and two of 2,113 (23.8 %) patients had BC. False-negative test rates of CYT (p < 0.001), FISH (p = 0.01) and NMP22-ELISA (p = 0.05) were lower in patients with muscle-invasive BC compared with patients with non-muscle-invasive BC. Furthermore, false-negative rates of CYT (p < 0.001), FISH (p = 0.0002) and NMP22-ELISA (p < 0.001) were lower in patients with G3/CIS compared with patients with G1–G2 BC. In patients with evidence of tumor in urethrocystoscopy, the presence of simultaneously positive CYT and NMP22 was associated with a 20-fold risk for G3/CIS (p < 0.0001).

Conclusions

This is the first study investigating the combined use of four urine markers in addition to cystoscopy to predict tumor aggressiveness. Our results indicate that combined application of urine markers as an adjunct to cystoscopy may facilitate identification of patients harboring high-grade tumors.     

Incidence and Predictors of Adenocarcinoma Following Endoscopic Ablation of Barrett’s Esophagus

Background

The rate and risk factors of recurrent or metachronous adenocarcinoma following endoscopic ablation therapy in patients with Barrett’s esophagus (BE) have not been specifically reported.

Aim

The aim of this study was to determine the incidence and predictors of adenocarcinoma after ablation therapy for BE high-grade dysplasia (HGD) or intramucosal carcinoma (IMC).

Methods

This is a single center, retrospective review of prospectively collected data on consecutive cases of endoscopic ablation for BE. A total of 223 patients with BE (HGD or IMC) were treated by ablation between 1996 and 2011. Primary outcome measures were recurrence and new development of adenocarcinoma after ablation. Recurrence was defined as the presence of adenocarcinoma following the absence of adenocarcinoma in biopsy samples from two consecutive surveillance endoscopies. Logistic regression analysis was performed to assess predictors of adenocarcinoma after ablation.

Results

One hundred and eighty-three patients were included in the final analysis, and 40 patients were excluded: 22 for palliative ablation, eight lost to follow-up, five for residual carcinoma and five for postoperative state. Median follow-up was 39 months. Recurrence or new development of adenocarcinoma was found in 20 patients (11 %) and the median time to recurrence/development of adenocarcinoma was 11.5 months. Independent predictors of recurrent or metachronous adenocarcinoma were hiatal hernia size ≥ 4 cm (odds ratio 3.649, P = 0.0233) and histology (HGD/adenocarcinoma) after first ablation (odds ratio 4.141, P = 0.0065).

Conclusions

Adenocarcinoma after endoscopic therapy for HGD or IMC in BE is associated with large hiatal hernia and histology status after initial ablation therapy.     

Fat Mass and Obesity-Associated Gene Enhances Oxidative Stress and Lipogenesis in Nonalcoholic Fatty Liver Disease

Background and Aim

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus. Several studies have found that fat mass and the obesity-associated (FTO) gene is linked to obesity. The aim of this work is to investigate the expression and function of FTO in liver with lipid metabolism diseases.

Methods

We investigated the basal FTO expression in an NAFLD rat model and compared it with control subjects. The function of FTO in lipid metabolism was further studied in L02 cells through overexpression experiments.

Results

A significant increase in FTO mRNA and protein levels was found in the NAFLD group. In addition, the FTO levels were positively associated with malondialdehyde and superoxide dismutase concentrations. FTO overexpression in L02 cells enhanced lipogenesis and oxidative stress.

Conclusions

This study demonstrates that increased FTO levels in the liver are involved in oxidative stress and lipid deposition, which characterize NAFLD.     

Oxidative stress is closely associated with insulin resistance in genotypes 1 and 3 chronic hepatitis C

Background

Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined.

Purpose

To evaluate the association between insulin resistance and oxidative stress in CHC patients.

Method

In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined.

Results

There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p < 0.001) and GSH levels were lower (p = 0.023) in insulin-resistant subjects compared to their insulin-sensitive counterparts.

Conclusions

It is concluded that in CHC, oxidative stress is an independent predictor of HOMA-IR, irrespective of virus genotype. Further studies on the role of oxidative stress in the development of insulin resistance in CHC are warranted.     

Influence of CPAP treatment on airway and systemic inflammation in OSAS patients

Aim

Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent respiratory disorders in the upper airways during sleep. Although continuous positive airway pressure (CPAP) has been accepted to be the most effective treatment for OSAS, its role on inflammation remains debatable. In this study, our aim was to examine the influence of 3 months of CPAP treatment on tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), 8-isoprostane, and peroxynitrite levels in exhaled breathing condensates (EBC) and serum.

Methods

Thirty-five patients who were newly diagnosed as moderate or severe OSAS with full night polysomnography and used CPAP therapy regularly for 3 months were included in the study. Polysomnography, spirometric tests, fasting blood samples, and EBC were ascertained on entry into the study and after 3 months of treatment. All patients were assessed monthly for treatment adherence and side effects.

Results

We found that all polysomnographic parameters were normalized after CPAP therapy in the control polysomnogram. Also, all markers in EBC and nitrotyrosine and 8-isoprostane levels in serum were decreased significantly with CPAP treatment. Sedimentation rate, C-reactive protein, IL-6, and TNF-α remained unchanged in serum after treatment. We found that baseline nitrotyrosine levels were significantly correlated with apnea–hypopnea index, oxygen desaturation index, and percent time in SpO₂?<?90 % (p?<?0.01).

Conclusions

CPAP therapy has primarily a relevant impact on airways, and nitrotyrosine levels correlated well with severity of OSAS. This treatment decreases both inflammation and oxidative stress levels in airways in OSAS patients. Also, this treatment helps to decrease systemic oxidative stress levels in serum.     

Protective Effect of Grape Seed and Skin Extract Against High-Fat Diet-Induced Liver Steatosis and Zinc Depletion in Rat

Background

Obesity is a tremendous public health problem, characterized by ectopic deposition of fat into non-adipose tissues as liver generating an oxidative stress that could lead to steato-hepatitis. Grape seed and skin extract (GSSE) is a complex mixture of polyphenolics exhibiting robust antioxidative properties.

Aim

We hypothesize that GSSE could protect the liver from fat-induced lipotoxicity and have a beneficial effect on liver function.

Methods

Hepatoprotective effect of GSSE was measured by using an experimental model of fat-induced rat liver steatosis. Male rats were fed a standard diet or a high-fat diet (HFD) during 6 weeks and treated or not with 500 mg/kg bw GSSE. Lipid deposition into the liver was assessed by triglyceride, cholesterol and phospholipid measurements. Fat-induced lipoperoxidation, carbonylation, depletion of glutathione and of antioxidant enzyme activities were used as oxidative stress markers with a special emphasis on transition metal distribution.

Results

HFD induced liver hypertrophy and inflammation as assessed by high liver transaminases. HFD also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in glutathione and antioxidant enzyme activities as glutathione peroxidase and superoxide dismutase and a drastic depletion in liver zinc. Importantly, GSSE prevented all the deleterious effects of HFD treatment.

Conclusions

Data suggest that GSSE could be used as a safe preventive agent against fat-induced liver lipotoxicity which could also have potential applications in other non-alcoholic liver diseases.