Nod2 protects mice from inflammation and obesity-dependent liver cancer.

Nod2 is a pattern recognition receptor that modulates host innate immune responses and protects from inflammation, steatosis, and obesity. Obesity and inflammation are risk factors for hepatocellular carcinoma, however, the role of Nod2 in obesity-dependent hepatic tumorigenesis is not known. Here we tested the hypothesis that Nod2 protects from high fat diet (HFD)-dependent hepatic cancer. We used an obesity-dependent hepatic tumor model. WT and Nod2-/- mice were treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD. Nod2-/- mice treated with DMBA and maintained on HFD gain significantly more weight and develop more liver tumors than similarly treated WT mice. Livers of Nod2-/- tumorigenic mice had increased expression of genes involved in cell proliferation, immune responses, and cholesterol biosynthesis, increased infiltration of neutrophils, inflammatory monocytes, and T cells, and increased activation of STAT3 and ERK during the later stages of tumorigenesis. Bioinformatic analyses of genes with differential expression predicted an increase in cancer, immune, and cholesterol biosynthesis pathways. In summary, we have identified a novel role for Nod2 and demonstrate that Nod2 protects from HFD-dependent liver malignancy and this protection is accompanied by decreased cell proliferation, inflammation, steroid biosynthesis, neutrophils and macrophages infiltration, and STAT3 and MAPK signaling in the liver.

Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis.

The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb.

A novel variable exonic region and differential expression of LINC00663 non-coding RNA in various cancer cell lines and normal human tissue samples.

Long non-coding RNAs (lncRNAs) are found to play crucial roles in several biological processes and have been associated with many complex human diseases including cancers. Several lines of evidences indicate that lncRNAs deregulated in many cancer tissues. In this particular study, differential expression of long intergenic non-coding RNA 663 (LINC00663) was demonstrated in various cancer cell lines and healthy human tissues by using RT-PCR and qPCR methods. While expression level of LINC00663 was most prominent in thyroid gland and uterus, it is least expressed in skeletal muscle tissues. Moreover, LINC00663 was found to be differentially expressed in various cancer cells. Particularly, its expression was highly diminished in DU-145, PC3, HGC-27, CRL-1469, A549, MCF7, and BCPAP cancer cells. Also, LINC00663 expression was most prominent in A172 glioblastoma cells. Additionally, a novel splice variant of LINC00663 RNA was also detected. The sequence and Basic Local Alignment Search Tool (BLAST) analysis results revealed the presence of a novel exonic region between exons 2 and 3. Subsequently, five potential splice variants showing high level of variation have been identified. Secondary structures of these variants with minimum free energy were also demonstrated. Furthermore, putative microRNA (miRNA) binding sites to these variants have been shown. In conclusion, LINC00663 was shown to be differentially expressed in various human tissues and cancer cell lines. Also, LINC00663 undergoes alternative splicing and the novel exonic region alters its secondary structure and its interactions with potential targeting miRNAs. The role of LINC00663 in cancer formation further needs to be investigated with a wide range of studies.

The effects of Nigella sativa (Ns), Anthemis hyalina (Ah) and Citrus sinensis (Cs) extracts on the replication of coronavirus and the expression of TRP genes family.

Extracts of Anthemis hyalina (Ah), Nigella sativa (Ns) and peels of Citrus sinensis (Cs) have been used as folk medicine to fight antimicrobial diseases. To evaluate the effect of extracts of Ah, Ns and Cs on the replication of coronavirus (CoV) and on the expression of TRP genes during coronavirus infection, HeLa-CEACAM1a (HeLa-epithelial carcinoembryonic antigen-related cell adhesion molecule 1a) cells were inoculated with MHV-A59 (mouse hepatitis virus-A59) at moi of 30. 1/50 dilution of the extracts was found to be the safe active dose. ELISA kits were used to detect the human IL-8 levels. Total RNA was isolated from the infected cells and cDNA was synthesized. Fluidigm Dynamic Array nanofluidic chip 96.96 was used to analyze the mRNA expression of 21 TRP genes and two control genes. Data was analyzed using the BioMark digital array software. Determinations of relative gene expression values were carried out by using the 2(-∆∆Ct) method (normalized threshold cycle (Ct) value of sample minus normalized Ct value of control). TCID50/ml (tissue culture infectious dose that will produce cytopathic effect in 50% of the inoculated tissue culture cells) was found for treatments to determine the viral loads. The inflammatory cytokine IL-8 level was found to increase for both 24 and 48 h time points following Ns extract treatment. TRPA1, TRPC4, TRPM6, TRPM7, TRPM8 and TRPV4 were the genes which expression levels changed significantly after Ah, Ns or Cs extract treatments. The virus load decreased when any of the Ah, Ns or Cs extracts was added to the CoV infected cells with Ah extract treatment leading to undetectable virus load for both 6 and 8 hpi. Although all the extract treatments had an effect on IL-8 secretion, TRP gene expression and virus load after CoV infection, it was the Ah extract treatment that showed the biggest difference in virus load. Therefore Ah extract is the best candidate in our hands that contains potential treatment molecule(s).

Exploring outcome measures for exercise intervention in people with Parkinson's disease.

Background. It is widely believed that exercise improves mobility in people with Parkinson's disease (PD). However, it is difficult to determine whether a specific type of exercise is the most effective. The purpose of this study was to determine which outcome measures were sensitive to exercise intervention and to explore the effects of two different exercise programs for improving mobility in patients with PD. Methods. Participants were randomized into either the Agility Boot Camp (ABC) or treadmill training; 4x/week for 4 weeks. Outcome measures were grouped by the International Classification of Function/Disability (ICF). To determine the responsiveness to exercise, we calculated the standardized response means. t-tests were used to compare the relative benefits of each exercise program. Results. Four of five variables at the structure/function level changed after exercise: turn duration (P = 0.03), stride velocity (P = 0.001), peak arm speed (P = 0.001), and horizontal trunk ROM during gait (P = 0.02). Most measures improved similarly for both interventions. The only variable that detected a difference between groups was postural sway in ABC group (F = 4.95; P = 0.03). Conclusion. Outcome measures at ICF body structure/function level were most effective at detecting change after exercise and revealing differences in improvement between interventions.

Lipid peroxides in obese patients and effects of weight loss with orlistat on lipid peroxides levels.

OBJECTIVE: Obesity is a well-known risk factor of atherosclerosis. Recent studies showed that obesity is associated with enhanced lipid peroxidation. The aim of this study is to investigate the effect of weight reduction with orlistat treatment on lipid peroxidation levels. We assessed lipid peroxidation by measuring the concentration of plasma malondialdehyde (MDA). DESIGN: A randomized, controlled, open-label 6-month study. SUBJECTS: In total, 36 obese (body mass index (BMI) >30 kg/m2) and 11 healthy age-matched control subjects were enrolled in the study. MEASUREMENTS: Fasting glucose, triglyceride, total cholesterol, HDL cholesterol and LDL cholesterol and MDA levels were measured in both groups. Obese subjects received orlistat, 120 mg three times daily together with hypocaloric diet. After 6 months of treatment laboratory tests were repeated. RESULTS: MDA levels were significantly higher in obese patients than the control group (P<0.0001). After 6 months of treatment in obese subjects, the mean weight of the patients decreased by 6.8 kg, the BMI by 3.2 kg/m2. Plasma MDA levels were significantly reduced by weight loss from 2+/-0.77 to 0.89+/-0.41 nmol/ml (P<0.001). BMI correlated with MDA levels at baseline (r=0.6, P<0.0001). Changes in BMI was positively associated with plasma MDA level reduction (r=0.36, P<0.05). CONCLUSION: These results indicate that obesity is associated with increases in endogenous lipid peroxides. Our data show that the indicator of lipid peroxidation-MDA-falls markedly in association with weight loss with orlistat. The demonstration of decreased free radical generation has important implications for oxidative mechanism underlying obesity-associated disorders.

The effect of iron supplementation on visual-evoked potentials in infants with iron-deficiency anemia.

Flash visual-evoked potentials were studied in 20 infants with iron-deficiency anemia to determine the effect of iron deficiency on visual function by using visual-evoked potentials in this type of anemia. After iron therapy for 12 weeks, visual-evoked potentials were retested in these otherwise healthy infants. All infants showed an excellent hematological response to iron therapy. Post-treatment visual-evoked potential N2 latencies (negative deflections) decreased significantly compared to the pre-treatment values (p < 0.05). These results suggest that iron-deficiency anemia causes subclinical visual impairment, and visual-evoked potentials may be a useful non-invasive means of detecting subtle effects of nutritional deficiencies and monitoring the nutritional status of infants.

[Lipoprotein (a) as a risk factor for coronary artery disease in women and elderly patients]. / Koroner arter hastaligi risk faktörü olarak kadinlarda ve yaslilarda lipoprotein (a).

OBJECTIVE: The role of lipoprotein (a) [Lp(a)] as a risk factor for coronary artery disease (CAD) in women and elderly is not clear. In this study we assessed the relation between serum Lp (a) levels and CAD, taking into account the differences in sex and age. METHODS: Lp (a) levels and other lipid variables were determined in 535 consecutive patients undergoing coronary angiography for chest pain evaluation. Among 535 patients, 163 patients had angiographically normal coronary arteries (70 men and 93 women) and 372 patients had significant coronary lesions at least one coronary artery (300 men and 72 women). RESULTS: After adjustment for hypertension, smoking, diabetes, low density lipoprotein-cholesterol (LDL-C), triglycerides and high density lipoprotein-cholesterol (HDL-C), elevated Lp (a) was independently predictive for CAD in both sexes under 55 years old (odds ratio [OR]: 5.1, p < 0.01 for men and OR: 2.3, p < 0.05 for women). In patients more than 55 years old elevated Lp (a) was not associated with CAD for both sexes (OR: 1.3, p = NS for men and OR: 1.2, p = NS for women). CONCLUSION: We did not find any relation between elevated Lp (a) concentrations and presence of angiographically detectable CAD both in men and women aged more than 55 years old. Our results suggest that elevated Lp (a) is an independent risk factor for premature CAD for both men and women.

Relation of functional capacity with the oxidative stress and antioxidants in chronic heart failure.

Chronic heart failure is a common, disabling disorder with high mortality. Oxidative stress may have both functional and structural effects on the myocardium, leading to myocardial decompensation. In this study, the authors examined the relationship of oxidative stress and functional capacity in patients with varying degrees of heart failure. Fifty-one patients with chronic heart failure and 31 control subjects were studied. The functional capacity of patients was determined. Plasma malondialdehyde, vitamin E, and beta-carotene levels were measured. The malondialdehyde levels were significantly different between control subjects and heart failure patients (p=0.03). There was a positive correlation between patients' malondialdehyde levels and New York Heart Association functional class (r=0.59; p<0.0001). There was a negative correlation between the functional class and vitamin E and beta-carotene levels (r=20.43; p<0.0001 and r=20.25; p<0.01, respectively). These data demonstrate that oxidative stress is increased systemically in patients with chronic heart failure. It seems that this increase correlates with functional class. (c)2001 CHF, Inc.

Susceptibility of apolipoprotein B-containing lipoproteins to oxidation and antioxidant status in acute coronary syndromes.

BACKGROUND: Oxidized lipoproteins may play an important role in the pathogenesis of atherosclerosis, and it has been shown that antioxidants have a protective effect against the progression of atherosclerosis. HYPOTHESIS: The aim of this study was to investigate the oxidative susceptibility of apolipoprotein B-containing lipoproteins and antioxidant status in patients with acute coronary syndromes and chronic stable angina pectoris. METHODS: The study population included 70 patients with acute coronary syndromes (14 with recent acute myocardial infarction and 56 with unstable angina pectoris), 105 patients with stable angina pectoris, and 75 control subjects. In addition to conventional lipid and lipoprotein analysis, the susceptibility of apolipoprotein B-containing lipoproteins to in vitro oxidation (lag phase) and plasma vitamin E and total carotene levels was measured. RESULTS: The lag phase was significantly shorter in patients with acute coronary syndromes (45 +/- 12 min) than in patients with stable angina pectoris (51 +/- 10 min) and in control subjects (58 +/- 9 min) (p < 0.0001). Both plasma vitamin E and total carotene levels were lowest in patients with acute coronary syndromes (1.11 +/- 0.32 mg/dl and 119 +/- 32 micrograms/dl, respectively), followed by patients with stable angina pectoris (1.25 +/- 0.37 mg/dl and 132 +/- 37 micrograms/dl) and then controls (1.52 +/- 0.31 mg/dl and 167 +/- 41 micrograms/dl). CONCLUSIONS: These data suggest that there is an intense oxidative process and a lower antioxidant status in acute coronary syndromes. This may lead to plaque instability due to the activation of the inflammatory response in coronary atherosclerotic lesions.

Relation between lipoprotein (a) and in vitro oxidation of apolipoprotein B-containing lipoproteins.

OBJECTIVES: To assess the relationship between lipoprotein (a) [Lp (a)] and lipoprotein oxidation in patients with coronary artery disease (CAD). DESIGN AND METHODS: Oxidation of apolipoprotein (apo)B-containing lipoproteins, vitamin E, carotenoids, lipid-lipoprotein levels were determined in 171 CAD and 70 non-CAD subjects. RESULTS: In CAD patients with Lp (a) concentrations >/= 30 mg/dL; total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and apo B levels were significantly higher and lag-time and age were significantly lower than those of CAD patients with Lp (a) concentrations < 30 mg/dL. In non-CAD subjects with Lp (a) concentrations >/= 30 mg/dL; TC, LDL-C, and vitamin E levels were significantly higher and lag-time was significantly lower than those of non-CAD subjects with Lp (a) concentrations < 30 mg/dL. In CAD patients, Lp (a) correlated negatively with lag-time and positively with MDA levels. Lp (a) correlated negatively with lag-time and vitamin E levels in non-CAD subjects. CONCLUSIONS: We have shown that plasma apo B-containing lipoproteins of both CAD and non-CAD subjects with Lp (a) levels >/= 30 mg/dL are more susceptible to in vitro oxidative modification than those of subjects with Lp (a) levels < 30 mg/dL. The relationship between Lp (a) and enhanced susceptibility of apo B-containing lipoproteins to oxidation, appears to support routine investigation of Lp (a).

Effect of successful coronary angioplasty and stent implantation on QT dispersion.

BACKGROUND: QT dispersion (defined as maximal QT interval minus minimal QT interval), as assessed using the surface ECG, has been shown to reflect regional inhomogeneities in ventricular repolarization. The aim of this study was to show the effect of coronary revascularization, by successful coronary angioplasty or stent implantation, on QT dispersion. METHODS: QT dispersion was defined on each ECG as the difference between the maximal and minimal measurements of QT interval. Of 135 patients studied, 52 patients underwent coronary angioplasty and 84 patients underwent stent implantation. Maximum and minimal QT interval and QT dispersion were measured using 12-lead electrocardiography before and 24 h after each successful procedure. RESULTS: QT dispersion decreased from 51 +/- 12 ms at baseline to 37 +/- 10 ms 24 after the procedure (P < 0.001). Before the procedure, the QT dispersion of patients undergoing angioplasty and stent implantation was 50 +/- 13 and 52 +/- 10 ms, respectively. After the procedure, the QT dispersions were 34 +/- 9 and 38 +/- 10 ms, respectively (P < 0.001). QT dispersion was significantly lower in both groups after the procedure. No differences were observed between the QT dispersions of patients undergoing angioplasty and of those undergoing stent implantation. CONCLUSIONS: Successful coronary angioplasty and stent implantation significantly reduced QT dispersion. The decreased QT dispersion may have been caused by improvements in myocardial perfusion and may be beneficial in reducing the likelihood of arrhythmias occurring.

Effects of fosinopril treatment on blood pressure during physical and mental stress test in essential hypertension.

In this study the effects of once daily administration of 10 mg fosinopril on blood pressure response to mental and physical stress were evaluated in mild to moderate essential hypertension. A total of 25 patients (14 women, 9 men) with mild to moderate essential hypertension were enrolled in this study. Before the treatment and after 10 mg/day fosinopril treatment for 2 months, systolic and diastolic blood pressure and heart rate were recorded at rest and while performing a mental arithmetic test. In addition, exercise stress testing with Bruce protocol were performed before and after the treatment and systolic and diastolic blood pressure and heart rate were recorded at rest and during peak exercise. Statistical analysis were done by using the paired t-test. During the mental arithmetic test, systolic and diastolic blood pressure were significantly reduced (p < 0.005 and p < 0.001, respectively) after 2 months fosinopril treatment. Systolic and diastolic blood pressure were also significantly reduced during the exercise stress test (p < 0.005 and p < 0.05) after the treatment. Heart rate did not change during either the mental arithmetic or the exercise test. As a result, once daily 10 mg fosinopril may be effective in reducing blood pressure, not only at rest, but also during stressful situations.

The Effects of Sublingual Administration of Captopril on Parameters of Exercise Test and Neurohormonal Activation in Patients With Stable Angina Pectoris

A prospective randomized, double-blind, and placebo-controlled study was designed to investigate the effects of sublingual administration of captopril on the parameters of exercise test and neurohormonal activation in patients with stable angina pectoris. A total of 31 patients (28 male, 3 female; mean age 55.4 +/- 9.4 years) took part in the study. Coronary angiography and left ventriculography were performed in all cases and the patients were classified according to the ejection fraction (EF). Following sublingual placebo or 25 mg captopril, plasma levels of renin, angiotensin II, norepinephrine, and serum aldosterone levels were measured at rest and maximal exercise. test was performed. Hormone levels were remeasured immediately after the exercise. The same procedure was repeated the next day using captopril or placebo. Sublingual captopril administration increased the time to angina, the time to 1 mm ST depression, maximal exercise capacity, maximal exercise duration and decreased maximal ST depression, maximal systolic blood pressure, and maximal double product (p < 0.001-0.01). After the maximal exercise test following captopril, the % difference of angiotensin II, aldosterone, and norepinephrine levels was found to be significant lower and the % difference of the renin level was found to be significantly higher than those of placebo (p < 0.001). The effects of sublingual captopril on exercise parameters were additionally assessed in different left ventricular systolic function subgroups. The favorable effects were more prominent in cases with left ventricular systolic dysfunction. There were no adverse effects related to sublingual captopril use. As a result, sublingual administration of captopril improved the parameters of maximal exercise test and suppressed the neurohormonal activation during exercise. We suggest that sublingual captopril may be used effectively before planned daily activities in patients with stable angina pectoris.

Experimental intraoperative use of perfluorotributylamine, perfluorodecaline, and perfluoropolyether

Perfluorocarbonos líquidos (PFCLs) säo compostos com uma gravidade específica maior que a água e utilizados como adjuntos no tratamento cirúrgico de casos complicados de descolamento de retina. 32 coelhos pigmentados foram submetidos a vitrectomia com injeçäo de PFCL dentro da cavidade vítrea: 8 receberam perfluorotributilamino (PFTA); 8 receberam perfluorodecalino (PFDC); 8 receberam perfluoropoliéter (PFPE); os restantes 8 olhos que serviram de controle, receberam soluçäo salina. Uma hora depois das injeçöes foi realizada troca PFCL/soluçäo salina. Os animais foram entäo sacrificados, os olhos enucleados e processados para exames histológicos. A microscopia óptica nenhuma diferença significativa foi demonstrada entre os olhos com PFCLs comparando com os controles. A microscopia óptica nenhuma diferença significativa foi demonstrada entre os olhos com PFCLs comparado com os controles. A microscopia eletrônica revelou somente pequenas alteraçöes, consistindo de alguns defeitos irregulares na forma dos segmentos externos dos fotorreceptores no grupo do PFTA, PFPE e PFDC, pelo menos em nosso modelo animal, näo é associado com nenhuma patologia retiniana significativa