The ACE inhibitory dipeptide Met-Tyr diminishes free radical formation in human endothelial cells via induction of heme oxygenase-1 and ferritin

Food sources such as soybeans and fish contain angiotensin I converting enzyme (ACE) inhibitory peptides with antihypertensive properties. Methionine-tyrosine (Met-Tyr) is an ACE inhibitory dipeptide derived from sardine muscle. The present study investigates the effect of Met-Tyr on the expression of the antioxidant stress proteins, heme oxygenase-1 (HO-1) and ferritin, in endothelial cells derived from the human umbilical vein and their contribution to the decrease in radical formation that occurs under the influence of this dipeptide. Preincubation of endothelial cells with Met-Tyr (10-300 micromol/L) followed by washout markedly diminished subsequently induced NADPH-mediated radical formation. This indirect protection was associated with a significant increase in protein expression of HO-1 and ferritin and abolished by the HO inhibitor zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG). The HO product bilirubin produced antioxidant effects comparable to those of Met-Tyr. Met-Tyr raised HO-1 mRNA levels by enhancing mRNA stability. Antioxidant effects were specific for Met-Tyr and not observed with other methionine-containing dipeptides or ACE inhibitory agents. Our results demonstrate that Met-Tyr protects endothelial cells from oxidative stress via induction of HO-1 and ferritin but independently of its ACE inhibitory properties. This pathway represents a novel, potentially antiatherogenic mechanism of Met-Tyr and dietary proteins releasing Met-Tyr during gastrointestinal digestion.     

Mutation screening of the androgen receptor promoter and untranslated regions in prostate cancer

BACKGROUND: Mechanisms, other than gene amplification, leading to overexpression of AR in androgen ablation-resistant prostate cancer remain unknown and could include genetic alterations in the promoter or untranslated regions (UTR) of the AR gene. MATERIALS AND METHODS: DNAs from five prostate cancer cell lines, 19 LuCaP xenografts, 44 clinical tumors, and 36 non-malignant controls were used for screening mutations in the upstream regulatory region, promoter and the 5'- and 3'-UTRs of the AR gene with denaturating high performance liquid chromatography (DHPLC) and sequencing. RESULTS: Ten different sequence variations were found in prostate cancer cell lines and xenografts. However, none of them were recurrent or were found in clinical prostate cancer specimens or in normal controls. CONCLUSIONS: Recurrent mutations in the promoter or UTRs of AR seem to be rare, and thus not likely mechanisms for the increased expression of the gene in the androgen ablation-resistant prostate cancer.     

Serious pregnancy complications in a patient with previously undiagnosed carnitine palmitoyltransferase 1 deficiency

Fetal defects in mitochondrial beta-oxidation have been linked with an increased risk for acute fatty liver of pregnancy and preeclampsia-related conditions. A woman with previously undiagnosed carnitine palmitoyltransferase 1 deficiency experienced hemolysis, elevated liver enzymes, low platelets-like syndrome late in her first pregnancy with an unaffected fetus. Carnitine palmitoyltransferase 1 deficiency should be considered as a potential cause of life-threatening complications of pregnancy.     

IR spectroscopy together with multivariate data analysis as a process analytical tool for in-line monitoring of crystallization process and solid-state analysis of crystalline product

Crystalline product should exist in optimal polymorphic form. Robust and reliable method for polymorph characterization is of great importance. In this work, infra red (IR) spectroscopy is applied for monitoring of crystallization process in situ. The results show that attenuated total reflection Fourier transform infra red (ATR-FTIR) spectroscopy provides valuable information on process, which can be utilized for more controlled crystallization processes. Diffuse reflectance Fourier transform infra red (DRIFT-IR) is applied for polymorphic characterization of crystalline product using X-ray powder diffraction (XRPD) as a reference technique. In order to fully utilize DRIFT, the application of multivariate techniques are needed, e.g., multivariate statistical process control (MSPC), principal component analysis (PCA) and partial least squares (PLS). The results demonstrate that multivariate techniques provide the powerful tool for rapid evaluation of spectral data and also enable more reliable quantification of polymorphic composition of samples being mixtures of two or more polymorphs. This opens new perspectives for understanding crystallization processes and increases the level of safety within the manufacture of pharmaceutics.     

Stress and resilience in rheumatic diseases: a review and glimpse into the future

Stress resilience factors, and interventions to ease stress and enhance resilience, are gaining increasing attention for the treatment of rheumatic conditions. This Review presents a digest of empirical work on the factors that determine the risk of adapting poorly to a rheumatic condition, and on the resilience factors that counteract such risks. We consider the types of stress-management and resilience treatments that are most effective in promoting the physical and psychological functioning of patients at risk of long-term adjustment problems. Prospective research shows that cognitive-behavioral and social risk and resilience factors predict the long-term physical and psychological functioning of patients with rheumatic conditions. Furthermore, validated screening instruments are becoming increasingly useful in clinical practice to identify and select patients at risk. Stress-management and resilience interventions offer promising ways to improve the long-term functioning of patients. These treatment methods might be especially useful when they are tailored to the specific risk and resilience factors of patients, and when they incorporate innovative approaches to the delivery of services, including internet applications such as eHealth, to increase efficiency and availability of treatments, and to optimize patient empowerment in rheumatic conditions.     

Effects of lidocaine infiltration on cost of rhinoplasty made under general anesthesia

This study aimed to compare the effects of combined and noncombined lidocaine with adrenaline infiltration in general anesthesia (GA) procedures, in which the standard anesthesia depth is monitored by Bispectral Index monitoring, on minimum alveolar concentration (MAC) levels and the costs. Following approval by the local ethics committee, an American Society of Anesthesiologists physical status I–II group of 40 adult patients for whom elective rhinoplasties under GA were planned was divided into 2 double-blind randomized groups. In group 1, GA and lidocaine + adrenaline were administered, whereas in group 2, only GA and adrenaline were administered. All the patients who had been taken to the operation room underwent electrocardiography and measurements of the peripheral oxygen saturation, end-tidal carbon dioxide, heart rate, mean blood pressure, and Bispectral Index monitoring. Using the operation time and the MAC% values, the total consumed inhalation agent amounts were calculated, and the cost difference was determined. The mean blood pressure values were lower in group 1 (P < 0.05). In group 1, the MAC% was 20.83% lower than that of group 2; the consumed desflurane amount was 20.29%, and the cost was 20.29% lower than that of group 2 (P < 0.05). In rhinoplasties under GA, the lidocaine + adrenaline combination infiltration not only decreased inhaled anesthetic requirement and cost but also supported the hemodynamic stability. In addition, surgical satisfaction increased in the lidocaine + adrenaline group because of small number of agitated patients during the recovery period.     

Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation

OBJECTIVE

To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN).

RESEARCH DESIGN AND METHODS

Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation.

RESULTS

The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1.

CONCLUSIONS

High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.In patients with type 1 diabetes, long duration of the disease and poor glycemic control increase the risk for micro- and macrovascular complications. A significant proportion of type 1 diabetic patients who develop these complications exhibit clinical features commonly seen in subjects with the metabolic syndrome (MetS), including dyslipidemia, insulin resistance, obesity, hypertension, and chronic inflammation (1,2). Vascular diseases are also common in patients with IgA glomerulonephritis (IgAGN), and those with a progressive form of the disease run a significantly elevated risk of developing different cardiovascular sequela (3). Whether the MetS is independently associated with the progression of IgAGN is currently unclear, but at least several related factors, including hyperuricemia, hypertriglyceridemia, weight, insulin resistance, and inflammation, seem to associate with the development of kidney dysfunction in IgAGN (4,5).Many of these clinical subphenotypes likely emerge from the complex interactions between a genetic background, lifestyle, and environmental factors. Recent studies have highlighted the role of the innate immune system in the developmental process of these metabolic abnormalities (6). Our living environment is inhabited with commensal and pathogenic bacteria, which have both beneficial and detrimental effects on human health. If the immune defense functions properly, these microorganisms rarely cause any serious infections in healthy individuals. The situation is different in immunocompromised patients—local infections, use of antibiotics, and even diet may lead to the colonization of opportunistic bacteria in various sites of the body. In diabetic patients, long duration of the disease and poor glycemic control increase the risk for urinary tract, pulmonary, oral, and skin infections (6,7).Lipopolysaccharides (LPS) are unique glycolipids in the cell wall of gram-negative bacteria. LPS molecules, also known as bacterial endotoxins, may trigger acute and chronic inflammation, leading to immune cell activation and cytokine release. HDL cholesterol is one of the most important factors involved in the elimination of LPS molecules from circulation. In healthy subjects, LPS is mainly bound to HDL, whereas in patients with sepsis, LPS is redistributed toward LDL and VLDL lipoproteins (8). High LPS activity combined with low HDL levels increases the risk for cardiovascular disease (9).LPS infusion in mammals leads to the appearance of factors known to be associated with the MetS: elevated levels of proinflammatory markers, dyslipidemia, fasting hyperglycemia, insulin resistance, and obesity (10–12). In some research applications, bacterial endotoxins have been used to induce acute kidney injury in animals. Monocyte chemoattractant protein-1 (MCP1) is a potential marker for progressive renal disease because its expression and excretion are also regulated by bacterial endotoxins (13,14).We have recently shown that high serum levels of LPS activity are associated with the development and progression of kidney disease in Finnish type 1 diabetic patients. Most of the patients with high serum LPS activity exhibited features of dyslipidemia and insulin resistance (15). These metabolic abnormalities are frequently observed in diabetic patients with micro- or macrovascular complications (2). To our knowledge, no previous studies have explored the potential links between bacterial endotoxins and the MetS in subjects with impaired kidney function. Therefore, we wanted to investigate whether serum LPS activity is associated with metabolic risk factors in three distinct study populations: type 1 diabetic patients with various degrees of kidney disease, patients with IgAGN, and nondiabetic subjects.