Effect of Acute Consumption of Blackcurrant Juice on Plasma and Urine Concentrations of Phenolic Acids and Flavonoids and on Antioxidant Status in Human Subjects

Epidemiological evidence suggests that consumption of fruits and vegetables rich in flavonoids is inversely linked to the risk of CVD, but the exact mechanisms are unclear. The present study investigated the effects of acute consumption of a 20% blackcurrant juice drink on plasma and urine concentrations of anthocyanin metabolites and plasma antioxidant status in humans. In a randomized, double-blind, placebo-controlled cross-over design, 20 healthy human subjects (ages 30-70 y, 11 females 9 males) consumed 250 mL of the 20% blackcurrant juice drink or a placebo drink on two intervention visits with one-month washout. Blood and urine samples were collected at baseline and periodically after juice intake for 8 hours, in addition to a 24-hour urine sample. Plasma vitamin C concentrations increased significantly from baseline after blackcurrant juice consumption compared to those of the control group throughout the study day (P = 0.001), particularly at 60 – 90 minutes after consumption. The plasma concentrations of phenolic acids that are known metabolites of flavonoids, namely benzoic acid, hippuric acid, salicylic acid and phenylacetic acid tended to increase at 30 and 180 minutes after blackcurrant juice intake, and a weak interaction was observed between juice treatment and time (P = 0.099). The urinary hippuric acid and total phenolics also tended to show non-significant increases after juice consumption. Delphinidin and cyanidin derivatives were not detected in urine samples at quantifiable concentrations, although there was some evidence of traces present in some samples. There were no significant treatment effects on the oxidative stability of plasma assessed by the Oxygen Radical Absorbance Capacity (ORAC) and Ferric Reducing Antioxidant Power (FRAP) values. Plasma uric acid concentration was significantly correlated with the FRAP value of plasma at 0 - 480 minutes after drink consumption (P = 0.000), which is consistent with the important contribution of uric acid to antioxidant capacity. Overall, the effects of the 20% blackcurrant juice drink on plasma concentrations of flavonoid metabolites and plasma antioxidant status did not reach statistical significance

Elevated levels of the small GTPase Cdc42 induces senescence in male rat mesenchymal stem cells

Mesenchymal stem cells (MSCs) represent a promising cell source for cellular therapy and tissue engineering and are currently being tested in a number of clinical trials for various diseases. However, like other somatic cells, MSCs age, and this senescence is accompanied by a progressive decline in stem cell function. Several lines of evidence suggest a role for the Rho family GTPase Cdc42 activity in cellular senescence processes. In the present study, we have examined aging-associated Cdc42 activity in rat adipose-derived mesenchymal stem cells (ADMSCs) and the consequences of pharmacological inhibition of Cdc42 in ADMSCs from aged rats. We demonstrate that ADMSCs show a decreased rate of cell growth and a decreased ability to differentiate into chrodrogenic, osteogenic and adipogenic cell lineages as a function of rat age. This is accompanied with an increased staining for SA-β-Gal activity and increased levels of Cdc42 bound to GTP. Treatment of ADMSCs from 24-month old rats with three Cdc42 inhibitors significantly increased proliferation rates, decreased SA-β-Gal staining, and reduced Cdc42-GTP. The Cdc42 inhibitor CASIN increased adipogenic and osteogenic differentiation potential in ADMSCs from 24-month old rats, and decreased the levels of radical oxygen species (ROS), p16INK4a levels, F-actin, and the activity of the ERK1/2 and JNK signaling pathways that were all elevated in these cells. These data suggest that ADMSCs show increased rates of senescence as rats age that appear to be due to elevated Cdc42 activity. Thus, Cdc42 plays important roles in MSC senescence and differentiation potential, and pharmacological reduction of Cdc42 activity can, at least partially, rejuvenate aged MSCs

Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1

Aminoacyl-tRNA synthetases possess unique domains. In this study the structure of the vertebrate IARS1 and EARS1 complex reveals that vertebrate IARS1 protects the DNA repair factor BRCA1 from proteolytic degradation via its UBX-fold domain. Aminoacyl-tRNA synthetases (ARSs) have evolved to acquire various additional domains. These domains allow ARSs to communicate with other cellular proteins in order to promote non-translational functions. Vertebrate cytoplasmic isoleucyl-tRNA synthetases (IARS1s) have an uncharacterized unique domain, UNE-I. Here, we present the crystal structure of the chicken IARS1 UNE-I complexed with glutamyl-tRNA synthetase 1 (EARS1). UNE-I consists of tandem ubiquitin regulatory X (UBX) domains that interact with a distinct hairpin loop on EARS1 and protect its neighboring proteins in the multi-synthetase complex from degradation. Phosphomimetic mutation of the two serine residues in the hairpin loop releases IARS1 from the complex. IARS1 interacts with BRCA1 in the nucleus, regulates its stability by inhibiting ubiquitylation via the UBX domains, and controls DNA repair function

Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment

A novel combined biomarker including plasma carotenoids, vitamin C and Ferric Reducing Antioxidant Power is more strongly associated with fruit and vegetable intake than the individual components

Monitoring of fruit and vegetable (F&V) intake is fraught with difficulties. Available dietary assessment methods are associated with considerable error and use of biomarkers offers an attractive alternative. Few studies to date have examined the use of plasma biomarkers to monitor or predict F&V intake of volunteers consuming a wide range of intake from both habitual F&V and manipulated diets. This study combined plasma vitamin C and carotenoid concentrations with Ferric Reducing Antioxidant Power (FRAP) as an integrated biomarker of F&V intake and compared the predictive powers of each single and integrated biomarker for F&V intake. Data from a randomized, controlled, dietary intervention study (FLAVURS) (n = 154) in which the test groups had observed sequential increases of 2.3, 3.2 and 4.2 portions of F&V every 6-wk across an 18-wk period was used in this study. A modified integrated plasma biomarker was devised which included plasma vitamin C, total carotenoids and FRAP values, and this gave a better correlation with F&V intake (r = 0.516, P = 0.000) than the individual biomarkers (r = 0.332, P = 0.000; r = 0.417, P = 0.000; r = 0.136, P = 0.099 respectively). Inclusion of urinary potassium concentration did not significantly improve the correlation. The modified integrated plasma biomarker more accurately predicted F&V intake to within 2 portions of the actual intake in 54.3 ± 4.9% of the population compared with plasma carotenoid concentration (48.3 ± 11.3%), although this difference did not reach statistical significance. Either plasma carotenoid concentration or the integrated biomarker could be used to distinguish high and low F&V consumers

Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatmen

Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment

Biomarkers of fruit and vegetable consumption: findings from the FLAVURS study

Increased consumption of fruits and vegetables (F&V) has been associated with decreased risk of chronic diseases such as CVD and certain types of cancers. Daily consumption of five portions (400 g) or more of F&V has been recommended by the WHO and the UK's Scientific Advisory Committee of Nutrition (SACN). Yet there is no clear advice on the optimum type or quantity of F&V for disease prevention. Epidemiological evidence supports the association of high–dietary flavonoid intake and reduced risk of CVD. However, dose response, randomised, controlled trials are required to confirm these findings

Induction of Apoptosis in U937 Cells by Using a Combination of Bortezomib and Low-Intensity Ultrasound

Background: We scrutinized the feasibility of apoptosis induction in blood cancer cells by means of low-intensity ultrasoundand the proteasome inhibitor bortezomib (Velcade). Material/Methods: Human leukemic monocyte lymphoma U937 cells were subjected to ultrasound in the presence of bortezomib and the echo contrast agent Sonazoid. Two types of acoustic intensity (0.18 W/cm2 and 0.05 W/cm2) were used for the experiments. Treated U937 cells were analyzed for viability and levels of early and late apoptosis. In addition, scanning electron microscopy analysis of treated cells was performed. Results: The percentage of cells that underwent early apoptosis in the group treated with ultrasound and Sonazoid was 8.0±1.31% (intensity 0.18 W/cm2) and 7.0±1.69% (0.05 W/cm2). However, coupling of bortezomib and Sonazoid resulted in an increase in the percentage of cells in the early apoptosis phase, up to 32.50±3.59% (intensity 0.18 W/cm2) and 33.0±4.90% (0.05 W/cm2). The percentage of U937 cells in the late apoptosis stage was not significantly different from that in the group treated with bortezomib only. Conclusions: Our findings indicate the feasibility of apoptosis induction in blood cancer cells by using a combination of bortezomib, ultrasound contrast agents, and low-intensity ultrasound