Chemopreventive effect of bacoside A on N-nitrosodiethylamine-induced hepatocarcinogenesis in rats

Purpose

Chemoprevention is an effective approach to control hepatocarcinogenesis. Bacoside A, the active constituent of Bacopa monniera Linn., is anticipated to play a role in chemoprevention of liver cancer.

Methods

In the present study, we investigated the chemopreventive effect of bacoside A against N-nitrosodiethylamine-induced hepatocarcinogenesis in an animal model.

Results

Administration of carcinogen showed a significant elevation in the levels of lipid peroxidation, serum tumor marker enzymes and liver injury marker enzymes with subsequent decrease in the levels of both hemolysate and liver antioxidant status. Bacoside A co-treatment maintained the N-nitrosodiethylamine-induced alterations at near normal level. Histopathological and electron microscopic study of the liver tissue also supports the above biochemical observations.

Conclusions

From our findings we conclude that bacoside A is effective to prevent DEN-induced hepatocellular carcinoma by quenching lipid peroxidation and enhancing antioxidant status through free radical scavenging mechanism and having potential of protecting endogenous enzymatic and non-enzymatic antioxidant activity.     

Aspirin is a substrate for paraoxonase-like activity: implications in atherosclerosis

Paraoxonase 1 (PON 1) is an enzyme that is promiscuous in its ability to hydrolyze various types of substrates. It hydrolyzes aryl esters, phosphate esters, lactones, and reduces lipid peroxides to hydroxides. Aspirin is an aryl ester with a short plasma half life. We hypothesized that aspirin would be effectively hydrolyzed by PON 1 and many of its anti-atherogenic effects, at least in part, could be accounted for by its antioxidant product, salicylic acid. In this study, we determined the ability of human plasma and PON 1-rich HDL to hydrolyze acetyl ester of salicylic acid (aspirin). The ability of aspirin to compete for the hydrolysis of paraoxon and p-nitrophenylacetate was determined. In addition, nitrated aspirin was synthesized and tested directly for hydrolysis. Aspirin competed for the hydrolysis of paraoxon and p-nitrophenylacetate by HDL in a dose-dependent manner. Human plasma and HDL were also able to hydrolyze nitroaspirin and aspirin and release nitrosalicylic acid and salicylic acid, respectively. These findings suggest that salicylic acid might be generated in the plasma from aspirin. The ability of long-term treatment with aspirin to retard atherosclerosis might be dependent on the generation of free salicylic acid, a scavenger of free radicals.     

Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome

Response inhibition is an important facet of executive function. Fragile X syndrome (FraX), with a known genetic etiology (fragile X mental retardation-1 (FMR1) mutation) and deficits in response inhibition, may be an ideal condition for elucidating interactions among gene-brain-behavior relationships. Functional magnetic resonance imaging (fMRI) studies have shown evidence of aberrant neural activity when individuals with FraX perform executive function tasks, though the specific nature of this altered activity or possible compensatory processes has yet to be elucidated. To address this question, we examined brain activation patterns using fMRI during a go/nogo task in adolescent males with FraX and in controls. The critical comparison was made between FraX individuals and age, gender, and intelligent quotient (IQ)-matched developmentally delayed controls; in addition to a control group of age and gender-matched typically developing individuals. The FraX group showed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) and right caudate head, and increased contralateral (left) VLPFC activation compared with both control groups. Individuals with FraX, but not controls, showed a significant positive correlation between task performance and activation in the left VLPFC. This potential compensatory activation was predicted by the interaction between FMR1 protein (FMRP) levels and right striatal dysfunction. These results suggest that right fronto-striatal dysfunction is likely an identifiable neuro-phenotypic feature of FraX and that activation of the left VLPFC during successful response inhibition may reflect compensatory processes. We further show that these putative compensatory processes can be predicted by a complex interaction between genetic risk and neural function.     

Hypolipidemic effect of triphala in experimentally induced hypercholesteremic rats

Hypercholesteremia is one of the risk factors for coronary artery disease. The present study highlights the efficacy of Ayurvedic herbal formulation Triphala (Terminalia chebula, Terminalia belerica, and Emblica officinalis) on total cholesterol, Low density lipoprotein (LDL), Very low density lipoprotein (VLDL), High density lipoprotein (HDL) and free fatty acid in experimentally induced hypercholesteremic rats. Four groups of rats were employed namely control, Triphala treated, hypercholesterolemia rats (4% Cholesterol + 1% cholic acid + egg yolk) and Triphala pre-treatment in hypercholesteremic rats. Results showed significant increase in the total cholesterol, LDL, VLDL, and free fatty acid in hypercholesteremic rats were significantly reduced in Triphala treated hypercholesteremic rats. The data demonstrated that Triphala formulation was associated with hypolipidemic effects on the experimentally induced hypercholesteremic rats.     

Charge-based interactions of mammalian sperm with oocytes: inhibition of fertilization of mouse oocytes by ligands of macrophage scavenger receptor(s)

Objective: To determine whether anionic ligands for the macrophage scavenger receptor inhibit the fertilization of mouse oocytes by mouse spermatozoa.

Design: In vitro study of sperm binding and two-cell embryo formation in the presence of scavenger receptor ligands. Sperm-oocyte interaction may be mediated by sulfated sugars. In this study, we tested other nonsulfated anionic ligands for the scavenger receptor for their ability to affect fertilization. The only common feature of these ligands is their anionic nature.

Setting: Oocytes and sperm from mice were used.

Main Outcome Measure(s): Binding of sperm to oocytes and subsequent formation of two cell embryos were determined.

Result(s): Fucoidin, polyinosinic acid, oxidized low-density lipoprotein, acetyl low-density lipoprotein, and malondialdehyde-modified LDL inhibited the binding and fertilization of mouse sperm to mouse oocytes. Addition of fresh sperm to oocytes previously treated with sperm in the presence of these agents restored the binding and fertilization.

Conclusion(s): These results show that charge-based interactions analogous to the interactions of the scavenger receptor with its ligands may play an important role in mammalian fertilization.     

Sleep and well-being of ICU housestaff

BACKGROUND: Our understanding of the effect of the Accreditation Council for Graduate Medical Education (ACGME)-mandated work-hour limitation on physicians' quality of life, sleepiness, and sleep-work habits is evolving. In this study, we sought to determine the effect of work-hour reduction on quality of life in residents and fellows (ICU housestaff) when subject to the ACGME-compliant schedule of one institution. To determine the effect of work-hour reduction on subjective and objective measures of sleepiness in ICU housestaff at a center. METHODS: A single-center study of 34 residents and 10 fellows who were studied before and after the ACGME-mandated work-hour limitation went into effect in July 2003. RESULTS: In a single center, after the work-hour reduction, residents reported statistically significant but minor improvements in sleep time, subjective sleepiness, and some aspects of quality of life (p < 0.05). Both before and after work-hour limitations, subjective sleepiness and quality-of-life indexes deteriorated during the course of the ICU rotation. Following work-hour reductions, subjective sleepiness improved (p < 0.05), but objective sleepiness was unchanged (p = 0.6). Moreover, after the implementation of work-hour reductions, 59%, 43%, and 25% of the ICU team had mean sleep latency < 10, 7, and 5 min, respectively, with 14% of the team manifesting sleep-onset rapid eye movement periods (signifying severe sleepiness) before beginning their extended work-hour period. CONCLUSIONS: In ICU housestaff, at a single center, small benefits to quality of life and subjective sleepiness were realized by an ACGME-compliant work-hour schedule. Significant levels of objective sleepiness, however, remained. Further measures may need to be undertaken to address the persistence of sleepiness in ICU housestaff. These findings may not be generalized outside of the scheduling system studied.     

A phase II trial evaluating the safety and effectiveness of the AastromReplicell system for augmentation of low-dose blood stem cell transplantation

To reduce the number of apheresis procedures and maintain the usual rate of hematopoietic recovery in patients treated with high-dose chemotherapy, we studied the effect of adding a small volume of ex vivo expanded bone marrow to low doses of CD34(+) blood stem cells. Thirty-four patients with breast cancer received G-CSF (10 microg/kg/day) priming followed by a limited volume (50-100 ml) bone marrow aspiration and standard 10-liter aphereses. Marrow was expanded ex vivo using the AastromReplicell system and infused along with low doses of blood-derived CD34(+) cells, collected in one apheresis. Thirty-one evaluable patients received a median CD34(+) blood stem cell dose of 0.7 x 10(6)/kg (range, 0.2-2.5) and 4.7 x 10(7) nucleated cells/kg (range, 1.98-8.7) of ex vivo expanded marrow. All patients recovered with normal blood counts and engrafted 500 neutrophils/microl and 20 000 platelets/microl in a median of 10 and 13 days, respectively. Multivariate analysis revealed that, in addition to CD34(+) lineage negative cell quantity, the quantity of stromal progenitors contained in the ex vivo expanded product correlated with engraftment outcome (r = 0.551, P = 0.004). Our results indicate that ex vivo expanded bone marrow is capable of facilitating engraftment when combined with low doses of mobilized blood derived CD34(+) cells.     

Differential effect of corticosterone deficiency on the expression of LH, prolactin and insulin receptors on rat Leydig cells

The adverse effects of glucocorticoid deficiency on the expression of genes encoding Leydig cell surface receptors and the response to LH/prolactin/insulin to produce testosterone production are yet to be recognized. Following metyrapone-induced corticosterone deficiency, serum corticosterone, testosterone and insulin levels decrease, whereas serum prolactin exhibits a significant increase and serum LH remains unaltered. LH binding and LH receptor mRNA expression were not altered, but a significant decrease in PRL and insulin binding and in the mRNA expressions of their receptors were observed in corticosterone-deficient rats in vivo. Corticosterone deficiency significantly decreases the Leydig cellular basal as well as hormone-stimulated testosterone production in vitro. Simultaneous administration of corticosterone prevented its deficiency-induced changes in Leydig cells both in vivo and in vitro. Our results show that metyrapone-induced corticosterone deficiency impairs Leydig cell insulin and prolactin receptors, and their mRNA expression and the response of Leydig cells to LH/PRL/insulin on testosterone production.