Clinical and nutritional benefits of cysteine-enriched protein supplements.

PURPOSE OF REVIEW: To review recently published research into the use of dietary cysteine and/or its derivatives as functional food supplements that will enhance antioxidant status and improve outcome in certain diseases. RECENT FINDINGS: L-cysteine is now widely recognized as a conditionally essential or (indispensible) sulphur amino acid. It plays a key role in the metabolic pathways involving methionine, taurine and glutathione (GSH), and may help fight chronic inflammation by boosting antioxidant status. In stressed and inflammatory states, sulphur amino acid metabolism adapts to meet the increased requirements for cysteine as a rate-limiting substrate for GSH. Critically ill patients receiving enteral or parenteral nutrition, enriched with cysteine, exhibit decreased cysteine catabolism and improved GSH synthesis. The naturally occurring cysteine-rich proteins, whey or keratin, have the potential to be manufactured into high quality, high cysteine-containing functional foods for clinical investigation. SUMMARY: Cysteine-rich proteins, such as keratin, may have advantages over the simple amino acid or its derivatives, as nutraceuticals, to safely and beneficially improve antioxidant status in health and disease.

Process evaluation of a community-based intervention promoting multiple maternal and neonatal care practices in rural Nepal.

BACKGROUND: The challenge of delivering multiple, complex messages to promote maternal and newborn health in the terai region of Nepal was addressed through training Female Community Health Volunteers (FCHVs) to counsel pregnant women and their families using a flipchart and a pictorial booklet that was distributed to clients. The booklet consists of illustrated messages presented on postcard-sized laminated cards that are joined by a ring. Pregnant women were encouraged to discuss booklet content with their families. METHODS: We examined use of the booklet and factors affecting adoption of practices through semi-structured interviews with district and community-level government health personnel, staff from the Nepal Family Health Program, FCHVs, recently delivered women and their husbands and mothers-in-law. RESULTS: The booklet is shared among household members, promotes discussion, and is referred to when questions arise or during emergencies. Booklet cards on danger signs and nutritious foods are particularly well-received. Cards on family planning and certain aspects of birth preparedness generate less interest. Husbands and mothers-in-law control decision-making for maternal and newborn care-seeking and related household-level behaviors. CONCLUSIONS: Interpersonal peer communication through trusted community-level volunteers is an acceptable primary strategy in Nepal for promotion of household-level behaviors. The content and number of messages should be simplified or streamlined before being scaled-up to minimize intervention complexity and redundant communication.

Farnesylthiosalicylic acid: inhibition of proliferation and enhancement of apoptosis of hormone-dependent breast cancer cells.

Farnesyltransferase inhibitors (FTIs) are being developed to block Ras-mediated actions, but current data suggest that the FTIs act through other non-Ras pathways. A new agent, farnesylthiosalicylic acid (FTS), blocks the binding of Ras to membrane acceptor sites and causes a marked reduction in Ras levels. Accordingly, FTS could be a useful new agent for the treatment of hormone-dependent breast cancer. We examined the dose-response effects of FTS on the growth of MCF-7 breast cancer cells in vitro and in vivo. Further, we dissected out its specific effects on cell proliferation and apoptosis by measuring BrdU incorporation into DNA and by using an ELISA assay to quantitate the magnitude of apoptosis. FTS and its solubilized conjoiner FTS-cyclodextrin markedly inhibited cell growth in MCF-7 breast cancer cells in culture and in xenografts. This agent exerted dual effects to reduce cell proliferation as assessed by BrdU incorporation and to enhance apoptosis as quantitated by ELISA assay. These data suggest that FTS is a promising agent to be developed for treatment of hormone-dependent breast cancer.

Are birth-preparedness programmes effective? Results from a field trial in Siraha district, Nepal.

The birth-preparedness package (BPP) promotes active preparation and decision-making for births, including pregnancy/postpartum periods, by pregnant women and their families. This paper describes a district-wide field trial of the BPP implemented through the government health system in Siraha, Nepal, during 2003-2004. The aim of the field trial was to determine the effectiveness of the BPP to positively influence planning for births, household-level behaviours that affect the health of pregnant and postpartum women and their newborns, and their use of selected health services for maternal and newborn care. Community health workers promoted desired behaviours through inter-personal counselling with individuals and groups. Content of messages included maternal and newborn-danger signs and encouraged the use of healthcare services and preparation for emergencies. Thirty-cluster baseline and endline household surveys of mothers of infants aged less than one year were used for estimating the change in key outcome indicators. Fifty-four percent of respondents (n=162) were directly exposed to BPP materials while pregnant. A composite index of seven indicators that measure knowledge of respondents, use of health services, and preparation for emergencies increased from 33% at baseline to 54% at endline (p=0.001). Five key newborn practices increased by 19 to 29 percentage points from baseline to endline (p values ranged from 0.000 to 0.06). Certain key maternal health indicators, such as skilled birth attendance and use of emergency obstetric care, did not change. The BPP can positively influence knowledge and intermediate health outcomes, such as household practices and use of some health services. The BPP can be implemented by government health services with minimal outside assistance but should be comprehensively integrated into the safe motherhood programme rather than implemented as a separate intervention.

The novel Ras antagonist, farnesylthiosalicylate, suppresses growth of prostate cancer in vitro.

BACKGROUND: The majority of men with advanced prostate cancer (PCa) respond to androgen deprivation therapy (ADT) with objective evidence of tumor regression. However, these tumors will regrow in the presence of low-androgen levels after 12-18 months. Regrowth after ADT is associated with upregulation of growth factor (GF) mediated pathways. The compound farnesylthiosalicylate (FTS), a specific antagonist of the 21 kDa Ras protein, suppresses GF signaling and it might be a useful therapy against advanced PCa. METHODS: We measured androgen and GF dependent growth of androgen dependent LNCaP and androgen hypersensitive CWR-R1 PCa cells in response to specific inhibitors of GF pathways, including FTS. Inhibition of GF mediated signaling and cell-cycle pathways was confirmed by Western blotting of extracts from treated cells. RESULTS: Both LNCaP and CWR-R1 cells were dependent on GF signaling pathways for cell growth. FTS, as well as suppressing cell growth, inhibited GF signaling pathway activity and reduced the levels of E2F1, p-Rb, and p-cdc2, all GF dependent mediators of cell-cycle progression. CONCLUSIONS: These data suggest that FTS might be a useful agent against PCa that has relapsed after ADT.

Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation.

E2 rapidly activates MAPK in breast cancer cells, and the mechanism for this effect has not been fully identified. Since growth factor-induced MAPK activation involves signaling via the adapter protein Shc (Src-homology and collagen homology) and its association with membrane receptors, we hypothesized that breast cancer cells utilize similar signaling mechanisms in response to E2. In the present study, we demonstrated that E2 rapidly induced Shc phosphorylation and Shc-Grb2 (growth factor receptor binding protein 2)-Sos (son of sevenless) complex formation in MCF-7 cells. Overexpression of dominant negative Shc blocked the effect of E2 on MAPK, indicating a critical role of Shc in E2 action. Using selective inhibitors, we also demonstrated that ERalpha and Src are upstream regulators of Shc. A rapid physical association between ERalpha and Shc upon E2 stimulation further evidenced the role of ERalpha on Shc activation. Mutagenesis studies showed that the phosphotyrosine binding and SH2 domains of Shc are required to interact with the activation function 1, but not activation function 2, domain of ERalpha. Using a glutathione-S-transferase-Shc pull-down assay, we demonstrated that this ERalpha-Shc association was direct. Biological consequences of this pathway were further investigated at the genomic and nongenomic levels. E2 stimulated MAPK-mediated Elk-1 transcriptional activity. Confocal microscopy studies showed that E2 rapidly induced formation of membrane ruffles, pseudopodia, and ERalpha membrane translocation. The E2-induced morphological changes were prevented by antiestrogen. Together our results demonstrate that ERalpha can mediate the rapid effects of E2 on Shc, MAPK, Elk-1, and morphological changes in breast cancer cells