α-Hederin inhibits G protein-coupled receptor kinase 2-mediated phosphorylation of ß2-adrenergic receptors.

BACKGROUND: Recently is has been shown that α- and ß-hederin increase the ß2-adrenergic responsiveness of alveolar type II cells (A549) and human airway smooth muscle cells (HASM), respectively, by inhibiting the internalization of ß2-adrenergic receptors (ß2AR) under stimulating conditions. Internalization of ß2AR is initiated by phosphorylations of certain serines and threonines by cAMP dependent protein kinase A (PKA) and G protein-coupled receptor kinases (GRK). PURPOSE: To evaluate the effect of α-hederin on PKA and GRK2 mediated phosphorylation of GFP-tagged ß2AR. STUDY DESIGN: To study this process we performed In-Cell Western using isoprenaline stimulated HEK293 cells overexpressing ß2AR as GFP fusion protein and specific antibodies against PKA (Ser345/346) and GRK2 (Ser355/356) phosphorylation sites. RESULTS: There was no effect found on the PKA mediated phosphorylation (n = 14) but we could show that α-hederin (1 µM, 12 h) significantly inhibits GRK2 mediated phosphorylation at Ser355/356 by 11 ± 5% (n ≥ 29, p ≤ 0.01) under stimulating conditions compared to the positive control. In Förster resonance energy transfer (FRET) experiments using the isolated kinases in solution α-hederin did not show any influence neither to GRK2 nor to PKA. CONCLUSION: Taken together, these results indicate that α-hederin acts as an indirect GRK2 inhibitor leading to a reduced homologous desensitization of ß2AR-GFP in HEK293 cells.

Pre-treatment with α-hederin increases ß-adrenoceptor mediated relaxation of airway smooth muscle.

Preparations of ivy leaves dry extract with secretolytic and bronchiolytic efficacy are widely used for the treatment of acute and chronic obstructive airway diseases. The mechanism by which ivy preparations improve lung functions is not fully understood. Here, we tested the influence of the three main saponins of ivy, α-hederin, hederacoside C and hederagenin, on the contraction and relaxation behaviour of isolated bovine tracheal smooth muscle strips by isometric tension measurements. None of the tested compounds altered histamine or methacholine-induced contraction of the smooth muscle strips. In contrast, the isoprenaline-induced relaxation of 100µM methacholine precontracted muscle strips was significantly enhanced when pre-treated with 1µM of α-hederin for 18h. The pre-treatment with hederacoside C or hederagenin had no effect on isoprenaline-induced relaxation. For the first time the bronchiolytic effect of α-hederin was demonstrated by isometric tension measurements using bovine tracheal smooth muscle strips. α-Hederin increases isoprenaline-induced relaxation indirectly, probably by inhibiting heterologous desensitization induced by high concentrations of muscarinic ligands like methacholine.

Obesity prevention: recommended strategies and challenges.

Lifelong healthy weight maintenance is an important goal for all Americans to avoid the health problems associated with excessive body weight. In those who are overweight, even modest weight loss can reduce the risk of developing diseases associated with obesity. Federal health agencies, including the Centers for Disease Control and Prevention and the US Department of Agriculture, have recognized the critical nature of the obesity epidemic and the importance of lifelong weight management. As a result, these agencies have published evidence-based dietary and exercise recommendations, as well as analyses of population-based efforts to achieve weight loss that specifically address strategies to maintain a healthy weight. Despite the availability of recommendations and increased public education efforts, however, obesity rates continue to climb. The rising prevalence of obesity in the United States suggests that current efforts to control weight have been inadequate. Large-scale prevention programs that involve interventions targeting individuals as well as the larger community, including initiatives spearheaded through workplaces and schools, are needed to control weight and reduce the risk of long-term health consequences.

Alpha-hederin, but not hederacoside C and hederagenin from Hedera helix, affects the binding behavior, dynamics, and regulation of beta 2-adrenergic receptors.

Hederacoside C, alpha-hederin, and hederagenin are saponins of dry extracts obtained from the leaves of ivy (Hedera helix L.). Internalization of beta(2)-adrenergic receptor-GFP fusion proteins after stimulation with 1 microM terbutaline was inhibited by preincubation of stably transfected HEK293 cells with 1 microM alpha-hederin for 24 h, whereas neither hederacoside C nor hederagenin (1 microM each) influenced this receptor regulation. After incubation of A549 cells with 5 nM Alexa532-NA, two different diffusion time constants were found for beta(2)AR-Alexa532-NA complexes by fluorescence correlation spectroscopy. Evaluation of the autocorrelation curve revealed diffusion time constants: tau(bound1) = 1.4 +/- 1.1 ms (n = 6) found for receptor-ligand complexes with unrestricted lateral mobility, and tau(bound2) = 34.7 +/- 14.1 ms (n = 6) for receptor-ligand complexes with hindered mobility. The distribution of diffusion time constants was 24.3 +/- 2.5% for tau(bound1) and 8.7 +/- 4.3% for tau(bound2) (n = 6). A549 cells pretreated with 1 microM alpha-hederin for 24 h showed dose-dependent alterations in this distribution with 37.1 +/- 5.5% for tau(bound1) and 4.1 +/- 1.1% for tau(bound2). Simultaneously, the level of Alexa532-NA binding was significantly increased from 33.0 +/- 6.8 to 41.2 +/- 4.6%. In saturation experiments, alpha-hederin did not influence the beta(2)-adrenergic receptor density (B(max)), whereas the K(D) value for Alexa532-NA binding decreased from 36.1 +/- 9.2 to 24.3 +/- 11.1 nM. Pretreatment of HASM cells with alpha-hederin (1 microM, 24 h) revealed an increased intracellular cAMP level of 13.5 +/- 7.0% under stimulating conditions. Remarkably, structure-related saponins like hederacoside C and hederagenin did not influence either the binding behavior of beta(2)AR or the intracellular cAMP level.

Impact of lifestyle intervention on lost productivity and disability: improving control with activity and nutrition.

OBJECTIVE: To evaluate the effectiveness of a lifestyle intervention (LI) in reducing work loss and disability days. METHODS: One year randomized controlled trial of health plan members (n = 147) with type 2 diabetes and obesity. Members were randomized to modest-cost LI or usual care (UC). Outcomes were group differences in cumulative days either missed at work or with disability using Mann-Whitney U-tests and Poisson regression models. RESULTS: LI reduced the risk of workdays lost by 64.3% (P

Cost-effectiveness of diabetes education.

Diabetes cost the United States an estimated $132 billion in 2002 as a result of medical costs and lost productivity. Because of these overwhelming numbers, the cost-efficacy of preventing and treating diabetes, and the cost-effectiveness of diabetes self-management training and medical nutrition therapy to treat diabetes are receiving increased attention. This article reviews the published research concerning the cost-effectiveness of diabetes education.

Effects of lifestyle intervention on health care costs: Improving Control with Activity and Nutrition (ICAN).

OBJECTIVE: To evaluate program and health care costs of a lifestyle intervention in a high-risk obese population. DESIGN: Twelve-month randomized controlled trial comparing lifestyle case management to usual care. SUBJECTS/SETTING: Health plan members (n=147) with obesity (body mass index >/=27) and type 2 diabetes. INTERVENTION: Lifestyle case management entailed individual and group education, support, and referrals by registered dietitians. Those in the usual-care group received educational material. MAIN OUTCOME MEASURES: Medical and pharmaceutical health care costs reimbursed by the participant's primary insurance company. STATISTICAL ANALYSIS: Total costs were modeled using the four-equation model using previous year cost as a predictor. RESULTS: Net cost of the intervention was $328 per person per year. After incorporating program costs, mean health plan costs were $3,586 (95% confidence interval [CI]: -$8,036, -$25, P<0.05) lower in case management compared to usual care. The difference was driven by group differences in medical (-$3,316, 95% CI: -$7,829 to -$320, P<0.05) but not pharmaceutical costs (-$239, 95% CI: -$870 to $280, not statistically significant), with fewer inpatient admissions and costs among case management compared with usual care (admission prevalence: 2.8% vs 22.5% respectively, P<0.001). CONCLUSION: Addition of a modest-cost, registered dietitian-led lifestyle case-management intervention to usual medical care did not increase health care costs and suggested modest cost savings among obese patients with type 2 diabetes. Larger trials are needed to determine whether these results can be replicated in a broader population. The findings can be judiciously applied to support that the addition of a registered dietitian-led lifestyle case-management program to medical care does not increase health care costs.