Selenite Inhibits Notch Signaling in Cells and Mice.

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta-Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.

Ph-activated nano-amorphous calcium phosphate-based cement to reduce dental enamel demineralization.

Enamel demineralization is destructive, esthetically compromised, and costly complications for orthodontic patients. Nano-sized amorphous calcium phosphate (NACP) has been explored to address this challenge. The 20% NACP-loaded ortho-cement notably exhibited favorable behavior on reducing demineralization of enamel around brackets in a caries model designed to simulate the carious attack. The 20% NACP-loaded ortho-cement markedly promotes higher calcium and phosphate release at a low pH, and the mineral loss was almost two fold lower and carious lesion depth decreased the by 1/3. This novel approach is promising co-adjuvant route for prevention of dental caries dissemination in millions of patients under orthodontic treatment.

National Athletic Trainers' Association position statement: evaluation of dietary supplements for performance nutrition.

OBJECTIVES: To help athletic trainers promote a "food-first" philosophy to support health and performance, understand federal and sport governing body rules and regulations regarding dietary supplements and banned substances, and become familiar with reliable resources for evaluating the safety, purity, and efficacy of dietary supplements. BACKGROUND: The dietary supplement industry is poorly regulated and takes in billions of dollars per year. Uneducated athletes need to gain a better understanding of the safety, eligibility, and efficacy concerns associated with choosing to take dietary supplements. The athletic trainer is a valuable athletic team member who can help in the educational process. In many cases, athletic trainers are asked to help evaluate the legality, safety, and efficacy of dietary supplements. For this position statement, our mission is to provide the athletic trainer with the necessary resources for these tasks. RECOMMENDATIONS: Proper nutrition and changes in the athlete's habitual diet should be considered first when improved performance is the goal. Athletes need to understand the level of regulation (or lack thereof) governing the dietary supplement industry at the international, federal, state, and individual sport-participation levels. Athletes should not assume a product is safe simply because it is marketed over the counter. All products athletes are considering using should be evaluated for purity (ie, truth in labeling), safety, and efficacy.

GABA supplementation and growth hormone response.

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hormones, GH-releasing hormone and somatostatin. These hormones are subject to modulation by a host of neurotransmitters and are the final mediators of endocrine and neural influences for GH secretion. Interest in the possible role of γ-aminobutyric acid (GABA) in the control of GH secretion began decades ago. However, interest in its role as an ergogenic aid is only recent. It is well accepted that GABAergic neurons are found in the hypothalamus and recent evidence suggests its secretion within the pituitary itself. Inhibition of GABA degradation and blockade of GABA transmission as well as administration of GABA and GABA mimetic drugs have all been shown to affect GH secretion. However, there are many controversial findings. The effects may depend on the site of action within the hypothalamic-pituitary unit and the hormonal milieu. Experimental and clinical evidence support the presence of a dual action of GABA - one mediated centrally, the other exerted directly at the pituitary level. The two sites of action may be responsible for excitatory and inhibitory effects of GABA on GH secretion. This chapter will outline the anatomical basis for possible influences of GABA on GH secretion and present evidence for a role of GABA in the control of GH release by actions at either hypothalamic or pituitary sites. The potential ergogenic benefits of oral GABA supplementation will also be discussed.

N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of µ/kappa-opioid heteromers.

Numerous G protein-coupled receptors (GPCRs) have been shown to form heteromeric receptors in cell-based assays. Among the many heteromers reported in the opioid receptor family are µ/κ, κ/δ, and µ/δ. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been established. Here we report a unique example of a ligand, N-naphthoyl-ß-naltrexamine (NNTA) that selectively activates heteromeric µ/κ-opioid receptors in HEK-293 cells and induces potent antinociception in mice. NNTA was an exceptionally potent agonist in cells expressing µ/κ-opioid receptors. Intriguingly, it was found to be a potent antagonist in cells expressing only µ-receptors. In the mouse tail-flick assay, intrathecal (i.t.) NNTA produced antinociception that was ~100-fold greater than by intracerebroventricular (i.c.v.) administration. The κ-antagonist, norBNI, decreased the i.t. potency, and the activity was virtually abolished in µ-opioid receptor knockout mice. No tolerance was induced i.t., but marginal tolerance (3-fold) was observed via the i.c.v. route. Moreover, NNTA produced neither significant physical dependence nor place preference in the ED50 dose range. Taken together, this work provides an important pharmacologic tool for investigating the in vivo functional relevance of heteromeric µ/κ-opioid receptors and suggests an approach to potent analgesics with fewer deleterious side effects.

A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm.

We have explored the concept of a molecular extender arm attached to a κ opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact with a complementary group on a neighboring opioid receptor. The molecular arm containing a terminal amine group was lengthened incrementally from 11 up to 18 atoms. Increasing the number of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency. In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16-atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED50 ratio of ∼130. Further lengthening led to a decreased ED50 ratio. In vivo selective antagonist studies of KDA-16 revealed that κ and δ opioid receptors were responsible for the greatly enhanced i.t. potency. Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate κ-δ heteromers. These data are consistent with the reported possible presence of heteromeric κ-δ opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics.

Changes in lower-leg blood flow during warm-, cold-, and contrast-water therapy.

OBJECTIVE: To examine arterial blood flow in the lower leg during warm-, cold-, and contrast-water therapy. DESIGN: A crossover trial with repeated measurements on the dependent variable. SETTING: Hydrotherapy area of a climate-controlled sports medicine clinic. PARTICIPANTS: A volunteer sample of 24 healthy men. INTERVENTION: Four randomly assigned treatments were performed on each subject on consecutive days. MAIN OUTCOME MEASURE: Arterial blood flow (mL per 100mL/min) from baseline measurements were recorded in a 3-minute to 1-minute on-off ratio for 20 minutes by using strain gauge plethysmography. RESULTS: Contrast therapy produced fluctuations in blood flow throughout the 20-minute treatment. Warm-water therapy (40 degrees C) resulted in significant (P < .001) changes in blood flow compared with the control and contrast conditions. Cold-water therapy (13 degrees C) did not produce significantly decreased blood flow as compared with the control condition. CONCLUSIONS: We suggest that further studies involving contrast therapy to the lower leg in injured populations be carried out to determine whether our initial findings are clinically relevant.

The Safety and Efficacy of Anabolic Steroid Precursors: What is the Scientific Evidence?

OBJECTIVE: Anabolic steroid precursors have gained widespread popularity as ergogenic supplements. Advertisements for these supplements claim that they increase endogenous testosterone production and protein synthesis, resulting in increased lean body mass and strength during training. At this time scientific support is limited, but the potential for serious side effects exists and the popularity of these supplements continues to grow. This review provides rationales for the ergogenic claims regarding steroid precursors and compares claims with data from scientifically controlled investigations. DATA SOURCES: A search of MEDLINE and SPORT Discus from 1960 to 2001 using the key words dehydroepiandrosterone, androstenedione, and androstenediol in combination with testosterone, estrogen, exercise, performance, and side effects. DATA SYNTHESIS: Although fairly new to the athletic community, steroid precursors have been used as ergogenic or anabolic agents for quite some time. Suggested gains in strength and lean body mass are attributed to an increase in the endogenous production of testosterone and enhanced protein synthesis. Most of the scientific data, however, do not support manufacturers' ergogenic claims, and the potential for serious side effects, such as decreased high-density lipoprotein cholesterol and increased estrogen concentrations, has been associated with precursor use. Thus, the safety and efficacy of these supplements must be questioned. CONCLUSIONS/RECOMMENDATIONS: It appears that the risks associated with the use of anabolic steroid precursors outweigh any possible ergogenic benefits. Furthermore, these supplements are banned by most athletic organizations. Thus, it is extremely important that athletic trainers are able to educate athletes on these issues so they can continue to perform at an optimum level in a safe and healthy manner.