Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites.

Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro.

Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2.

The transcription factor Nrf2 regulates the basal and inducible expression of a battery of cytoprotective genes. Whereas numerous Nrf2-inducing small molecules have been reported, very few chemical inhibitors of Nrf2 have been identified to date. The quassinoid brusatol has recently been shown to inhibit Nrf2 and ameliorate chemoresistance in vitro and in vivo.

The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.

The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation.

Neurometabolite effects of response to quetiapine and placebo in adolescents with bipolar depression.

Objective: Mood stabilizers have been reported to affect brain concentrations of myo-inositol (mI) and N-acetylaspartate (NAA). We examined the effects of quetiapine (QUET), an atypical antipsychotic, on these neurochemicals, and potential predictors of response to QUET in adolescents with bipolar depression.

Methods: Twenty-six adolescents with bipolar depression participated in an 8-week placebo-controlled trial of QUET monotherapy.

Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.

Objectives: This study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission.

Method: Adolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 μg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points.

A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder.

Objective: To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar I disorder.

Method: Thirty-two adolescents (ages 12-18 years) with a depressive episode associated with bipolar I disorder were randomized to eight weeks of double-blind treatment with quetiapine, 300-600 mg/day, or placebo. This two-site study was conducted from March 2006 through August 2007.

Lithium treatment effects on Myo-inositol in adolescents with bipolar depression.

Background: The neurochemical effects of lithium in adolescents with bipolar disorder largely are unknown. This study used proton magnetic resonance spectroscopy (1H MRS) to identify the in vivo effects of lithium on myo-inositol (mI) concentrations in adolescent bipolar depression.

Methods: Twenty-eight adolescents (12-18 years old) with bipolar I disorder, current episode depressed, received open-label lithium 30 mg/kg, adjusted to achieve serum levels of 1.

Open-label lithium for the treatment of adolescents with bipolar depression.

Objectives: To investigate the effectiveness and tolerability of lithium for the treatment of acute depression in adolescents with bipolar disorder. We hypothesized that patients receiving open-label treatment with lithium during a 6-week period would experience a statistically and clinically significant decrease in depressive symptoms and tolerate lithium treatment fairly well.

Method: Twenty-seven adolescents (12-18 years old) with an episode of depression associated with bipolar disorder type I received open-label lithium 30 mg/kg (twice-daily dosing), which was adjusted to achieve a therapeutic serum level (1.

The S-Caine peel: a novel topical anesthetic for cutaneous laser surgery.

Background: The S-Caine peel (Zars, Inc., Salt Lake City, UT) is a novel eutectic lidocaine/tetracaine mixture that is applied as a cream, drying upon exposure to air to form a flexible film that can be peeled off easily. The patented formulation can be used to anesthetize the skin prior to a variety of cutaneous procedures.