Mechanochemical Synthesis of Resveratrol-Piperazine Cocrystals.

The 1:1 resveratrol-piperazine cocrystal was successfully synthesized and scaled-up to 300 g scale with the mechanochemical method, as a result of investigating key process parameters, namely the solvent and the grinding time. The use of water, ethanol or ethanol-water mixtures and reaction times up to 50 min were evaluated relative to the dry grinding process. Cocrystal formation and purity were monitored through X-ray diffraction and calorimetry measurements.

Synthesis and biological evaluation of novel tamoxifen analogues.

A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines.

Tryptamine serves as a proligand of the AhR transcriptional pathway whose activation is dependent of monoamine oxidases.

The function of the aryl hydrocarbon receptor (AhR) in mediating the biological effect to environmental pollutants is well established. However, accumulated evidence indicates a wide range of physiological and pathological functions mediated by the AhR, suggesting the existence of endogenous AhR ligand(s). The nature of an AhR ligand remain elusive; however, it is known that the AhR is activated by several compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin or the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole.

The aryl hydrocarbon receptor ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene regulate distinct genetic networks.

The two estrogen receptor isoforms ERα and ERβ mediate biological effects of estrogens, but are also targets for endocrine disruptive chemicals (EDCs), compounds that interfere with hormonal signaling. 3-Methylcholanthrene (3-MC) and dioxin (TCDD) are EDCs and prototypical aryl hydrocarbon receptor (AhR) agonists, and can inhibit ER signaling. However, in contrast to TCDD, 3-MC gives rise to metabolites with estrogenic properties.

Epigenetic regulation of glucose transporter 4 by estrogen receptor β.

Glucose transporter 4 (Glut4) is an important regulator of cellular glucose uptake in adipose tissue and skeletal muscle. The estrogen receptors α and β (ERα and ERβ) have been shown to regulate Glut4. However, the regulatory mechanisms are unclear, and there are conflicting results about the effects of the two ER isoforms on Glut4 activity.

The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α.

XAP2 (also known as aryl hydrocarbon receptor interacting protein, AIP) is originally identified as a negative regulator of the hepatitis B virus X-associated protein. Recent studies have expanded the range of XAP2 client proteins to include the nuclear receptor family of transcription factors. In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells.

A single dose of enterolactone activates estrogen signaling and regulates expression of circadian clock genes in mice.

Enterolactone (EL) is an enterolignan produced by gut microbiota from dietary plant lignans. Epidemiological and experimental studies suggest that EL and plant lignans may reduce the risk of breast and prostate cancer as well as cardiovascular disease. These effects are thought to at least in part involve modulation of estrogen receptor activity.

AhR and ARNT modulate ER signaling.

The aryl hydrocarbon receptor (AhR), in complex with its binding partner ARNT, mediates the cellular response to xenobiotic compounds such as the environmental pollutant dioxin. In addition, the AhR has important regulatory roles in normal physiology. For instance, there is extensive data showing an intricate relationship between the AhR and estrogen receptor (ER) pathways.

Regulation of estrogen receptor beta activity and implications in health and disease.

Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ER beta ) mediates many of the physiological effects of estrogens. As ER beta is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ER beta regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor.

The endogenous retinoid metabolite S-4-oxo-9-cis-13,14-dihydro-retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo.

Retinoic acid receptor (RAR) and retinoid X receptor are ligand-induced transcription factors that belong to the nuclear receptor family. The receptors are activated by small hydrophobic compounds, such as all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Interestingly, these receptors are also targets for a number of exogenous compounds.

Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders.

Endocrine disruption refers to the ability of chemicals to interfere with hormonal systems, and has raised considerable concern in recent years. Endocrine disruptive chemicals (EDCs) pose a documented risk to wildlife and have the potential to negatively influence human health. This review focuses on the molecular mechanisms of endocrine disruption and the possible involvement of EDCs in metabolic disorders.

Receptors mediating toxicity and their involvement in endocrine disruption.

Many toxic compounds exert their harmful effects by activating of certain receptors, which in turn leads to dysregulation of transcription. Some of these receptors are so called xenosensors. They are activated by external chemicals and evoke a cascade of events that lead to the elimination of the chemical from the system.

An amphioxus orthologue of the estrogen receptor that does not bind estradiol: insights into estrogen receptor evolution.

Background: The origin of nuclear receptors (NRs) and the question whether the ancestral NR was a liganded or an unliganded transcription factor has been recently debated. To obtain insight into the evolution of the ligand binding ability of estrogen receptors (ER), we comparatively characterized the ER from the protochordate amphioxus (Branchiostoma floridae), and the ER from lamprey (Petromyzon marinus), a basal vertebrate.

Results: Extensive phylogenetic studies as well as signature analysis allowed us to confirm that the amphioxus ER (amphiER) and the lamprey ER (lampER) belong to the ER group.

Expression levels of estrogen receptor beta are modulated by components of the molecular clock.

Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERbeta) is, together with ERalpha, a member of the nuclear receptor superfamily and a key mediator of estrogen action.

3-Methylcholanthrene displays dual effects on estrogen receptor (ER) alpha and ER beta signaling in a cell-type specific fashion.

The biological effects of 17beta-estradiol (E(2)) are mediated by the two estrogen receptor (ER) isoforms ERalpha and ERbeta. These receptors are ligand-inducible transcription factors that belong to the nuclear receptor superfamily. These receptors are also targets for a broad range of natural and synthetic compounds that induce ER activity, including dietary compounds, pharmaceuticals, and various types of environmental pollutants such as bisphenols and polychlorinated hydroxy-biphenyls.

The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin.

The biological effects of dioxins are mediated by the aryl hydrocarbon receptor (AhR) and its dimerization partner, the AhR nuclear translocator (ARNT), and include interference with hormonal signaling pathways like the response to estrogens. The effects of estrogens are mediated by two estrogen receptor (ER) isoforms, ERalpha and ERbeta, which belong to the family of nuclear receptors. We have previously shown that ARNT can act as coactivator of the ERs.

Diet-derived polyphenol metabolite enterolactone is a tissue-specific estrogen receptor activator.

Numerous dietary compounds can modify gene expression by binding to the members of the nuclear receptor superfamily of transcription factors. For example, dietary polyphenols, such as soy isoflavones genistein and daidzein, modulate the activity of the estrogen receptors (ERs)-alpha and ERbeta. An additional class of dietary polyphenols that modulate cellular signaling pathways are lignans, compounds that are common constituents of Western diets.

The co-chaperone XAP2 is required for activation of hypothalamic thyrotropin-releasing hormone transcription in vivo.

Transcriptional control of hypothalamic thyrotropin-releasing hormone (TRH) integrates central regulation of the hypothalamo-hypophyseal-thyroid axis and hence thyroid hormone (triiodothyronine (T(3))) homeostasis. The two beta thyroid hormone receptors, TRbeta1 and TRbeta2, contribute to T(3) feedback on TRH, with TRbeta1 having a more important role in the activation of TRH transcription. How TRbeta1 fulfils its role in activating TRH gene transcription is unknown.

The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription.

The biological effects of estrogens are mediated by the estrogen receptors ERalpha and ERbeta. These receptors regulate gene expression through binding to DNA enhancer elements and subsequently recruiting factors such as coactivators that modulate their transcriptional activity. Here we show that ARNT (aryl hydrocarbon receptor nuclear translocator), the obligatory heterodimerization partner for the aryl hydrocarbon receptor and hypoxia inducible factor 1alpha, functions as a potent coactivator of ERalpha- and ERbeta- dependent transcription.

Two parallel pathways mediate cytoplasmic localization of the dioxin (aryl hydrocarbon) receptor.

The dioxin receptor is a ligand-dependent transcription factor that mediates the biological effects of dioxin and related environmental pollutants. In the absence of ligand the receptor is present in the cytoplasmic compartment of the cell associated with the hsp90-dependent chaperone complex. This complex regulates several functions of the receptor such as ligand binding and nuclear import.

Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90.

The dioxin (aryl hydrocarbon) receptor is a ligand inducible transcription factor, which mediates cellular responses to a variety of xenobiotic compounds such as dioxins. In the absence of ligand the receptor is associated with the molecular chaperone hsp90 and the tetratricopeptide repeat (TPR-) containing immunophilin-like protein XAP2. XAP2 has been implicated in regulation of the intracellular localization of the dioxin receptor and protection of the receptor against degradation.