Neurosteroids and their receptors in ischemic stroke: From molecular mechanisms to therapeutic opportunities.

Extensive progress has been made to understand the pathophysiology of stroke but it is still a major cause of mortality and disability worldwide. There are few strategies for the treatment of this disease and the use of thrombolytic tissue plasminogen activator is limited due to the narrow time window. However, the administration of neuroactive steroids could be considered as a potential treatment approach to decrease ischemia-induced lesions. Neurosteroids receptors play important roles in neuroprotection mediated by these hormones. Membrane and intracellular receptors are both involved in the protective effects of estrogen and progesterone on ischemic brain injury. The intracellular receptors often regulate the gene transcription while the membrane receptors act through modulation of signal transduction pathways. Besides, allopregnanolone acts as a potent positive modulator of the GABA receptor. Moreover, the neuroprotective effects of vitamin D and dehydroepiandrosterone (DHEA) are mediated through the binding to vitamin D receptor (VDR) and several intracellular and membrane receptors, respectively. Activation of VDR could affect various processes including apoptosis, calcium metabolism, oxidative stress, immune modulation, inflammation and detoxification, and DHEA can modulate neurogenesis, neuronal function, and mitochondrial oxidative capacity. The present study aimed to describe the neuroprotective roles of the aforementioned neurosteroids with a focus on their receptors against ischemic stroke.

An Assay on the Possible Effect of Essential Oil Constituents on Receptors Involved in Women's Hormonal Health and Reproductive System Diseases.

Aromatic herbal remedies, hydrosols, and essential oils are widely used for women's hormonal health. Scientific investigation of their major constituents may prevent unwanted infertility cases, fetal abnormalities, and drug-herb interactions. It also may lead to development of new medications. A list of 265 volatile molecules (mainly monoterpenes and sesquiterpenes) were prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils that are used for women's hormonal and reproductive health conditions. The PDB (protein data bank) files of the receptors (136 native PDB files) that involve with oxytocin, progesterone, estrogen, prolactin, acetyl choline, androgen, dopamine, human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, aromatase, and HER2 receptors were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interactions of the ligands with the receptors. Drug likeliness was investigated for the most active molecules using DruLiTo software. Aristola-1(10),8-diene, bergapten (5-methoxypsoralen), α-bergamotene, bicyclogermacrene, α-bisabolol oxide A, α-bisabolone oxide, p-cymen-8-ol, 10-epi elemol, α-elemol, ß-eudesmol, 7-epi-ß-eudesmol, ficusin, ß-humulene, methyl jasmonate, nerolidol, pinocarvone, (+)-spathulenol, and thujone had better interactions with some androgen, aromatase, estrogen, progesterone, HER2, AChR, and/or dopamine receptors. Most of these molecules had an acceptable drug likeliness except for α-bergamotene, bicyclogermacrene, ß-humulene, and aristola-1(10),8-diene. Some volatile natural molecules can be considered as lead compound for drug development to treat hormonal conditions.

Corticosterone Replacement Alleviates Hippocampal Neuronal Apoptosis and Spatial Memory Impairment Induced by Dexamethasone via Promoting Brain Corticosteroid Receptor Rebalance after Traumatic Brain Injury.

The balance of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) is indispensable for maintaining the normal function and structure of the hippocampus. However, changes in GR/MR and their effect on the survival of hippocampal neurons after traumatic brain injury (TBI) are still unclear. Previous studies have indicated that high-dose glucocorticoids (GC) aggravate hippocampal neuronal damage after TBI. We hypothesize that the imbalance of GR/MR expression and activation caused by injury and irrational use of dexamethasone (DEX) aggravates post-traumatic hippocampal apoptosis and spatial memory dysfunction, but that restoration by refilling MR and inhibiting GR promotes the survival of neurons. Using rat controlled cortical impact model, we examined the plasma corticosterone (CORT), corticosteroid receptor expression, apoptosis, and cell loss in the hippocampus, and, accordingly, the spatial memory after TBI and GC treatment within 7 days. Plasma CORT, MR, and GR expression level were significantly reduced at 2 days after TBI. Accordingly, the number of apoptotic cells also peaked at 2 days. Compared with the TBI control group, DEX treatment (5 mg/kg) significantly reduced plasma CORT, upregulated GR expression, and increased the number of apoptotic cells and cell loss, whereas CORT replacement (0.3 mg/kg) upregulated MR expression, inhibited apoptosis, and improved spatial memory. The deleterious and protective effects of DEX and CORT were counteracted by spironolactone and mifepristone respectively. The results suggest that inhibition of GR by RU486 or the refilling of MR by CORT protects hippocampal neurons and alleviates spatial memory impairment via promoting GR/MR rebalancing after TBI.

Characterizing the potential estrogenic and androgenic activities of two disinfection byproducts, mono-haloacetic acids and haloacetamides, using in vitro bioassays.

Exposure to disinfection byproducts (DBPs) is potentially related to cytotoxic, genotoxic, mutagenic, and tumorigenic effects in humans, in addition to their adverse effects on the environment. However, their impacts on endocrine disruption, especially reproductive toxicity, remain largely unknown. In this study, the estrogenic and androgenic activities of DBPs and corresponding antagonistic activities were investigated using a yeast-based reporter assay, focusing on haloacetic acids and haloacetamides. We also examined the cytotoxicity of DBPs and mechanisms of antagonistic activities. Of the DBPs assayed, iodoacetamide (IAM) and bromoacetamide (BAM) were the most cytotoxic, with LC50 values of 0.0462 and 0.0537 mM, respectively, followed by chloroacetic acid (CAA; LC50 = 4.87 mM) and chloroacetamide (CAM; LC50 = 5.28 mM). Iodoacetic acid (IAA) and bromoacetic acid (BAA) were the least cytotoxic, with LC50 values of 5.52 and 6.35 mM, respectively. IAA (EC10 = 0.00573 mM; EC50 = 0.0215 mM) exhibited most potent estrogenic activity, and CAA (EC10 = 0.0434 mM) and BAM (EC10 = 0.0150 mM) showed weak estrogenic and androgenic activities, respectively. By contrast, IAM exhibited anti-estrogenic effects. These results suggest that DBPs interact with hormone receptors.

Nuclear Receptors: Recent Drug Discovery for Cancer Therapies.

Nuclear receptors (NRs) are transcription factors actively involved in many aspects of human physiology and pathology, serving as sensors of stimuli, master regulators of downstream molecular events, and hubs governing complex gene regulatory networks. The importance of various members of the NR superfamily in cancer has led to substantial efforts to target them therapeutically. Notably, drugs that block the action of estrogen receptor (ER)α in patients with ERα+ breast cancer or the androgen receptor (AR) in patients with prostate cancer have provided remarkable improvements in survival. However, there is continuing need for novel drugs that target ERα or the AR owing to resistance to established drugs, and there are also promising opportunities for targeting other NRs in cancer. In this review, we provide an overview of NR-based drug discovery in cancer and related resistance mechanisms, focusing on novel strategies for targeting well-established NR targets, including ERα, the AR, the glucocorticoid receptor, and the progesterone receptor, as well as opportunities to target other NRs that are attracting interest in immuno-oncology, such as liver X receptors, retinoic acid-related orphan receptors, and farnesoid X receptors.

Lipid Exchange Factors at Membrane Contact Sites in African Swine Fever Virus Infection.

African swine fever (ASF) is a hemorrhagic fever of wild and domestic pigs with a high rate of mortality. Originally endemic in Africa, this disease is currently disseminating in Europe and China, causing a large socioeconomic impact. ASF is caused by a DNA virus, African swine fever virus (ASFV). There is no vaccine available against ASFV, limiting the options for disease control. ASFV reorganizes intracellular membranes to generate viral factories (VFs) in order to amplify its genome. However, little is known about the process involved in the formation of these viral replication organelles. Membrane contact sites (MCSs) allow nonvesicular lipids and ion exchange between organelles. Lipid exchange to form VFs apparently requires a number of proteins at MCSs, such as the oxysterol-binding protein (OSBP), the acyl-coenzyme A binding domain containing 3 (ACBD3) and the phosphatidylinositol-phosphate-4-kinase III beta (PI4Kß). Itraconazole (ITZ) is an antifungal agent that targets sterol-transport molecules such as OSBP and OSBP-related protein 4 (ORP4). 25-Hydroxycholesterol (25-HC) inhibits lipid transport by high affinity binding OSBP. In this work, we analyzed the antiviral function of ITZ and 25-HC against ASFV in Vero cell cultures using the cell-adapted Ba71V isolate. ITZ and 25-HC decreased significantly ASFV replication. Our study revealed OSBP distribution in cytoplasmic membranes in uninfected Vero cells and to the periphery of VFs in infected cells. In addition, we showed that OSBP and OSBP-related proteins, PI4Kß and ACBD3 were recruited to VFs in the context ASFV infection.

Di(2-ethylhexyl)phthalate induces reproductive toxicity via JAZF1/TR4 pathway and oxidative stress in pubertal male rats.

Di(2-ethylhexyl)phthalate (DEHP) is a typical endocrine-disrupting chemical and reproductive toxicant. Although previous studies have attempted to describe the mechanism by which DEHP exposure results in reproductive dysfunction, few studies focused on puberty, a critical period of reproductive development, and the increased susceptibility to injury in adolescents. To elucidate the mechanism underpinning the testicular effects of DEHP in puberty, we sought to investigate the JAZF1/TR4 pathway in the testes of pubertal rats. Specifically, we focused on the role of the JAZF1/TR4 pathway in male reproduction, including the genes JAZF1, TR4, Sperm 1, and Cyclin A1. In the present study, rats were exposed to increasing concentrations of DEHP (0, 250, 500, and 1000 mg/kg/day) by oral gavages for 30 days. Then we assayed testicular zinc and oxidative stress levels. Our results indicated that DEHP exposure could lead to oxidative stress and decrease the contents of testicular zinc. Additionally, significant morphological changes and cell apoptosis were observed in testes exposed to DEHP, as identified by hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase-mediated nick and labeling assay. By measuring the expression levels of the above relevant genes by qPCR, we found the DEHP-induced increased expression of JAZF1 and decreased expression of TR4, Sperm 1, and Cyclin A1. Therefore, we have demonstrated that in vivo exposure to DEHP might induce reproductive toxicity in pubertal male rats through the JAZF1/TR4 pathway and oxidative stress.

Rapid Intracellular Zn2+ Dysregulation via Membrane Corticosteroid Receptor Activation Affects In Vivo CA1 LTP.

Involvement of membrane mineralocorticoid (MC) and glucocorticoid (GC) receptors in synaptic Zn2+ dynamics remains unclear. Here, we tested whether synaptic plasticity is affected by rapid intracellular Zn2+ dysregulation via membrane MC and GC receptor activation, in comparison with intracellular Ca2+ dysregulation. In anesthetized rats, extracellular Zn2+ level was increased under local perfusion of the hippocampal CA1 with 500 ng/ml corticosterone. In vivo CA1 long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses was attenuated by the pre-perfusion with corticosterone prior to tetanic stimulation, and the attenuation was canceled by co-perfusion with CaEDTA, an extracellular Zn2+ chelator, suggesting that corticosterone-induced increase in extracellular Zn2+ is involved in the subsequent attenuation of LTP. In rat brain slices, corticosterone-induced increases in extracellular and intracellular Zn2+ were blocked in the presence of spironolactone, a MC receptor antagonist that canceled corticosterone-induced attenuation of LTP. Mifepristone, a GC receptor antagonist, which canceled corticosterone-induced attenuation of LTP, also blocked corticosterone-induced increase in intracellular Zn2+, but not extracellular Zn2+. Moreover, corticosterone-induced decrease in phosphorylated CaMKII was restored in the presence of CaEDTA or spironolactone. These results indicate that glucocorticoid rapidly induces the increase in intracellular Zn2+, which occurs via membrane MC and GC receptor activations, and decreases phosphorylated CaMKII level, resulting in attenuating LTP. Membrane MC and GC receptors induce intracellular Zn2+ dysregulation via differential mechanisms. In contrast, glucocorticoid-induced intracellular Ca2+ dysregulation is not crucial for affecting LTP.

Cellular, transcriptomic and methylome effects of individual and combined exposure to BPA, BPF, BPS on mouse spermatocyte GC-2 cell line.

Environmental factors, particularly xenoestrogens adversely affect reproductive health and their main mechanism is based on steroid-signaling pathway alterations. The presence of bisphenol A (BPA) in the environment has been confirmed and it is about to be replaced by analogues such as bisphenol F (BPF) and bisphenol S (BPS). Whether the BPF and BPS exert similar adverse effects to BPA has become the subject of intense scientific scrutiny. The aim of the present study was to evaluate and compare the cellular, transcriptomic and methylome effects of exposure to BPA, BPF, BPS individually and in combination on GC-2 spermatocyte cell line. The results show that all studied compounds affect cell viability, induce apoptosis and cause cellular damage. BPA, BPF and BPS also influence GC-2 cell steroid receptor and steroidogenesis related genes expressions. In addition to specific molecular mechanisms, all studied compounds also increase global DNA methylation. Exposure to a combination of all the studied compounds caused comparable effects on cell culture to each of them examined separately. These data suggest that exposure to BPA and its main substitutes- BPF and BPS induced multitude of effects and hence, BPF and BPS are not safe alternative to BPA in terms of male reproductive health.

Essential oils of culinary herbs and spices activate PXR and induce CYP3A4 in human intestinal and hepatic in vitro models.

Essential oils (EOs) are extensively used in food industry, gastronomy and alternative medicine. They are multicomponent mixtures of bioactive compounds; hence, their potential for food-drug interactions is substantial. In this study, we investigated the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of pregnane X receptor (PXR) and expression of cytochrome P450 3A4 (CYP3A4), using human intestinal and hepatic in vitro models. All tested EOs activated PXR in intestinal LS180 cells transiently transfected with PXR, as revealed by a reporter gene assay. Consistently, all EOs induced CYP3A4 mRNA expression in PXR-transfected LS180 cells, primary human hepatocytes and wild-type hepatic progenitor HepaRG cells. EO-mediated induction of CYP3A4 mRNA expression was nullified in PXR-knock out HepaRG cells, suggesting the involvement of PXR in these effects. Collectively, we showed that EOs of culinary herbs and spices might be common activators of PXR and inducers of CYP3A4 at doses present in foods, thereby, they might have a potential for food-drug interactions. Follow-up studies are warranted to identify the bioactive constituents in the tested EOs.

Oxysterol-binding protein-related protein (ORP) 6 localizes to the ER and ER-plasma membrane contact sites and is involved in the turnover of PI4P in cerebellar granule neurons.

Oxysterol-binding protein (OSBP)-related proteins (ORPs) are conserved lipid binding proteins found in organisms ranging from yeast to mammals. Recent findings have indicated that these proteins mainly localize to contact sites of 2 different membranous organelles. ORP6, a member of the ORP subfamily III, is one of the least studied ORPs. Using approaches in molecular cell biology, we attempted to study the characteristics of ORP6 and found that ORP6 is abundantly expressed in mouse cultured neurons. Deconvolution microscopy of cultured cerebellar granular cells revealed that ORP6 is localized to the endoplasmic reticulum (ER) and ER-plasma membrane (PM) contact sites, where it co-localized with extended synaptotagmin2 (E-Syt2), a well-known ER-PM contact site marker. E-Syt2 also co-localized with ORP3, another subfamily III member, and ORP5, a subfamily IV member. However, ORP5 does not distribute to the same ER-PM contact sites as subfamily III members. Also, the co-expression of ORP3 but not ORP5 altered the distribution of ORP6 into the processes of cerebellar neurons. Immunoprecipitation demonstrated binding between the intermediate region of ORP6 and ORP3 or ORP6 itself. Additionally, the localization of ORP6 in the PM decreased when co-expressed with the intermediate region of ORP6, in which the pleckstrin homology (PH) domain and OSBP-related ligand binding domain (ORD) are deleted. Over-expression of this intermediate region shifted the location of a phophtidylinositol-4-phosphate (PI4P) marker from the Golgi to the PM. Knockdown of ORP6 resulted in the same shift of the PI4P marker. Collectively, our data suggests that the recruitment of ORP6 to ER-PM contact sites is involved in the turnover of PI4P in cerebellar granular neurons.

Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis.

INTRODUCTION: Endometriosis is a chronic estrogen and progestogen responsive inflammatory disease associated with pain symptoms and infertility. The medical therapy of endometriosis aims to induce decidualization within the hormonally dependent ectopic endometrium, and it is often administered to ameliorate women' pain symptoms or to prevent post-surgical disease recurrence. A variety of progestins have been used in monotherapy for the medical management of women with endometriosis. Areas covered: This review aims to offer the reader a complete overview of pharmacokinetic (PK) and clinical efficacy of progestins for the treatment of endometriosis. Expert opinion: Each progestin has a distinct PK parameters and pharmacodynamics affinity not only for progesterone receptor, but also for other steroid receptors, such as estrogen, androgen, and glucocorticoid. Moreover, progestins can also be delivered in different formulations. All these characteristics influence their final biological effect. Randomized, controlled, non-blinded studies support the use of oral progestin-only treatment for pelvic pain associated with endometriosis. Currently, the only two progestins approved by Food and Drug Administration (FDA) for the treatment of endometriosis are norethindrone acetate (NETA) and depot medroxyprogesterone acetate (DMPA).

Nuclear receptors as potential drug targets in osteoarthritis.

Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis.

Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes.

Phenobarbital (PB), a constitutive androstane receptor (CAR) activator, produces liver tumours in rodents by a mitogenic mode of action involving CAR activation. In this study, the hepatic effects of sodium phenobarbital (NaPB) were compared in male C57BL/6J wild type (WT) mice and in humanized mice, where both the mouse CAR and pregnane X receptor (PXR) have been replaced by their human counterparts (hCAR/hPXR mice). Investigations were also performed in cultured male C57BL/6J and CD-1 mouse, male Sprague-Dawley rat and male and female human hepatocytes. The treatment of WT and hCAR/hPXR mice with 186-984 ppm NaPB in the diet for 7 days resulted in increased relative liver weight, hypertrophy and induction of cytochrome P450 (CYP) enzyme activities. Treatment with NaPB also produced dose-dependent increases in hepatocyte replicative DNA synthesis (RDS), with the effect being more marked in WT than in hCAR/hPXR mice. While the treatment of cultured C57BL/6J and CD-1 mouse, Sprague-Dawley rat and human hepatocytes with 100 and/or 1000 µM NaPB for 4 days induced CYP enzyme activities, increased RDS was only observed in mouse and rat hepatocytes. However, as a positive control, epidermal growth factor increased RDS in hepatocytes from all three species. In summary, although human hepatocytes are refractory to the mitogenic effects of NaPB, treatment with NaPB induced RDS in vivo in hCAR/hPXR mice, which is presumably due to the human CAR and PXR receptors operating in a mouse hepatocyte regulatory environment. As the response of the hCAR/hPXR mouse to the CAR activator NaPB differs markedly from that of human hepatocytes, the hCAR/hPXR mouse is thus not a suitable animal model for studies on the hepatic effects of nongenotoxic rodent CAR activators.

[Synthesis and binding affinity to human steroid hormone receptors of 3-phenoxy-4-hydroxycoumarins and 3-phenoxy-4-phenylcoumarins]. / Synthèse et affinité de fixation aux récepteurs d'hormones stéroïdes humains de 3-phénoxy-4-hydroxycoumarines et de 3-phénoxy-4-phénylcoumarines.

The synthesis and the study of the binding affinity to human receptors of glucocorticoids, mineralcorticoids, androgens, estrogens and progesterone of 3-phenoxy-4-hydroxycoumarins and 3-phenoxy-4-phenylcoumarins were performed. It shows the absence of any binding affinity of all these derivatives to glucocorticoid and mineralcorticoid receptors and a non-selective binding affinity to androgen, oestrogen and progesterone receptors with 3-phenoxy-4-phényl-coumarins.

Endocrine Disruptors and Obesity.

PURPOSE OF REVIEW: The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure. RECENT FINDINGS: Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period. In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.

Systematic review of the association between oil and natural gas extraction processes and human reproduction.

This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.

Editor's Highlight: Neonatal Activation of the Xenobiotic-Sensors PXR and CAR Results in Acute and Persistent Down-regulation of PPARα-Signaling in Mouse Liver.

Safety concerns have emerged regarding the potential long-lasting effects due to developmental exposure to xenobiotics. The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are critical xenobiotic-sensing nuclear receptors that are highly expressed in liver. The goal of this study was to test our hypothesis that neonatal exposure to PXR- or CAR-activators not only acutely but also persistently regulates the expression of drug-processing genes (DPGs). A single dose of the PXR-ligand PCN (75 mg/kg), CAR-ligand TCPOBOP (3 mg/kg), or vehicle (corn oil) was administered intraperitoneally to 3-day-old neonatal wild-type mice. Livers were collected 24 h post-dose or from adult mice at 60 days of age, and global gene expression of these mice was determined using Affymetrix Mouse Transcriptome Assay 1.0. In neonatal liver, PCN up-regulated 464 and down-regulated 449 genes, whereas TCPOBOP up-regulated 308 and down-regulated 112 genes. In adult liver, there were 15 persistently up-regulated and 22 persistently down-regulated genes following neonatal exposure to PCN, as well as 130 persistently up-regulated and 18 persistently down-regulated genes following neonatal exposure to TCPOBOP. Neonatal exposure to both PCN and TCPOBOP persistently down-regulated multiple Cyp4a members, which are prototypical-target genes of the lipid-sensor PPARα, and this correlated with decreased PPARα-binding to the Cyp4a gene loci. RT-qPCR, western blotting, and enzyme activity assays in livers of wild-type, PXR-null, and CAR-null mice confirmed that the persistent down-regulation of Cyp4a was PXR and CAR dependent. In conclusion, neonatal exposure to PXR- and CAR-activators both acutely and persistently regulates critical genes involved in xenobiotic and lipid metabolism in liver.

Imaging Diagnostic and Therapeutic Targets: Steroid Receptors in Breast Cancer.

Estrogen receptor alpha (ERα) and progesterone receptor (PR) are important steroid hormone receptor biomarkers used to determine prognosis and to predict benefit from endocrine therapies for breast cancer patients. Receptor expression is routinely measured in biopsy specimens using immunohistochemistry, although such testing can be challenging, particularly in the setting of metastatic disease. ERα and PR can be quantitatively assayed noninvasively with PET. This approach provides the opportunity to assess receptor expression and function in real time, within the entire tumor, and across distant sites of metastatic disease. This article reviews the current evidence of ERα and PR PET imaging as predictive and early-response biomarkers for endocrine therapy.

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis.