Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis.

Liver X receptors (LXRα and LXRβ) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαβ-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRα and LXRβ are expressed in the colonic epithelium and that in aging LXRαβ mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor β (ERβ) levels.

Liver X receptors and estrogen receptor β, two players in a rare subtype of NSCLC.

Liver X receptors (LXRαβ) play essential roles in the maintenance of the normal functions of macrophages, in modulation of immune system responses and cholesterol homeostasis. We have reported that LXRαβ mice develop squamous cell lung cancer. We now report that those LXRαβ mice, which live to 18-months of age, spontaneously develop a second type of lung cancer resembling a rare subtype of NSCLC (TTF-1 and P63-positive).

Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats.

Background: Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model.

Methods: Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group.

Liver X Receptor Regulation of Glial Cell Functions in the CNS.

In this review, we discuss the role of liver X receptors (LXRs) in glial cells (microglia, oligodendrocytes and astrocytes) in the central nervous system (CNS). LXRs are oxysterol-activated nuclear receptors that, in adults, regulate genes involved in cholesterol homeostasis, the modulation of inflammatory responses and glutamate homeostasis. The study of LXR knockout mice has revealed that LXRβ plays a key role in maintaining the health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord and retinal ganglion cells in the eye.

Ablation of Liver X receptor β in mice leads to overactive macrophages and death of spiral ganglion neurons.

Age-related hearing loss is the most common type of hearing impairment, and is typically characterized by the loss of spiral ganglion neurons (SGNs). The two Liver X receptors (LXRs) are oxysterol-activated nuclear receptors which in adults, regulate genes involved in cholesterol homeostasis and modulation of macrophage activity. LXRβ plays a key role in maintenance of health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord, and retinal ganglion cells in adult mice.

25 years of ERβ: a personal journey.

After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer.

Drivers and suppressors of triple-negative breast cancer.

To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women.

Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.

Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane.

Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host's Innate Antiviral Immunity to Attack Tumor Cells.

One of the major hurdles for cancer immunotherapy is the host's innate antiviral defense mechanisms. They include innate immune cells, such as natural killer (NK) cells and macrophages, which can be recruited within hours to the site of injection to clear the introduced oncolytic viruses. Here, we report a strategy to redirect these infiltrating innate immune cells to attack tumor cells instead by arming herpes simplex virus (HSV)-derived oncolytic viruses with secreted chimeric molecules that can engage these innate immune cells with tumor cells to kill the latter.

Estrogen receptor β regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3.

Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN.

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.

Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβ]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβ mice was similar to, but more severe than, that in the ERβmice.

Motor Function Deficits in the Estrogen Receptor Beta Knockout Mouse: Role on Excitatory Neurotransmission and Myelination in the Motor Cortex.

Background: Male estrogen receptor beta (ERβ) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration, and reduced GABAergic signaling. The effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERβ loss have not been investigated.

Objective: The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex.

Targeting ERβ in Macrophage Reduces Crown-like Structures in Adipose Tissue by Inhibiting Osteopontin and HIF-1α.

Proinflammatory processes in adipose tissue contribute to development of breast cancer and insulin resistance. Crown-like structures (CLS) are histologic hallmarks of the proinflammatory process in adipose tissue. CLS are microscopic foci of dying adipocytes surrounded by macrophages mostly derived from monocytes in blood.

Retinal and optic nerve degeneration in liver X receptor β knockout mice.

The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons.

Estrogen receptor subtypes dictate the proliferative nature of the mammary gland.

Estrogen induces proliferation of breast epithelial cells and is responsible for breast development at puberty. This tightly regulated control is lost in estrogen-receptor-positive (ER+) breast cancers, which comprise over 70% of all breast cancers. Currently, breast cancer diagnosis and treatment considers only the α isoform of ER; however, there is a second ER, ERβ.

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

Background: Upregulation of estrogen receptor beta (ERβ) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERβ and breast carcinogenesis is still missing.

Methods: To study the role of ERβ in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERβ and p53 in the mammary gland epithelium.

Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate.

As estrogen receptor β (ERβ) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERβ mice and their WT littermates. We also treated young and old WT mice with an ERβ-selective agonist and evaluated protein expression.

An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice.

Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself.

Dysregulation of Notch and ERα signaling in AhR-/- male mice.

The aryl hydrocarbon receptor (AhR) is now recognized as an important physiological regulator in the immune and reproductive systems, and in the development of the liver and vascular system. AhR regulates cell cycle, cell proliferation, and differentiation through interacting with other signaling pathways, like estrogen receptor α (ERα), androgen receptor (AR), and Notch signaling. In the present study, we investigated Notch and estrogen signaling in AhR mice.

Ablation of Liver X receptors α and β leads to spontaneous peripheral squamous cell lung cancer in mice.

The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and β (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea.

Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue.

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure.

Role for HIF-1α and Downstream Pathways in Regulating Neuronal Injury after Intracerebral Hemorrhage in Diabetes.

Background/aims: HIF-1α is accumulated in the cellular nucleus and cytoplasm under conditions of oxygen deprivation and engaged in pathophysiologic changes of homeostasis by modulating the expression of several target genes. As an endogenous signaling protein, HIF-1α contributes to in neuroprotection, erythropoiesis, and apoptosis modulation. The purpose of this study was to examine the role played by HIF-1α in regulating neurological injury evoked by intracerebral hemorrhage (ICH) through its downstream product, namely vascular endothelial growth factor (VEGF).

Syntheses and structures of one CuI-containing coordination polymer and two macrocyclic supramolecular complexes based on flexible 1,3,4-oxadiazole-containing ligands.

Three coordination complexes with Cu(I) centres have been prepared using the symmetrical flexible organic ligands 1,3-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propane (L1) and 1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}butane (L2). Crystallization of L1 with Cu(SO3CF3)2 and of L2 with Cu(BF4)2 and Cu(ClO4)2 in a CH2Cl2/CH3OH mixed-solvent system at room temperature afforded the coordination complexes catena-poly[[copper(I)-μ-1,3-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propane] methanesulfonate dichloromethane 0.6-solvate], {[Cu(C25H18N6O2S2)](CF3SO3)·0.

Capillarisin Suppresses Lipopolysaccharide-Induced Inflammatory Mediators in BV2 Microglial Cells by Suppressing TLR4-Mediated NF-κB and MAPKs Signaling Pathway.

Capillarisin, one of the major bioactive compounds derived from Artemisia capillaries Thunb, has been reported to have extensive pharmacological properties, such as ant-inflammatory and anti-nociceptive activities. However, the molecular mechanisms responsible for the anti-inflammatory activity of capillarisin have not been elucidated in microglia. In the present study, we investigated the anti-inflammatory effects and molecular mechanisms of capillarisin on LPS-stimulated BV2 microglial cells.

Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes.