Heme oxygenase-1 protects cells from replication stress.

Heme oxygenase-1 (HO-1, HMOX1) degrades heme protecting cells from heme-induced oxidative damage. Beyond its well-established cellular functions, heme has emerged as a stabilizer of G-quadruplexes. These secondary DNA structures interfere with DNA replication.

Glial expression of DmMANF is required for the regulation of activity, sleep and circadian rhythms in the visual system of Drosophila melanogaster.

DmMANF, Drosophila melanogaster mesencephalic astrocyte-derived neurotrophic factor (DmMANF) is an evolutionarily conserved orthologue of mammalian MANF. This neurotrophic factor exerts many functions in the Drosophila brain, particularly those dependent on glial cells. As we found in our earlier study, downregulation of DmMANF in glia induces degeneration of glial cells in the first optic neuropil (lamina) where DmMANF abundance is especially high.

Proximity Ligation Assay Detection of Protein-DNA Interactions-Is There a Link between Heme Oxygenase-1 and G-quadruplexes?

G-quadruplexes (G4) are stacked nucleic acid structures that are stabilized by heme. In cells, they affect DNA replication and gene transcription. They are unwound by several helicases but the composition of the repair complex and its heme sensitivity are unclear.

Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI-ceruloplasmin expression in liver macrophages.

Jackson toxic milk mutant mice (tx-J) carrying a missense mutation in the Atp7b gene are animal models of the Wilson disease. In both the Wilson patients and the tx-J mice, mutations in the ATP7B/Atp7b gene lead to disturbances in copper metabolism. The dysfunction of ATP7B/Atp7b leads to a reduction in the incorporation of copper into apoceruloplasmin; this decreases the ferroxidase activity of ceruloplasmin necessary for the efflux of iron from cells and reduces the release of copper from hepatocytes to the bile; this results in a massive hepatic copper accumulation.

Effects of PINK1 mutation on synapses and behavior in the brain of Drosophila melanogaster.

Mutations in the PINK1 gene are responsible for typical symptoms of Parkinson's disease. Using Drosophila melanogaster mutant PINK1B9 and after PINK1 silencing with RNAi using transgenic lines, we observed defects in synapses and behavior. The lack or reduced expression of PINK1 prolonged sleep during the day (nap) and decreased the total locomotor activity during 24 h, in addition to a decrease in climbing ability and a reduced lifespan.

Circadian Plasticity in the Brain of Insects and Rodents.

In both vertebrate and invertebrate brains, neurons, glial cells and synapses are plastic, which means that the physiology and structure of these components are modified in response to internal and external stimuli during development and in mature brains. The term plasticity has been introduced in the last century to describe experience-dependent changes in synapse strength and number. These changes result from local functional and morphological synapse modifications; however, these modifications also occur more commonly in pre- and postsynaptic neurons.

Different Levels of Expression of the Clock Protein PER and the Glial Marker REPO in Ensheathing and Astrocyte-Like Glia of the Distal Medulla of Optic Lobe.

Circadian plasticity of the visual system of depends on functioning of both the neuronal and glial oscillators. The clock function of the former is already quite well-recognized. The latter, however, is much less known and documented.

Downregulation of in Glial Cells Results in Neurodegeneration and Affects Sleep and Lifespan in .

In , mesencephalic astrocyte-derived neurotrophic factor (DmMANF) is an evolutionarily conserved ortholog of mammalian MANF and cerebral dopamine neurotrophic factor (CDNF), which have been shown to promote the survival of dopaminergic neurons in the brain. We observed especially high levels of DmMANF in the visual system of , particularly in the first optic neuropil (lamina). In the lamina, DmMANF was found in glial cells (surface and epithelial glia), photoreceptors and interneurons.

Atp7a and Atp7b regulate copper homeostasis in developing male germ cells in mice.

The maintenance of copper homeostasis is critical for all cells. As learned from mice with disturbed copper metabolism, this trace element is also important for spermatogenesis. The experiments conducted in yeasts have demonstrated that appropriate copper level must be preserved to enable meiosis progression; however, increased copper level is toxic for cells.

Benzophenone-3 Impairs Autophagy, Alters Epigenetic Status, and Disrupts Retinoid X Receptor Signaling in Apoptotic Neuronal Cells.

Benzophenone-3 (BP-3) is the most widely used compound among UV filters for the prevention of photodegradation. Population studies have demonstrated that it penetrates through the skin and crosses the blood-brain barrier. However, little is known about the impact of BP-3 on the nervous system and its possible adverse effects on the developing brain.

Dietary hemoglobin rescues young piglets from severe iron deficiency anemia: Duodenal expression profile of genes involved in heme iron absorption.

Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption.

Apoptosis Induced by the UV Filter Benzophenone-3 in Mouse Neuronal Cells Is Mediated via Attenuation of Erα/Pparγ and Stimulation of Erβ/Gpr30 Signaling.

Although benzophenone-3 (BP-3) has frequently been reported to play a role in endocrine disruption, there is insufficient data regarding the impact of BP-3 on the nervous system, including its possible adverse effects on the developing brain. Our study demonstrated that BP-3 caused neurotoxicity and activated apoptosis via an intrinsic pathway involving the loss of mitochondrial membrane potential and the activation of caspases-9 and -3 and kinases p38/MAPK and Gsk3β. These biochemical alterations were accompanied by ROS production, increased apoptotic body formation and impaired cell survival, and by an upregulation of the genes involved in apoptosis.

Copper therapy reduces intravascular hemolysis and derepresses ferroportin in mice with mosaic mutation (Atp7a): An implication for copper-mediated regulation of the Slc40a1 gene expression.

Mosaic mutant mice displaying functional dysfunction of Atp7a copper transporter (the Menkes ATPase) are an established animal model of Menkes disease and constitute a convenient tool for investigating connections between copper and iron metabolisms. This model allows to explore changes in iron metabolism in suckling mutant mice suffering from systemic copper deficiency as well as in young and adult ones undergone copper therapy, which reduces lethal effect of the Atp7a gene mutation. Our recent study demonstrated that 14-day-old mosaic mutant males display blood cell abnormalities associated with intravascular hemolysis, and show disturbances in the functioning of the hepcidin-ferroportin regulatory axis, which controls systemic iron homeostasis.

Mottled Mice and Non-Mammalian Models of Menkes Disease.

Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB).

RXRα, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells.

In the present study, we investigated the role of the retinoid X receptor (RXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the apoptotic and toxic effects of nonylphenol in mouse primary neuronal cell cultures. Our study demonstrated that nonylphenol activated caspase-3 and induced lactate dehydrogenase (LDH) release in hippocampal cells, which was accompanied by an increase in the mRNA expression and protein levels of RXRα, PXR and CAR. Nonylphenol stimulated Rxra, Pxr, and Car mRNA expression.

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity.

Dichlorodiphenyldichloroethylene (DDE) is a primary environmental and metabolic degradation product of the pesticide dichlorodiphenyltrichloroethane (DDT). It is one of the most toxic compounds belonging to organochlorines. DDE has never been commercially produced; however, the parent pesticide DDT is still used in some developing countries for disease-vector control of malaria.

Selective Aryl Hydrocarbon Receptor Modulator 3,3'-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia.

The neuroprotective potential of 3,3'-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor β (ERβ).

Haemolysis and perturbations in the systemic iron metabolism of suckling, copper-deficient mosaic mutant mice - an animal model of Menkes disease.

The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction.

Apoptotic and neurotoxic actions of 4-para-nonylphenol are accompanied by activation of retinoid X receptor and impairment of classical estrogen receptor signaling.

4-para-Nonylphenol (NP) is a non-ionic surfactant that has widespread and uncontrolled distribution in the environment. Little is known, however, about its actions on neuronal cells during critical developmental periods. This study aimed to investigate the mechanisms underlying the apoptotic and toxic actions of NP on mouse embryonic neuronal cells and the possible interactions of NP with estrogen receptor (ER)- and retinoid X receptor (RXR)-mediated intracellular signaling.

Neuroprotective action of raloxifene against hypoxia-induced damage in mouse hippocampal cells depends on ERα but not ERβ or GPR30 signalling.

Raloxifene is the selective estrogen receptor modulator (SERM) currently used in clinical practice to activate estrogen receptors (ERs) in bone tissue and to antagonise ERs in breast and uterine cancers. Little is known, however, about mechanisms of action of raloxifene on hypoxia-induced neuronal cell damage. The aim of the present study was to investigate the neuroprotective potential of raloxifene against hypoxia-induced damage of mouse hippocampal cells in primary cultures, with a particular focus on raloxifene interactions with the classical nuclear ERs (ERα, ERβ) and the recently identified membrane ER G-protein-coupled receptor 30 (GPR30).

External and circadian inputs modulate synaptic protein expression in the visual system of Drosophila melanogaster.

In the visual system of Drosophila melanogaster the retina photoreceptors form tetrad synapses with the first order interneurons, amacrine cells and glial cells in the first optic neuropil (lamina), in order to transmit photic and visual information to the brain. Using the specific antibodies against synaptic proteins; Bruchpilot (BRP), Synapsin (SYN), and Disc Large (DLG), the synapses in the distal lamina were specifically labeled. Then their abundance was measured as immunofluorescence intensity in flies held in light/dark (LD 12:12), constant darkness (DD), and after locomotor and light stimulation.

The key involvement of estrogen receptor β and G-protein-coupled receptor 30 in the neuroprotective action of daidzein.

Phytoestrogens have received considerable attention because they provide an array of beneficial effects, such as neuroprotection. To better understand the molecular and functional link between phytoestrogens and classical as well as membrane estrogen receptors (ERs), we investigated the effect of daidzein on the glutamate-mediated apoptotic pathway. Our study demonstrated that daidzein (0.

Ferroportin expression in haem oxygenase 1-deficient mice.

HO1 (haem oxygenase 1) and Fpn (ferroportin) are key proteins for iron recycling from senescent red blood cells and therefore play a major role in controlling the bioavailability of iron for erythropoiesis. Although important aspects of iron metabolism in HO1-deficient (Hmox1-/-) mice have already been revealed, little is known about the regulation of Fpn expression and its role in HO1 deficiency. In the present study, we characterize the cellular and systemic factors influencing Fpn expression in Hmox1-/- bone marrow-derived macrophages and in the liver and kidney of Hmox1-/- mice.

Prenatal treatment of mosaic mice (Atp7a mo-ms) mouse model for Menkes disease, with copper combined by dimethyldithiocarbamate (DMDTC).

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels.