RNAi Knockdown of in Maternal Expression of Prader-Willi Syndrome Genes.

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader-Willi Syndrome (PWS)-related genes, such as and , are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC.

Suppression of systemic inflammation and signs of acute and chronic cholangitis by multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione.

An aberrant activity of growth factor receptors followed by excessive cell proliferation plays a significant role in pathogenesis of cholangitis. Therefore, inhibition of these processes could be a fruitful therapeutic strategy. The effects of multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione (MI-1) on the hepatic and systemic manifestations of acute and chronic cholangitis in rats were addressed.

FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents.

Heterozygous loss-of-function mutations in the transcription factor FOXP1 are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygous Foxp1 (Foxp1) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygous Foxp1 deletion to study cell-autonomous regulation by Foxp1.

An essential role for MEF2C in the cortical response to loss of sleep in mice.

Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep-loss response are not well understood.

Pyrrole derivatives as potential anti-cancer therapeutics: synthesis, mechanisms of action, safety.

Pyrrole derivatives (PDs) chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1H-pyrrole-2,5-dione (MI-1) and 5-amino-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrole-3-one (D1) were synthesised as inhibitors of several protein kinases including EGFR and VEGFR. The aim of the study was to reveal the exact mechanisms of PDs' action EGFR and VEGFR are involved in. We observed, that both PDs could bind with EGFR and VEGFR and form stable complexes.

Water-soluble pristine C fullerene attenuates acetaminophen-induced liver injury.

Oxidative stress has been suggested as the main trigger and pathological mechanism of toxic liver injury. Effects of powerful free radical scavenger С fullerene on rat liver injury and liver cells (HepG2 line) were aimed to be discovered. Acute liver injury (ALI) was simulated by single acetaminophen (APAP, 1000 mg/kg) administration, on a chronic CLI, by 4 weekly APAP administrations.

Synthesis and biological activity of 4-amino-3-chloro-1-pyrrole-2,5-diones.

4-Amino-3-chloro-1-pyrrole-2,5-dione derivatives were designed and synthesized as potential tyrosine kinase inhibitors. One of them has been shown to inhibit growth of cancer cell lines and in vivo tumors. To determine the impact of side groups on biological activity the ability of different 4-amino-3-chloro-1-pyrrole-2,5-diones to interact with ATP-binding domains of growth factor receptors and with model cell membranes were aimed to be discovered.

Effects of 5-Amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one Intake on Digestive System in a Rat Model of Colon Cancer.

Introduction: Pyrrol derivate 5-amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) has shown antiproliferative activities in vitro, so investigation of the impact of D1 intake on gut organs in rats that experienced colon cancer seems to be necessary.

Materials And Methods: D1 at the dose of 2.3 mg/kg was administered per os daily for 27 (from the 1st day of experiment) or 7 (from the 21st week of experiment) weeks to rats that experienced 1,2-dimethylhydrazine (DMH)-induced colon cancer for 20 weeks.

Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis.

Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K(+). Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels.

Comparative study of membranotropic action of single- and multi-walled carbon nanotubes.

The aim of the present work is the investigation of the interactions of single-walled and multi-walled carbon nanotubes (further referred as SWCNTs and MWCNTs, respectively) with bimolecular lipid model membrane (BLM) and cellular plasma membrane (PM). The findings demonstrate that both SWCNTs and MWCNTs (in concentration range of 10⁻⁴ to 10⁻¹ mg ml⁻¹) are capable to penetrate through the region of hydrophobic fatty acid residues of phospholipids and to form molecular associates in the bilayer that have conductive properties of molecular pores type. The formed pores were shown to enable phosphatidylserine externalization from inner to outer PM leaflet.

The intracellular Ca²⁺ channels of membrane traffic.

Regulation of organellar fusion and fission by Ca ( 2+) has emerged as a central paradigm in intracellular membrane traffic. Originally formulated for Ca ( 2+) -driven SNARE-mediated exocytosis in the presynaptic terminals, it was later expanded to explain membrane traffic in other exocytic events within the endo-lysosomal system. The list of processes and conditions that depend on the intracellular membrane traffic includes aging, antigen and lipid processing, growth factor signaling and enzyme secretion.

Membrane potential regulates nicotinic acid adenine dinucleotide phosphate (NAADP) dependence of the pH- and Ca2+-sensitive organellar two-pore channel TPC1.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent second messenger that mobilizes Ca(2+) from the acidic endolysosomes by activation of the two-pore channels TPC1 and TPC2. The channel properties of human TPC1 have not been studied before, and its cellular function is not known. In the present study, we characterized TPC1 incorporated into lipid bilayers.

Activation of aerobic metabolism by Amaranth oil improves heart rate variability both in athletes and patients with type 2 diabetes mellitus.

The aim of present research was to study the effects of Amaranth oil (AmO) supplementation on aerobic metabolism and heart rate variability (HRV) in type 2 diabetes mellitus patients and in athletes. Several parameters of aerobic metabolism and HRV were assessed. Supplementation with AmO caused mild pro-oxidant activity resulting in improved uptake of oxidative destruction products and modulation of catalase and SOD activity with subsequent development of an antioxidant effect.

The C terminus of Bax inhibitor-1 forms a Ca2+-permeable channel pore.

Bax inhibitor-1 (BI-1) is a multitransmembrane domain-spanning endoplasmic reticulum (ER)-located protein that is evolutionarily conserved and protects against apoptosis and ER stress. Furthermore, BI-1 is proposed to modulate ER Ca(2+) homeostasis by acting as a Ca(2+)-leak channel. Based on experimental determination of the BI-1 topology, we propose that its C terminus forms a Ca(2+) pore responsible for its Ca(2+)-leak properties.

Polycystin-2 expression and function in adult mouse lacrimal acinar cells.

Purpose: Lacrimal glands regulate the production and secretion of tear fluid. Dysfunction of lacrimal gland acinar cells can ultimately result in ocular surface disorders, such as dry eye disease. Ca(2+) homeostasis is tightly regulated in the cellular environment, and secretion from the acinar cells of the lacrimal gland is regulated by both cholinergic and adrenergic stimuli, which both result in changes in the cytosolic Ca(2+) concentration.

Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia.

Background: Hypokalemic periodic paralysis (HypoPP) is associated with mutations in either the Ca(V)1.1 calcium channel or the Na(V)1.4 sodium channel.

The unliganded long isoform of estrogen receptor beta stimulates brain ryanodine receptor single channel activity alongside with cytosolic Ca2+.

Ca(2+) release from intracellular stores mediated by endoplasmic reticulum membrane ryanodine receptors (RyR) plays a key role in activating and synchronizing downstream Ca(2+)-dependent mechanisms, in different cells varying from apoptosis to nuclear transcription and development of defensive responses. Recently discovered, atypical "nongenomic" effects mediated by estrogen receptors (ER) include rapid Ca(2+) release upon estrogen exposure in conditions implicitly suggesting involvement of RyRs. In the present study, we report various levels of colocalization between RyR type 2 (RyR2) and ER type beta (ER beta) in the neuronal cell line HT-22, indicating a possible functional interaction.

Anion control of voltage sensing by the motor protein prestin in outer hair cells.

The outer hair cell from Corti's organ possesses voltage-dependent intramembranous molecular motors evolved from the SLC26 anion transporter family. The motor, identified as prestin (SLC26a5), is responsible for electromotility of outer hair cells and mammalian cochlear amplification, a process that heightens our auditory responsiveness. Here, we describe experiments designed to evaluate the effects of anions on the motor's voltage-sensor charge movement, focusing on prestin's voltage-dependent Boltzmann characteristics.

The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction.

Presenilin-1 (PS1) and presenilin-2 (PS2) form the catalytic core in gamma-secretase complexes and mutations in these proteins result in aberrant cleavage of amyloid precursor protein leading to accumulation of the beta-amyloid in the brain of familial Alzheimer Disease patients. PS2 possesses a hydrophilic cytoplasmic N-terminal domain (PS2 NTF1-87) dispensable for gamma-secretase activity with physiological functions yet to be determined. The effects of this soluble 87 amino acid fragment of mouse PS2 on single channel activity of mouse brain ryanodine receptors (RyR) were determined.

The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity.

Ryanodine receptors (RyRs) amplify intracellular Ca(2+) signals by massively releasing Ca(2+) from intracellular stores. Exaggerated chronic Ca(2+) release can trigger cellular apoptosis underlying a variety of neurodegenerative diseases. Aberrant functioning of presenilin-1 (PS1) protein instigates Ca(2+)-dependent apoptosis, providing a basis for the "calcium hypothesis" of Alzheimer's disease (AD).

On the temperature and tension dependence of the outer hair cell lateral membrane conductance GmetL and its relation to prestin.

Recently, we identified an outer hair cell (OHC) lateral membrane conductance, GmetL, that colocalizes with prestin and passes Cl-, thereby influencing prestin's (SLC26A5) electromechanical activity. In this study, we report on a comparison of the temperature and tension dependence of GmetL and prestin. Though we find significant temperature and tension dependence of each, substantial differences exist which indicate their independent identity.

Cl- flux through a non-selective, stretch-sensitive conductance influences the outer hair cell motor of the guinea-pig.

Outer hair cells underlie high frequency cochlear amplification in mammals. Fast somatic motility can be driven by voltage-dependent conformational changes in the motor protein, prestin, which resides exclusively within lateral plasma membrane of the cell. Yet, how a voltage-driven motor could contribute to high frequency amplification, despite the low-pass membrane filter of the cell, remains an enigma.