A Novel Quinoline Inhibitor of the Canonical NF-κB Transcription Factor Pathway.

The NF-κB family of transcription factors is a master regulator of cellular responses during inflammation, and its dysregulation has been linked to chronic inflammatory diseases, such as inflammatory bowel disease. It is therefore of vital importance to design and test new effective NF-κB inhibitors that have the potential to be utilized in clinical practice. In this study, we used a commercial transgenic HeLa cell line as an NF-κB activation reporter to test a novel quinoline molecule, Q3, as a potential inhibitor of the canonical NF-κB pathway.

Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain.

Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain.

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice.

The ΔE9 mutation causes a familial form of Alzheimer's disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months.

Unusual seven-membered ring sugars and nucleosides: synthesis and biological properties.

Methods of the synthesis and the investigation of the properties of unnatural seven-memebered cyclic sugars and nucleosides, are of high interest. Septanoses provide conformationally more flexible sugars and due to their similarity to natural carbohydrates they have interesting and potentially useful physical, chemical, and biological properties. Additionally, nucleosides with seven-membered sugar moiety are commonly found in natural products and biologically active molecules.

Multicomponent Reaction of Aldehydes, Amines and Oxalacetate Analogues Leading to Biologically Attractive Pyrrole Derivatives.

Pyrrole is a very important pharmacophoric moiety. It has been widely incorporated into the skeleton of antitumor, anti-inflammatory, antibacterial, antioxidant and antifungal active substances. Access to this key heterocycle by diverse routes is particularly attractive in terms of chemistry, and also from the environmental point of view.

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids.

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system.

Lack of correlation between the activity of the mesolimbic dopaminergic system and the rewarding properties of pregabalin in mouse.

Rationale: Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans.

Design, Synthesis, and Biological Evaluation of Novel C5-Modified Pyrimidine Ribofuranonucleosides as Potential Antitumor or/and Antiviral Agents.

Background: Nucleoside analogues are well-known antitumor, antiviral, and chemotherapeutic agents. Alterations on both their sugar and the heterocyclic parts may lead to significant changes in the spectrum of their biological activity and the degree of selective toxicity, as well as in their physicochemical properties.

Methods: C5-arylalkynyl-β-D-ribofuranonucleosides 3-6, 3΄-deoxy 12-15, 3΄-deoxy-3΄-C-methyl- β-D-ribofurananucleosides 18-21 and 2΄-deoxy-β-D-ribofuranonucleosides 23-26 of uracil, were synthesized using a one-step Sonogashira reaction under microwave irradiation and subsequent deprotection.

Synthesis of novel -acyl--d-glucopyranosylamines and ureas as potential lead cytostatic agents.

Novel classes of acetylated and fully deprotected -acyl--d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per--acetylated -d-glucopyranosylurea (), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (-) gave the protected -acyl--d-glucopyranosylureas (-), in acceptable-to-moderate yields. Subsequent deacetylation of analogues - under Zemplén conditions afforded the fully deprotected derivatives , while the desired urea was formed after treatment of with dibutyltin oxide.

Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation.

The use of non-invasive brain stimulation like repetitive transcranial magnetic stimulation (rTMS) is an increasingly popular set of methods with promising results for the treatment of neurological and psychiatric disorders. Despite great enthusiasm, the impact of non-invasive brain stimulation on its neuronal substrates remains largely unknown. Here we show that rTMS applied over the frontal cortex of awaken mice induces dopamine D2 receptor dependent persistent changes of CDK5 and PSD-95 protein levels specifically within the stimulated brain area.

Triazole double-headed ribonucleosides as inhibitors of eosinophil derived neurotoxin.

Eosinophil derived neurotoxin (EDN) is an eosinophil secretion protein and a member of the Ribonuclease A (RNase A) superfamily involved in the immune response system and inflammatory disorders. The pathological actions of EDN are strongly dependent on the enzymatic activity and therefore, it is of significant interest to discover potent and specific inhibitors of EDN. In this framework we have assessed the inhibitory potency of triazole double-headed ribonucleosides.

Glycogen phosphorylase as a target for type 2 diabetes: synthetic, biochemical, structural and computational evaluation of novel N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors.

Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-β-D-glucopyranosylamines (Parmenopoulou et al., Bioorg.

Dissipation, metabolism and sorption of pesticides used in fruit-packaging plants: Towards an optimized depuration of their pesticide-contaminated agro-industrial effluents.

Wastewaters from the fruit-packaging industry constitute a serious point source contamination with pesticides. In the absence of effective depuration methods, they are discharged in municipal wastewater treatment plants or spread to land. Modified biobeds could be an applicable solution for their treatment.

An easy microwave-assisted synthesis of C8-alkynyl adenine pyranonucleosides as novel cytotoxic antitumor agents.

We describe the synthesis of C8-alkynyl adenine pyranonucleosides 4, 5, and 8-phenylethynyl-adenine (II), via Sonogashira cross-coupling reaction under microwave irradiation. Compounds 4e and II were less cytostatic than 5-fluorouracil (almost an order of magnitude) against murine leukemia (L1210) and human cervix carcinoma (HeLa) cells, while the same compounds proved to be more active than 5-fluorouracil against human lymphocyte (CEM) cells.

Branched-chain sugar nucleosides: stereocontrolled synthesis and bioevaluation of novel 3'-C-trifluoromethyl and 3'-C-methyl pyranonucleosides.

A new series of 3'-C-trifluoromethyl- and 3'-C-methyl-β-d-allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-α-D-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-β-D-allopyranose.

Synthesis of novel thiopurine pyranonucleosides: evaluation of their bioactivity.

We report the synthesis of novel thiopurine pyranonucleosides. Direct coupling of silylated 6-mercaptopurine and 6-thioguanine with the appropriate pyranoses 1a-e via Vorbrüggen nucleosidation, gave the N-9 linked mercaptopurine 2a-e and thioguanine 4a-e nucleosides, while their N-7 substituted congeners 10a-e and 7a-e, were obtained through condensation of the same acetates with 6-chloro and 2-amino-6-chloropurines, followed by subsequent thionation. Nucleosides 3a-e, 5a-e, 8a-e, and 11a-e were evaluated for their cytostatic activity in three different tumor cell proliferative assays.

Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats.

Background: Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.

Structure based inhibitor design targeting glycogen phosphorylase B. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines.

Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-β-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a 'consensus scoring' approach to ranking of ligand binding affinities for the active site.

Comparison of the growth curves of cancer cells and cancer stem cells.

A fundamental problem in cancer research is identification of the cells responsible for tumor formation. The latest field of cancer research has revealed the existence and role of cancer stem cells (CSCs). These findings support the idea that malignancies originate from a small fraction of cancer cells that show self-renewal and multi- or pluripotency.

Stereoselective facile synthesis of 2'-spiro pyrimidine pyranonucleosides via their key intermediate 2'-C-cyano analogues. Evaluation of their bioactivity.

A novel series of 2'-spiro pyrimidine pyranonucleosides has been designed and synthesized. Their precursors, 2'-C-cyano nucleosides 5a,b and 6a,b, were obtained by subjecting 1a,b to the sequence of selective protection of the primary hydroxyl group, acetalation, oxidation, and finally treatment with sodium cyanide. Deoxygenation at the 2'-position of cyanohydrins 5a,b or 6a,b led to the 2'-deoxy derivatives 9a,b.

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition.

Study of the interaction among Notch pathway receptors, correlation with stemness, as well as their interaction with CD44, dipeptidyl peptidase-IV, hepatocyte growth factor receptor and the SETMAR transferase, in colon cancer stem cells.

Context: The Notch signaling pathway is one of the most important pathways during normal development and implicated in self-renewal of adult stem cells and differentiation of progenitor cells. Abnormal expression of Notch receptors has been associated with many epithelial metaplastic and neoplastic lesions. OBJECTIVE-MATERIALS AND METHODS: In this particular study, it was determined the relative gene expression of Notch receptors after knockdown experiments in colon cancer stem cells (CSCs) and the gene expression changes in stemness transcription factors (Oct4, Sox2, Nanog), as well in dipeptidylpeptidase-4, CD44 antigen, Met proto-oncogene and in Metnase transposase.

Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice.

Rationale: Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a "paradoxical" calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood.

Rapid microwave-enhanced synthesis of C5-alkynyl pyranonucleosides as novel cytotoxic antitumor agents.

A microwave-assisted, one-pot, coupling reaction for the synthesis of C5-alkynyl-uracil and cytosine glucopyranonucleosides has been developed. The reaction is carried out under standard Sonogashira coupling conditions from glucopyranonucleosides of 5-iodouracil or 5-iodocytosine and various terminal alkynes. All compounds were evaluated for their cytostatic and antiviral activity.

Stereocontrolled synthesis of 4'-C-cyano and 4'-C-cyano-4'-deoxy pyrimidine pyranonucleosides as potential chemotherapeutic agents.

A new series of 4'-C-cyano and 4'-C-cyano-4'-deoxy pyrimidine pyranonucleosides has been designed and synthesized. Commercially available 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1) was condensed with silylated 5-fluorouracil, uracil, and thymine, respectively to afford after deacetylation 1-(α-D-mannopyranosyl)nucleosides (2a-c). Subjecting 2a-c to the sequence of specific acetalation, selective protection of the primary hydroxyl group and oxidation, the 4'-ketonucleosides 6a-c and 7c were obtained.