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Santosh Kumar, Sunil Kumar, Narayan S Punekar
The catabolism of fungal 4-aminobutyrate (GABA) occurs via succinic semialdehyde (SSA). Succinic semialdehyde dehydrogenase (SSADH) from the acidogenic fungus Aspergillus niger was purified from GABA grown mycelia to the highest specific activity of 277 nmol min(-1) mg(-1), using phenyl Sepharose and DEAE Sephacel chromatography. The purified enzyme was specific for its substrates SSA and NAD+. The substrate inhibition observed with SSA was uncompetitive with respect to NAD+. While product inhibition by succinate was not observed, NADH inhibited the enzyme competitively with respect to NAD+ and noncompetitively with respect to SSA...
February 2015: Indian Journal of Experimental Biology
Takehiro Takahashi, Masashi Yamamoto, Kazutoshi Amikura, Kozue Kato, Takashi Serizawa, Kanako Serizawa, Daisuke Akazawa, Takumi Aoki, Koji Kawai, Emi Ogasawara, Jun-Ichi Hayashi, Kazuto Nakada, Mie Kainoh
The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl-4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure...
February 2015: Journal of Pharmacology and Experimental Therapeutics
Diego J Martinel Lamas, Jorge E Cortina, Clara Ventura, Helena A Sterle, Eduardo Valli, Karina B Balestrasse, Horacio Blanco, Graciela A Cremaschi, Elena S Rivera, Vanina A Medina
The radioprotective potential of histamine on healthy tissue has been previously demonstrated. The aims of this work were to investigate the combinatorial effect of histamine or its receptor ligands and gamma radiation in vitro on the radiobiological response of 2 breast cancer cell lines (MDA-MB-231 and MCF-7), to explore the potential molecular mechanisms of the radiosensitizing action and to evaluate the histamine-induced radiosensitization in vivo in a triple negative breast cancer model. Results indicate that histamine significantly increased the radiosensitivity of MDA-MB-231 and MCF-7 cells...
2015: Cancer Biology & Therapy
Sonja Lieber, Frithjof Scheer, Florian Finkernagel, Wolfgang Meissner, Gavin Giehl, Cornelia Brendel, Wibke E Diederich, Sabine Müller-Brüsselbach, Rolf Müller
The stilbene derivative (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine)amino]phenyl}acrylonitrile (DG172) was developed as a highly selective inhibitory peroxisome proliferator-activated receptor (PPAR)β/δ ligand. Here, we describe a novel PPARβ/δ-independent, yet highly specific, effect of DG172 on the differentiation of bone marrow cells (BMCs). DG172 strongly augmented granulocyte-macrophage-colony-stimulating factor (GM-CSF)-induced differentiation of primary BMCs from Ppard null mice into two specific populations, characterized as mature (CD11c(hi)MHCII(hi)) and immature (CD11c(hi)MHCII(lo)) dendritic cells (DCs)...
February 2015: Molecular Pharmacology
James M Kasper, Raymond G Booth, Joanna Peris
The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2-N,N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons...
February 2015: Synapse
A Ahnaou, X Langlois, T Steckler, J M Bartolome-Nebreda, W H I M Drinkenburg
RATIONALE: Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved in neuronal plasticity, and disturbance in vigilance states and cortical network connectivity contribute significantly to cognitive deficits described in schizophrenia and Alzheimer's disease...
March 2015: Psychopharmacology
Christian Gege, Thomas Schlüter, Thomas Hoffmann
Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ...
November 15, 2014: Bioorganic & Medicinal Chemistry Letters
Céline Bruyère, Véronique Mathieu, Anne Vessières, Pascal Pigeon, Siden Top, Gérard Jaouen, Robert Kiss
Platinum coordination complexes represent an important class of anti-tumor agents. Due to recognized drawbacks, research into other types of metallodrugs has been diversified with the aim of finding new chemical entities with alternative mechanisms of action to overcome classical chemoresistance. P5 and DP1, two closely related ferrocenyl complexes bearing a similar ferrocenyl-ene-phenyl motif and displaying marked differences in their conformations and oxidation state versatility, were assayed in cancer cell models characterized by various sensitivities to pro-apoptotic stimuli...
December 2014: Journal of Inorganic Biochemistry
Omar S Mabrouk, Riccardo Viaro, Mattia Volta, Ada Ledonne, Nicola Mercuri, Michele Morari
δ opioid peptide (DOP) receptors are considered a therapeutic target in Parkinson's disease, although the use of DOP agonists may be limited by side effects, including convulsions. To circumvent this issue, we evaluated whether blockade of nociceptin/orphanin FQ (N/OFQ) tone potentiated the antiparkinsonian effects of DOP agonists, thus allowing for reduction of their dosage. Systemic administration of the N/OFQ receptor (NOP) antagonist J-113397 [(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one] and the DOP receptor agonist SNC-80 [(+)-4-[(αR)-α-(2S,5R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide] revealed synergistic attenuation of motor deficits in 6-hydroxydopamine hemilesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice...
September 24, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Kuniki Hata, Ayumi Urushibara, Shinichi Yamashita, Mingzhang Lin, Yusa Muroya, Naoya Shikazono, Akinari Yokoya, Haiying Fu, Yosuke Katsumura
Reactions of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) with deoxyguanosine monophosphate (dGMP) hydroxyl radical adducts were investigated by pulse radiolysis technique. Edaravone was found to reduce the dGMP hydroxyl radical adducts through electron transfer reactions. The rate constants of the reactions were greater than 4 × 10(8) dm(3) mol(-1) s(-1) and similar to those of the reactions of ascorbic acid, which is a representative antioxidant. Yields of single-strand breaks, base lesions, and abasic sites produced in pUC18 plasmid DNA by gamma ray irradiation in the presence of low concentrations (10-1000 μmol dm(-3)) of edaravone were also quantified, and the chemical repair activity of edaravone was estimated by a method recently developed by the authors...
January 2015: Journal of Radiation Research
Janaína K Barbiero, Ronise M Santiago, Daniele Suzete Persike, Maria José da Silva Fernandes, Fernanda S Tonin, Claudio da Cunha, Suelen Lucio Boschen, Marcelo M S Lima, Maria A B F Vital
A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-α agonist fenofibrate (100mg/kg) and PPAR-γ agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts...
November 1, 2014: Behavioural Brain Research
Barbora Šalovská, Ivo Fabrik, Kamila Ďurišová, Marek Link, Jiřina Vávrová, Martina Řezáčová, Aleš Tichý
DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)-triggered by radiation-induced double strand breaks-is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells...
2014: International Journal of Molecular Sciences
Amirah Abdul Rahman, A Rahman A Jamal, Roslan Harun, Norfilza Mohd Mokhtar, Wan Zurinah Wan Ngah
BACKGROUND: Gamma-tocotrienol (GTT), an isomer of vitamin E and hydroxy-chavicol (HC), a major bioactive compound in Piper betle, has been reported to possess anti-carcinogenic properties by modulating different cellular signaling events. One possible strategy to overcome multi-drug resistance and high toxic doses of treatment is by applying combinational therapy especially using natural bioactives in cancer treatment. METHODS: In this study, we investigated the interaction of GTT and HC and its mode of cell death on glioma cell lines...
2014: BMC Complementary and Alternative Medicine
Virginia F Rodrigues, Rodrigo R Oliveira, Maria Raquel G Vega
A new isocoumarin, 3-phenyl-8-hydroxy-6-methoxy-5-gamma,gamma-dimethylallyl-isocoumarin, named cajavilmina (1) and eight known compounds: a-amirenone (2), beta-amirenone (3), lupenone (4), 5-hydroxy-7-methoxydihydroflavone (5), longistilin C (6), 3-hydroxy-5-methoxystilbene (7), beta-sitosterol (8) and stigmasterol (9) were identified in a dichloromethane fraction from Cajanus cajan leaves. Structures were elucidated by analysis of spectral data, mainly those afforded by 1H, NOEDIFF and 13C NMR (1D and 2D NMR HMQC, HMBC and COSY) and mass spectra...
April 2014: Natural Product Communications
Priya Ahuja, Nadeem Siddiqui
A series of thirty indole C-3 substituted 5-amino-6-(5-substituted-2-phenyl-1H-indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thione 5a-f, 6a-f, 7a-f, 8a-f and 9a-f were synthesized to explore prospective anticonvulsant agents. The derivative 1-(1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indol-3-yl)ethanone (6b) had significant activity in maximal electroshock test with minimal duration of limb extension (5.40 ± 0.61 s) and quantitative median dose of 7 mg/kg. In subcutaneous pentylenetetrazole screen 1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indole-3-sulfonamide (7b) increased the seizure latency to onset of clonus and was effective at a median dose of 35 mg/kg...
June 10, 2014: European Journal of Medicinal Chemistry
Jung-Tung Hung, Yi-Chieh Tsai, Wen-Der Lin, Jia-Tsrong Jan, Kun-Hsien Lin, Jing-Rong Huang, Jing-Yan Cheng, Ming-Wei Chen, Chi-Huey Wong, Alice L Yu
H5N1 influenza virus is a highly pathogenic virus, posing a pandemic threat. Previously, we showed that phenyl analogs of α-galactosylceramide (α-GalCer) displayed greater NKT stimulation than α-GalCer. Here, we examined the adjuvant effects of one of the most potent analogs, C34, on consensus hemagglutinin based DNA vaccine (pCHA5) for H5N1 virus. Upon intramuscular electroporation of mice with pCHA5 with/without various α-GalCer analogs, C34-adjuvanted group developed the highest titer against consensus H5 and more HA-specific IFN-γ secreting CD8 cells (203±13...
July 2014: Antiviral Research
Kinga Sałat, Agnieszka Cios, Elżbieta Wyska, Robert Sałat, Szczepan Mogilski, Barbara Filipek, Krzysztof Więckowski, Barbara Malawska
BACKGROUND: Anticancer drugs - oxaliplatin (OXPT) and paclitaxel (PACLI) cause painful peripheral neuropathy activating Transient Receptor Potential (TRP) channels. Here we investigated the influence of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) and pregabalin on nociceptive thresholds in neuropathic pain models elicited by these drugs. Pharmacokinetics of LPP1 and its ability to attenuate neurogenic pain caused by TRP agonists: capsaicin and allyl isothiocyanate (AITC) were also investigated...
July 2014: Pharmacology, Biochemistry, and Behavior
Christine Swanson, Marina Emborg
OBJECTIVE: To characterize the distribution of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the substantia nigra of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated hemiparkinsonian monkeys, in order to validate PPAR-gamma as a target for neuroprotection. METHODS: Immunohistochemical analysis of PPAR-gamma expression was performed in the substantia nigra and other select brain regions of fifteen rhesus monkeys including controls (n = 3), hemiparkinsonian necropsied after 3 (n = 5) or 12 (n = 3) months after MPTP, and animals who received MPTP+5 mg/kg of the PPAR-gamma agonist pioglitazone (n = 4)...
July 2014: Neurological Research
Ji-Min Han, Miao Xu, Brian Wang, Na Wu, Xiaomei Yang, Haori Yang, Bill J Salter, Ling Zang
Development of low cost, easy-to-use chemical sensor systems for low dose detection of γ radiation remains highly desired for medical radiation therapy and nuclear security monitoring. We report herein on a new fluorescence sensor molecule, 4,4'-di(1H-phenanthro[9,10-d]imidazol-2-yl)biphenyl (DPI-BP), which can be dissolved into halogenated solvents (e.g., CHCl3, CH2Cl2) to enable instant detection of γ radiation down to the 0.01 Gy level. The sensing mechanism is primarily based on radiation induced fluorescence quenching of DPI-BP...
April 2, 2014: Journal of the American Chemical Society
Hang-Suk Chun, Sun Hye Shin, Sunjoo Ahn, Dae-Seop Shin, Sun-Sil Choi, Jin Hee Ahn, Myung Ae Bae
Peroxisome proliferator-activated receptor γ (PPARγ) is a target of antidiabetic drugs. However, many PPARγ activators, including rosiglitazone, show unwanted side effects, such as weight gain. The KR-62980 [1-(trans-methylimino-N-oxy)-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carboxylic acid ethyl ester], a novel partial agonist of PPARγ, is a new compound for diabetes with antihyperglycemic activity and weak antiadipogenic activity. This study was performed to elucidate the mechanism of the weak adipogenesis induced by KR-62980 despite its being a PPARγ agonist in zebrafish...
April 2014: Zebrafish
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