Pyridoindole

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Jun Yeob Lee - One of the best experts on this subject based on the ideXlab platform.

Chil Won Lee - One of the best experts on this subject based on the ideXlab platform.

Cimen Karasu - One of the best experts on this subject based on the ideXlab platform.

  • protective effects of novel substituted triazinoindole inhibitors of aldose reductase and epalrestat in neuron like pc12 cells and bv2 rodent microglial cells exposed to toxic models of oxidative stress comparison with the Pyridoindole antioxidant stobadine
    Neurotoxicity Research, 2021
    Co-Authors: Zubeyir Elmazoglu, Milan Stefek, Marta Soltesova Prnova, Asli F Ceylan, Michael Aschner, Edgar Rangellopez, Abel Santamaria, Cimen Karasu
    Abstract:

    Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the Pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1-1000 μM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 μM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.

  • effects of antioxidant stobadine on protein carbonylation advanced oxidation protein products and reductive capacity of liver in streptozotocin diabetic rats role of oxidative nitrosative stress
    Biofactors, 2007
    Co-Authors: Ahmet Cumaoǧlu, Cemal Cevik, Lucia Rackova, Nuray Ari, Cimen Karasu
    Abstract:

    BACKGROUND Increased oxidative/nitrosative stress is important in the pathogenesis of diabetic complications, and the protective effects of antioxidants are a topic of intense research. The purpose of this study was to investigate whether a Pyridoindole antioxidant stobadine (STB) have a protective effect on tissue oxidative protein damage represented by the parameters such as protein carbonylation (PC), protein thiol (P-SH), total thiol (T-SH) and non-protein thiol (Np-SH), nitrotyrosine (3-NT), and advanced oxidation protein products (AOPP) in streptozotocin-diabetic rats. METHODS Diabetes was induced in male Wistar rats by intraperitonal injection of streptozotocin (55 mg/kg). Some of the non-diabetic (control) and diabetic rats treated with STB (24.7 mg/kg/day) during 16 weeks, and the effects on blood glucose, PC, AOPP, 3-NT, P-SH, T-SH and Np-SH were studied. Biomarkers were assayed by enzyme-linked immunosorbent assay (ELISA) or by colorimetric methods. RESULTS Administration of stobadine to diabetic animals lowered elevated blood glucose levels by approximately 16% relative to untreated diabetic rats. Although stobadine decreased blood glucose, poor glycemic control was maintained in stobadine treated diabetic rats during the treatment period. Biochemical analyses of liver proteins showed significant diminution of sulfhydryl groups, P-SH, T-SH, Np-SH, and elevation of carbonyl groups in diabetic animals in comparison to healthy controls. As a biomarker of nitrosative stress, 3-NT levels did not significantly change by diabetes induction or by stobadine treatment when compared to control animals. However, the treatment with stobadine resulted in a significant decrease in PC, AOPP levels and normalized P-SH, T-SH, Np-SH groups in liver of diabetic animals. CONCLUSIONS The results are in accordance with the pro-oxidant role of chronic hyperglycemia, and the ability of stobadine to attenuate protein oxidation and improving tissue reductive capacity may account, at least partly for its observed beneficial effects on tissue function in diabetes.

Claude Helene - One of the best experts on this subject based on the ideXlab platform.

  • Alternate Strand Recognition of Double-Helical DNA by (T,G)-Containing Oligonucleotides in the Presence of a Triple Helix-Specific Ligand
    Nucleic Acids Research, 1996
    Co-Authors: Therese De Bizemont, Emile Bisagni, Therese Garestier, Guy Duval-valentin, Jian-sheng Sun, Claude Helene
    Abstract:

    : Triple helix formation requires a polypurine- polypyrimidine sequence in the target DNA. Recent works have shown that this constraint can be circumvented by using alternate strand triplex-forming oligonucleotides. We have previously demonstrated that (T,G)-containing triplex- forming oligonucleotides may adopt a parallel or an antiparallel orientation with respect to an oligopurine target, depending upon the sequence and, in particular, upon the number of 5'-GpT-3' and 5'-TpG-3' steps [Sun et al. (1991) C.R. Acad. Sci. Paris Ser III, 313, 585-590]. A single (T,G)-containing oligonucleotide can therefore interact with two oligopurine stretches which alternate on the two strands of the target DNA. The (T,G) switch oligonucleotide contains a 5'-part targeted to one of the oligopurine sequences in a parallel orientation followed by a 3'-part that adopts an antiparallel orientation with respect to the second oligopurine sequence. We show that a limitation to the stability of such a triplex may arise from the instability of the antiparallel part, composed of reverse-Hoogsteen C.GxG and T.AxT base triplets. Using DNase I footprinting and ultraviolet absorption experiments, we report that a benzo[e]Pyridoindole derivative [(3-methoxy- 7H-8-methyl-11-[(3'-amino-propyl) amino] benzo[e]pyrido [4,3-b]indole (BePI)], a drug interacting more tightly with a triplex than with a duplex DNA, strongly stabilizes triplexes with reverse-Hoogsteen C.GxG and T.AxT triplets thus allowing a stabilization of the triplex-forming switch (T,G) oligonucleotide on alternating oligopurine- oligopyrimidine 5'-(Pu)14(Py)14-3' duplex sequences. These results lead to an extension of the range of oligonucleotide sequences for alternate strand recognition of duplex DNA.

  • triple helix specific ligands stabilizeh dna conformation
    Journal of Molecular Biology, 1995
    Co-Authors: Guy Duvalvalentin, Emile Bisagni, Jeanlouis Mergny, Therese De Bizemont, Masashi Takasugi, Claude Helene
    Abstract:

    Abstract Under superhelical stress, oligopurine-oligopyrimidine mirror-repeat sequences are able to adoptH-DNA conformations where a triple-helical and a single-stranded structure co-exist. We have previously shown that a benzo[e]pyridonindole derivative (BePI), an antitumor drug interacting more tightly with triplex than with duplex DNA, strongly stabilizes intermolecular triple helices formed upon binding of homopyrimidine oligonucleotides to the major groove of double-stranded DNA at oligopurine-oligopyrimidine sequences. Here we show that an intramolecular triple helix is also strongly stabilized by this ligand.In vitroelongation performed by different DNA polymerases (bacteriophage T7,Escherichia coliorTaqpolymerase) could be irreversibly inhibited by theH-DNA structure in the presence of BePI. A mirror-repeat polypurine-polypyrimidine sequence inserted between theE. coliβ-lactamase gene (conferring ampicillin resistance) and itsblapromoter strongly inhibited transcription of the β-lactamase genein vivo. In the absence of supercoiling, transition to theH-conformation did not occur, but BePI stabilized theH-DNA structure induced by supercoiling as shown by chemical probes (chloroacetaldehyde). The results presented here open a new field of investigation for antitumor agents targeted to a novel class of genetic structures able to regulate gene expression.

  • characterization of a triple helix specific ligand bepi 3 methoxy 7h 8 methyl 11 3 amino propylamino benzo e pyrido 4 3 b indole intercalates into both double helical and triple helical dna
    Journal of Molecular Biology, 1993
    Co-Authors: Daniel S Pilch, Michael J Waring, Michel Rougee, Chihung Nguyen, Emile Bisagni, Therese Garestier, Claude Helene
    Abstract:

    Abstract A benzo[e]Pyridoindole derivative, 3-methoxy-7H-8-methyl-11-[(3′-amino)propylamino]-benzo[e]pyrido[4,3-b]indole (BePI), and its interactions with double and triple-helical DNA have been investigated by a variety of fluorescence, spectrophotometric, hydrodynamic and molecular modeling techniques. Binding to DNA stabilizes the doubly charged (+2) form of BePI, increasing the apparent pKa of the 10-NH proton by ≈ 1 pH unit. Binding to DNA also quenches the fluorescence of BePI, with a greater extent of quenching upon binding triplex relative to duplex DNA. BePI preferentially binds (and stabilizes) triple-helical relative to double-helical DNA. This preferential binding is not restricted to triplexes containing solely T × A · T base triplets. In addition, BePI preferentially stabilizes the poly(dA) · poly(dT) relative to the poly[d(A-T)]·poly[d(A-T)] duplex. Viscosity studies demonstrate that, upon binding, BePI induces the unwinding of negative supercoils in the pBR322 plasmid, and increases the relative contour lengths of double and triple-helical polydeoxynucleotides. Fluorescence studies reveal that energy transfer occurs from polynucleotide bases to bound BePI molecules in both BePI/duplex and BePI/triplex complexes. In a BePI/triplex complex, an average of 4·8 bases appear to transfer excitation energy totally to a bound BePI molecule, while in various BePI/duplex complexes an average of only 2·5 bases appear to do so, indicating that energy transfer is more efficient in the former complex. Measurements of fluorescence quenching indicate that BePI is protected from quenching by acrylamide when bound to either double or triple-helical polynucleotides. The viscosity and fluorescence behavior of BePI are fully consistent with the conclusion that BePI intercalates into both double and triple-helical DNA. Molecular modeling studies suggest that stronger stacking interactions between intercalated BePI and adjacent bases in BePI/triplex relative to BePI/duplex complexes may account for the enhanced thermal stability of the former complex.

Cumaoğlu Ahmet - One of the best experts on this subject based on the ideXlab platform.

  • Age- and diabetes-induced regulation of oxidative protein modification in rat brain and peripheral tissues: Consequences of treatment with antioxidant Pyridoindole
    'Elsevier BV', 2013
    Co-Authors: Ari Nuray, Cumaoğlu Ahmet, Karasu Çimen, Şakul Arzu, Aydın Elif, Dilsiz Nihat
    Abstract:

    The increased glyco- and lipo-oxidation events are considered one of the major factors in the accumulation of non-functional damaged proteins, and the antioxidants may inhibit extensive protein modification and nitrosylated protein levels, enhancing the oxidative damage at the cellular levels in aging and diabetes. Because of its central role in the pathogenesis of age-dependent and diabetes-mediated functional decline, we compared the levels of oxidatively modified protein markers, namely AGEs (Advanced Glycation End-protein adducts), 4-HNE (4-hydroxy-nonenal-histidine) and 3-NT (3-nitrotyrosine), in different tissues of young and old rats. Separately, these three oxidative stress parameters were explored in old rats subjected to experimentally induced diabetes and following a long-term treatment with a novel synthetic Pyridoindole antioxidant derived from stobadine-SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indolinium dichloride). Diabetes induced by streptozotocin injection in rats aged 13-15 months, and SMe1EC2 treatment was applied during 4 months to aged diabetic rats. AGEs and 4-HNE levels were significantly elevated in brain, ventricle and kidney, but not in lens and liver of aged rats when compared with young rats. Diabetes propagated ageing-induced increase in AGEs and 4-HNE in brain, ventricle and kidney, and raised significantly lens and liver AGEs and 4-HNE levels in aged rats. In aged diabetic rats, SMe1EC2 protected only the kidney against increase in AGEs, and inhibited significantly 4-HNE levels in brain, kidney, liver and lens that were observed more pronounced in lens. 3-NT was significantly increased in brain of aged rats and in kidney, lens and ventricle of aged diabetic rats, while SMe1EC2 has no protective effect on 3-NT increase. Results demonstrate that (1) the responsiveness of different tissue proteins to glyco-lipo-oxidative and nitrosative stress in the course of normal aging was miscellaneous. (2) Diabetes is a major factor contributing to accelerated aging. (3) SMe1EC2 selectively inhibited the generation of oxidatively modified proteins, only in a limited number of tissues. (C) 2013 Elsevier Inc. All rights reserved

  • Novel hexahydroPyridoindole derivative as prospective agent against oxidative damage in pancreatic β cells
    'Bentham Science Publishers Ltd.', 2011
    Co-Authors: Račková Lucia, Cumaoğlu Ahmet, Bağrıacık E Umit, Štefek Milan, Maechler Pierre, Karasu Çimen
    Abstract:

    The potential protective effect of (±)-8-methoxy-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (II) was assessed against hydrogen peroxide (H2O2)-cytotoxicity in rat pancreatic INS-1E β cells and compared with the effect of the related Pyridoindole, stobadine (I), a promising indole-type reference antioxidant. Only pre-treatment with the compound (II) led to a significant preservation of the metabolic and secretory functions of the cells exposed to H2O2. The caspase-9 and -3 activities, as well as the early apoptotic changes of plasma membrane, were suppressed in the cells pre-incubated with both of compounds tested. However, only Pyridoindole (II) inhibited profoundly the time-delayed apoptotic changes, These results suggest that Pyridoindole (II) characterized by enhanced intrinsic antioxidant efficiency, may protect β cells against cytotoxic effects of H2O2, involved in the development of both type 1 and type 2 diabetes

  • Glycoxidative and nitrosative stress in kidney of experimental diabetic rats: Effects of the prydoindole antioxidant stobadine
    2010
    Co-Authors: Ari Nuray, Štefek Milan, Karasu Çimen, Aricioglu Aysel, Bauer Viktor, Cumaoğlu Ahmet
    Abstract:

    OBJECTIVES: Recent basic research and clinical data have provided new insights into the role of glycoxidative and nitrosative stresses (both oxidative stress) in diabetic complications, such as diabetic nephropathy, suggesting a different and innovative approach to antioxidant therapy. In streptozotocin-induced diabetic rat kidney, the present study investigated the effects of the sythetic Pyridoindole antioxidant stobadine (STB) on renal total antioxidant potential (AOP) and protein oxidation parameters such as protein carbonyl content (PCC), advanced oxidation protein products (AOPPs) and nitrotyrosine (NT), a marker specific for protein modification by peroxynitrite

  • Effects of antioxidant stobadine on protein carbonylation, advanced oxidation protein products and reductive capacity of liver in streptozotocin-diabetic rats: Role of oxidative/nitrosative stress
    'Wiley', 2007
    Co-Authors: Cevik Cemal, Račková Lucia, Karasu Çimen, Ari Nuray, Cumaoğlu Ahmet
    Abstract:

    Background: Increased oxidative/nitrosative stress is important in the pathogenesis of diabetic complications, and the protective effects of antioxidants are a topic of intense research. The purpose of this study was to investigate whether a Pyridoindole antioxidant stobadine (STB) have a protective effect on tissue oxidative protein damage represented by the parameters such as protein carbonylation (PC), protein thiol (P-SH), total thiol (T-SH) and non-protein thiol (Np-SH), nitrotyrosine (3-NT), and advanced oxidation protein products (AOPP) in streptozotocin-diabetic rats

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